Deroose CM, Leupe H, Hicks RJ
… +33 more, Virgolini I, Braat AJAT, Mittra ES, Albert NL, Bailey DL, Bodei L, Chan DL, Dekervel J, Denecke T, Dromain C, Falconi M, Fournier L, Grozinsky-Glasberg S, Hofland J, Hope TA, Karfis I, Kos-Kudła B, Koumarianou A, Lamarca A, Litière S, Pavel M, Stroobants S, Strosberg J, Sundin A, Taïeb D, Trikalinos N, Unterrainer M, Verslype C, Vijayvergia N, Wild D, Kjaer A, Ambrosini V, Prasad V
Somatostatin receptor PET imaging is integral to the management of patients with neuroendocrine tumours (NETs), yet standardised criteria for therapy response assessment with the use of this modality are not available. T...Somatostatin receptor PET imaging is integral to the management of patients with neuroendocrine tumours (NETs), yet standardised criteria for therapy response assessment with the use of this modality are not available. This Policy Review reports the development of the European Neuroendocrine Tumor Society somatostatin receptor PET response assessment framework, established through a structured modified Delphi process coordinated by the European Neuroendocrine Tumor Society. 34 international experts from nuclear medicine, radiology, oncology, endocrinology, surgery, and related disciplines participated in four iterative rounds evaluating 76 statements, with consensus defined as at least 75% agreement. The framework proposes response categorisation based primarily on volumetric changes in somatostatin receptor-expressing target lesions, complemented by assessment of new lesions, rather than reliance on standardised uptake value-based metrics. Partial response is defined by at least 40% reduction in target lesion volume without new lesions, whereas progressive disease is defined by at least 40% volume increase of target lesions or the emergence of new lesions. Complete response requires absence of pathological tracer uptake, and a category of unconfirmed progressive disease is introduced for equivocal cases warranting short-interval reassessment. Although not yet validated against survival outcomes, this expert-derived framework (SSTR-PeRForm) provides a pragmatic foundation for harmonising somatostatin receptor PET-based response assessment in clinical trials and routine practice and represents a key step towards outcome-based validation.
BACKGROUND: Baseline exposure to antibiotics and proton pump inhibitors has been associated with reduced efficacy of immune checkpoint inhibitors in patients with advanced tumours, possibly through gut microbiome disrupt...BACKGROUND: Baseline exposure to antibiotics and proton pump inhibitors has been associated with reduced efficacy of immune checkpoint inhibitors in patients with advanced tumours, possibly through gut microbiome disruption. Whether this outcome extends to those with earlier-stage disease remains unclear. We aimed to assess the association of baseline antibiotics and proton pump inhibitors with progression-free survival and overall survival in patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS: PACIFIC was a randomised, double-blind, placebo-controlled phase 3 trial done in patients aged 18 years or older with unresectable stage III squamous or non-squamous NSCLC, WHO performance status 0-1, and no progression after two or more cycles of concurrent chemoradiotherapy. Patients were randomly assigned (2:1) to durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months or placebo, starting 1-42 days after chemoradiotherapy; patients were stratified by age, sex, and smoking history. This post-hoc analysis was based on the final 5-year data cutoff date of the completed trial and included the treated population with consent for exploratory analyses. Co-primary endpoints were progression-free survival and overall survival, assessed according to baseline exposure to proton pump inhibitors and systemic antibiotics. This trial is registered on ClinicalTrials.gov (NCT02125461). FINDINGS: Between May 9, 2014, and April 22, 2016, 713 patients were randomly assigned; 660 were included in this post-hoc analysis, of whom 449 received durvalumab and 211 received placebo; 203 (30·8%) were female and 453 (68·6%) were male. Race was reported as Asian in 153 (23·1%) patients, Black or African American in five (0·7%), White in 424 (64·2%), and unknown in 78 (11·8%). Baseline proton pump inhibitor exposure was recorded in 263 (40%) of 660 patients and antibiotic exposure was recorded in 69 (10%). Median follow-up in the pooled population was 62·4 (IQR 61·9-63·2) months. In the durvalumab group baseline exposure to proton pump inhibitors was associated with shorter progression-free survival (9·4 months [95% CI 7·6-13·7] vs 17·2 months [15·4-23·2]; hazard ratio [HR] 1·57 [95% CI 1·28-1·93]; p<0·0001) and overall survival (33·0 months [95% CI 21·9-46·7] vs 57·9 months [48·7-not computable (NC)]; HR 1·66 [95% CI 1·30-2·13]; p<0·0001) compared to no exposure to proton pump inhibitors, while baseline exposure to antibiotics was associated with shorter progression-free survival (9·2 months [95% CI 4·9-18·1] vs 15·6 months [13·6-17·6]; HR 1·50 [95% CI 1·08-2·10]; p=0·016) compared to no exposure to antibiotics, but there was no significant change in overall survival (37·7 months [95% CI 18·8-NC; 28 events] vs 49·2 months [39·7-57·3]; HR 1·33 [95% CI 0·90-1·97]; p=0·16). In the placebo group, neither proton pump inhibitor exposure nor antibiotic exposure was associated with changes in progression-free survival and overall survival. Interactions between treatment and proton pump inhibitors for progression-free survival (p=0·023) and overall survival (p<0·0001) were significant, but not for antibiotics. INTERPRETATION: Baseline exposure to proton pump inhibitors and antibiotics was associated with inferior outcomes with durvalumab, but not with placebo, consistent with potential attenuation of the benefit of durvalumab with proton pump inhibitors and antibiotics in patients with unresectable stage III NSCLC. FUNDING: None.
Hu H, Shen X, Li Y
… +35 more, Zhou J, Liu P, Zhang J, Hou Y, Wang X, Deng J, Zheng Z, Li J, Lan P, Wu X, Kang L, Huang M, He Z, He X, Yang Z, Huang L, Wang H, Wang H, Luo S, Chen D, Xie X, Zhang Y, Zhai X, Li S, Li W, Hu J, Yang T, Wang C, Deng W, Huang Y, Cao W, Li F, Shi L, Ling L, Deng Y
BACKGROUND: Neoadjuvant immune checkpoint blockade has shown remarkable activity in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H), locally advanced colorectal cancer. Preclinical studies sug...BACKGROUND: Neoadjuvant immune checkpoint blockade has shown remarkable activity in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H), locally advanced colorectal cancer. Preclinical studies suggest that COX-2 inhibition might modulate the inflammatory tumour microenvironment and augment the effect of PD-1 blockade. We aimed to investigate whether the addition of the COX-2 inhibitor celecoxib to neoadjuvant toripalimab would increase the pathological complete response in this population. METHODS: PICC-2 was a multicentre, open-label, randomised, controlled, phase 2 trial conducted at three academic hospitals in China. Eligible patients were aged 18-75 years; had histologically confirmed dMMR or MSI-H colorectal cancer, of clinical stage T3-T4 or any clinical T stage with lymph node positivity (N+); had an Eastern Cooperative Oncology Group performance status score of 0 or 1; and had adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1) via an interactive web response system, stratified by tumour location and clinical T stage, to receive neoadjuvant toripalimab plus celecoxib or toripalimab monotherapy every 14 days for 12 cycles, followed by surgery. Toripalimab 3 mg/kg was administered intravenously on day 1 in both groups; patients in the toripalimab plus celecoxib group also received celecoxib 200 mg orally twice daily on days 1-14. The primary endpoint was the proportion of patients with pathological complete response, defined as no presence of residual viable tumour in the primary tumour and all sampled lymph nodes at surgery, assessed by central blinded independent pathological review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03926338, and is ongoing. FINDINGS: Between May 5, 2022, and Jan 20, 2025, 110 patients were randomly assigned to toripalimab plus celecoxib (n=55) or toripalimab monotherapy (n=55). Overall, 65 (59%) patients were male, all patients were Chinese, 76 (69%) had cT4 tumours, and 105 (95%) had clinically node-positive disease. At the data cutoff date (Oct 10, 2025), median follow-up was 18·1 months (IQR 11·5-25·3). 49 (89%) of 55 patients in each group completed all 12 planned cycles of neoadjuvant therapy. Surgery was done in 53 (96%) of 55 patients in the toripalimab plus celecoxib group and 51 (93%) of 55 in the monotherapy group. Pathological complete response was observed in 49 of 55 patients (89% [95% CI 78-96]) in the toripalimab plus celecoxib group versus 38 of 55 (69% [55-81]) in the monotherapy group (between-group difference 19 percentage points [95% CI 4-34]; p=0·014). Grade 3 treatment-related adverse events occurred in three (5%) patients and four (7%) patients, respectively; grade 3 treatment-related adverse events were tumour perforation (two [4%]) and bowel obstruction (one [2%]) in the toripalimab plus celecoxib group, and rash (one [2%]), tumour perforation (one [2%]), increased aminotransferase (one [2%]), and hypothyroidism (one [2%]) in the monotherapy group. No grade 4 or 5 treatment-related adverse events occurred. INTERPRETATION: In patients with dMMR or MSI-H locally advanced colorectal cancer, neoadjuvant toripalimab plus celecoxib significantly increased the proportion of patients attaining pathological complete response compared with toripalimab monotherapy, with a similar safety profile. These findings support further investigation of this combination strategy in larger phase 3 trials. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research, the National Key Clinical Discipline of China, the Program of Guangdong Provincial Clinical Research Center for Digestive Diseases, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Yao H, Zhang Q, Li H
… +38 more, Yin Y, Wang S, Ouyang Q, Sun T, Li W, Wang X, Yan M, Wang B, Cheng J, Tong Z, Wei W, Wang X, Xie W, Sun Z, Yuan P, Geng C, Gan L, Han X, Li W, Zhou S, Yan X, Gao J, Yi T, Wu J, Niu Z, Fu F, Nie J, Wang Y, Zhao B, Wu Z, Zhu Z, Yang Y, Zhao J, Sheng Z, Zhang Y, Cheng L, Zhu X, Song E
BACKGROUND: Trastuzumab rezetecan has shown antitumour activity in a phase 1 trial. Pyrotinib plus capecitabine is the current standard treatment for patients with HER2-positive advanced or metastatic breast cancer after...BACKGROUND: Trastuzumab rezetecan has shown antitumour activity in a phase 1 trial. Pyrotinib plus capecitabine is the current standard treatment for patients with HER2-positive advanced or metastatic breast cancer after trastuzumab and chemotherapy (taxane or anthracycline). We aimed to evaluate the efficacy and safety of trastuzumab rezetecan versus pyrotinib plus capecitabine in this patient population. METHODS: This interim analysis of a multicentre, open-label, randomised, controlled, phase 3 trial was conducted at 50 hospitals in China. Eligible patients were aged 18-75 years with histologically confirmed HER2-positive unresectable or metastatic breast cancer; previously received a taxane and trastuzumab at the advanced stage or had disease progression within 12 months after (neo)adjuvant treatment with an anti-HER2 monoclonal antibody and taxane-based regimen; had measurable lesions; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1; stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease), using permuted blocks to intravenous trastuzumab rezetecan (4·8 mg/kg) on day 1 of each 21-day cycle or oral pyrotinib 400 mg once per day continuously plus oral capecitabine 1000 mg/m twice per day on days 1-14 of each 21-day cycle. Protocol amendments led to a temporary modification (between Nov 29, 2022, and July 12, 2023) of trastuzumab rezetecan dose to 6·4 mg/kg; primary evaluation focuses on the 4·8 mg/kg group. The primary endpoint was progression-free survival per blinded independent central review in the modified intention-to-treat population 1 (defined as all patients randomly assigned to the trastuzumab rezetecan 4·8 mg/kg or control groups). Results presented here are from a prespecified interim analysis. This study was registered with ClinicalTrials.gov, NCT05424835 (active, not recruiting). FINDINGS: From Aug 4, 2022, to Aug 9, 2024, 414 patients with HER2-positive metastatic breast cancer were assessed for eligibility, 127 were ineligible and 287 were randomly assigned to trastuzumab rezetecan (n=142) or pyrotinib plus capecitabine (control group; n=145) in the modified intention-to-treat population 1. All 287 patients were female and the median age was 55·0 years (IQR 49·0-60·0). 268 (93%) patients self-reported as Han Chinese and 19 (7%) as other Chinese ethnicity. At data cutoff of the interim analysis on June 30, 2025, after a median follow-up of 15·0 months (IQR 12·9-18·5) for the trastuzumab rezetecan group versus 13·9 months (11·4-17·8) for the control group, 124 progression-free survival events had occurred (37 [26%] vs 87 [60%]). The median progression-free survival was 30·6 months (95% CI 16·8-not reached [NR]) with trastuzumab rezetecan and 8·3 months (6·9-11·0) with pyrotinib plus capecitabine (HR 0·22 [0·15-0·34]; p<0·0001). The 12-month progression-free survival rate was 84·7% (77·0-90·0) in the trastuzumab rezetecan group versus 35·5% (26·8-44·2) in the control group. The most common (grade ≥3) treatment-related adverse events were decreased neutrophil count (77 [54%] with trastuzumab rezetecan vs 13 [9%] with the control), decreased white blood cell count (29 [20%] vs four [3%]), and decreased platelet count (15 [11%] vs two [1%]); whereas treatment-related serious adverse events occurred in 19 (13%) versus 17 (12%). Two adverse events led to death (one [1%] septic shock unrelated to trastuzumab rezetecan treatment and one [1%] unknown reason related to pyrotinib plus capecitabine treatment). Interstitial lung disease occurred in four (3%) patients in the trastuzumab rezetecan group. INTERPRETATION: Trastuzumab rezetecan improved progression-free survival versus pyrotinib plus capecitabine and showed a distinct safety profile in patients with HER2-positive breast cancer, presenting as a potential new treatment option. FUNDING: Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Biau J, Beddok A, Sharma M
… +19 more, Malik N, Ghosh Laskar S, Cacicedo J, Embring A, Nuyts S, Mayo C, Paradis KC, Ward MC, Bonomo P, Gan GN, Bahl A, Balermpas P, Chua MLK, Popovtzer A, Simone CB, Vasquez Osorio E, Yom SS, Blanchard P, Reirradiation Collaborative Group (ReCOG) and ESTRO Reirradiation Focus Group Collaborators
Reirradiation can be considered for some patients with recurrent or second primary head and neck squamous cell carcinoma arising within previously irradiated regions, a clinical scenario associated with few therapeutic o...Reirradiation can be considered for some patients with recurrent or second primary head and neck squamous cell carcinoma arising within previously irradiated regions, a clinical scenario associated with few therapeutic options. The increasing use of modern conformal radiotherapy techniques, including intensity-modulated radiotherapy, proton therapy, and stereotactic body radiotherapy, has expanded the feasibility of reirradiation in clinical practice. However, evidence remains heterogeneous, and clinical choices are challenged by substantial variability in patient presentation, previous treatments, and toxicity risk. This international expert consensus statement aims to provide pragmatic guidance across key domains, including patient selection, imaging, target delineation, treatment planning, dose accumulation, and toxicity management. Developed through a structured expert consensus process with formal agreement assessment, this document reflects current expert practice. By offering a shared clinical framework, this consensus seeks to promote more consistent practice, facilitate communication across centres, and support future research efforts in this complex and evolving field.
Adriaansen LME, Merks JHM, van Dalen EC
… +33 more, Andersen KF, Asaftei SD, Bernabeu D, Boye K, Campello A, Capra M, Costa Dias S, Dávila Fajardo R, Dziuk M, van Ewijk R, Gaspar N, Gerrand C, Herrmann K, Isnardi V, Jehanno N, von Kalle T, Lancharro Zapata AM, van Langevelde K, Morland D, Mulder RL, Palmerini E, Rajesparan K, Rogasch JMM, Safwat A, Sirvent Cerdá S, Spinnato P, Strauss SJ, Vieth V, Vöö S, Woering MP, Ter Horst SAJ, Braat AJAT, van Rijn RR
Imaging is central to diagnosing, staging, evaluating treatment response, and guiding post-therapy surveillance in osteosarcoma and Ewing sarcoma, yet no international consensus defines optimal modalities or schedules. T...Imaging is central to diagnosing, staging, evaluating treatment response, and guiding post-therapy surveillance in osteosarcoma and Ewing sarcoma, yet no international consensus defines optimal modalities or schedules. This European guideline, developed by 36 multidisciplinary experts, seeks to standardise imaging for research and enhance patient care. A systematic review identified 2026 studies, of which 13 met criteria, revealing marked heterogeneity in diagnoses, chemotherapy regimens, and imaging protocols. Evidence remains inconclusive regarding the optimal modality for detecting bone metastases, and no metabolic imaging indices or MRI parameters consistently predict response or survival. Data are similarly insufficient to define the ideal frequency of post-treatment surveillance. Recommendations for clinical practice were formulated according to International Guideline Harmonization Group standards, based on evidence and expert opinion. In total, 32 consensus-based recommendations were issued. Substantial evidence gaps persist, underscoring the need for international prospective imaging studies to establish robust, harmonised standards for future patient care.
Triple-negative breast cancer-the most aggressive breast cancer subtype-has a high propensity for brain metastases, with limited treatments and poor prognosis. The blood-brain barrier, long viewed as an impermeable thera...Triple-negative breast cancer-the most aggressive breast cancer subtype-has a high propensity for brain metastases, with limited treatments and poor prognosis. The blood-brain barrier, long viewed as an impermeable therapeutic sanctuary, is the core barrier to effective care. This Review advocates a key paradigm shift for clinical and translational research: from merely circumventing the blood-brain barrier to actively targeting and exploiting its biology. We delineate triple-negative breast cancer-specific mechanisms of blood-brain barrier breach and evaluate emerging therapies via a clinically actionable three-pillar framework: physical and focal blood-brain barrier disruption, biological blood-brain barrier exploitation, and microenvironmental modulation. We also summarise advances in preclinical models for blood-brain barrier-targeted drug development. Synthesising the latest preclinical and clinical evidence, this Review provides a translational roadmap for unmet clinical needs, emphasising that integrated, blood-brain barrier-centric strategies are crucial to improving patient outcomes.
Giordano FA, Ganslandt O, Münter MW
… +23 more, Combs SE, Diehl C, Meyer B, Herrlinger U, Schneider M, Kahl KH, Shiban E, Goenka A, Schulder M, Lucas A, Plans G, Brehmer S, Ruder AM, García-Cabezas S, Solivera J, Cifarelli CP, Wenz F, Sarria GR, Pope WB, Layer JP, Tsien CI, Petrecca K, INTRAGO-II Study Group
BACKGROUND: Despite maximal safe resection and chemoradiotherapy, most glioblastomas recur locally. We aimed to evaluate whether additional intraoperative radiotherapy compared with standard of care improves outcomes in...BACKGROUND: Despite maximal safe resection and chemoradiotherapy, most glioblastomas recur locally. We aimed to evaluate whether additional intraoperative radiotherapy compared with standard of care improves outcomes in patients with newly diagnosed glioblastoma. METHODS: INTRAGO-II was an open-label, multicentre, randomised, controlled, phase 3 trial enrolling patients aged 18-80 years with supratentorial glioblastoma amenable to resection of the contrast enhancing tumour with Karnofsky performance score (KPS) of ≥60%. Patients from 18 centres in Brazil, Canada, China, Germany, Spain, South Korea, and the USA were randomly assigned (1:1) intraoperatively to receive additional kilovoltage intraoperative radiotherapy with 30 Gy (intraoperative radiotherapy group) or surgery alone (standard-of-care group), stratified by age, KPS, and residual tumour. Postoperative treatment consisted of external-beam radiotherapy to 60 Gy with concurrent temozolomide (75 mg/m), followed by six adjuvant cycles of temozolomide (150-200 mg/m, days 1-5 every 28 days). The primary endpoint was median progression-free survival in the full-analysis set, confirmed by masked, centralised review. This ongoing study is closed to recruitment and is registered with ClinicalTrials.gov, NCT02685605. FINDINGS: Between Dec 9, 2016, and June 17, 2024, of 411 patients assessed for eligibility, 314 were randomly assigned. The full-analysis set comprised 298 patients (intraoperative radiotherapy, n=161; standard-of-care, n=137), of whom 127 (43%) patients were female and 171 (57%) were male. Data on race and ethnicity were not collected. At a median follow-up of 17·2 months (IQR 10·5-27·1), median progression-free survival was 11·0 months (95% CI 9·2-12·6) in the intraoperative radiotherapy group versus 11·4 months (9·7-13·9) in the standard-of-care group (hazard ratio [HR] 1·1, 95% CI 0·85-1·44; p=0·47). Local recurrence was the predominant pattern of failure in both groups (76 [72%] in the intraoperative radiotherapy group vs 60 [71%] in the standard-of-care group, p=0·87). The most common grade 3-4 adverse events were seizure (21 [13%] in the intraoperative radiotherapy group vs nine [7%] in the standard-of-care group), radiation necrosis (11 [7%] vs three [2%]; p=0·06), thrombocytopenia (seven [4%] vs 11 [8%]), and muscle weakness (12 [7%] vs 19 [14%]). In total, 252 serious adverse events occurred in 105 (65%) patients in the intraoperative radiotherapy group and 142 serious adverse events in 72 (53%) patients in the standard-of-care group. Of these, 65 (26%) events in 40 (38%) patients in the intraoperative radiotherapy group and 27 (19%) events in 19 (26%) patients in the standard-of-care group were considered possibly related to the treatment. Of all grade five adverse events reported, 14 in the intraoperative radiotherapy group (CNS toxicity [n=2], myocardial infarction [n=2], sepsis [n=2], and one each cardiac arrest, fever, lung infection, fracture, postoperative haemorrhage, neoplasm, haematoma, and not otherwise specified death) and six in the standard-of-care group (lung infection [n=2], and one each multiorgan failure, encephalitis, neoplasm, and cystitis) were attributable to specific CTCAE terms. INTERPRETATION: Instant, spatially precise dose escalation with intraoperative radiotherapy added to standard of care did not improve outcomes, questioning the value of further local dose intensification in resectable glioblastoma. FUNDING: Universities of Heidelberg and Bonn, Carl Zeiss Meditec, Deutsche Forschungsgemeinschaft.
Rovers KP, Bakkers C, van den Heuvel TBM
… +30 more, van de Vlasakker VCJ, Kerkhoff TME, Nienhuijs SW, Burger JWA, Creemers GM, van Hellemond IEG, Tuynman JB, Kusters M, Buffart TE, Aalbers AGJ, Kok NFM, Chalabi M, Boerma D, Brandt-Kerkhof ARM, de Reuver PR, Hemmer PHJ, van Grevenstein WMU, van der Speeten K, Snaebjornsson P, Lee-Law PY, Lahaye MJ, Nederend J, Kranenburg O, Bouma JM, Punt CJA, Dijkgraaf MGW, Tanis PJ, de Hingh IHJT, CAIRO6 Investigators, Dutch Peritoneal Oncology Group and the Dutch Colorectal Cancer Group
BACKGROUND: Data are sparse on the value of perioperative systemic therapy in patients with resectable colorectal peritoneal-only metastases. This trial aimed to compare the efficacy of perioperative systemic therapy ver...BACKGROUND: Data are sparse on the value of perioperative systemic therapy in patients with resectable colorectal peritoneal-only metastases. This trial aimed to compare the efficacy of perioperative systemic therapy versus surgery alone in this population. METHODS: This randomised, open-label, phase 3 trial was done at all nine Dutch tertiary centres and one Belgian tertiary centre. Eligible patients were aged 18 years or older with a WHO performance status of 0 or 1 and pathologically proven resectable peritoneal-only metastases of a colorectal adenocarcinoma who did not receive systemic therapy for at least 6 months. Enrolled patients were randomly assigned (1:1) to perioperative systemic therapy and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC; perioperative systemic therapy group) or upfront CRS-HIPEC alone (surgery alone group) using a web-based system with minimisation stratified by previous systemic therapy, synchronous or metachronous peritoneal metastases, peritoneal cancer index 0-10 or 11-20, and mitomycin C-based or oxaliplatin-based HIPEC. At investigator's choice, perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (intravenous oxaliplatin 130 mg/m followed by oral capecitabine 1000 mg/m twice per day on days 1-14), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (intravenous oxaliplatin 85 mg/m with intravenous leucovorin 400 mg/m, followed by bolus intravenous 5-fluorouracil 400 mg/m, and continuous intravenous 5-fluorouracil 2400 mg/m for 48 h), or six 2-week neoadjuvant cycles of FOLFIRI (intravenous irinotecan 180 mg/m with intravenous leucovorin 400 mg/m, followed by bolus intravenous 5-fluorouracil 400 mg/m, and continuous intravenous 5-fluorouracil 2400 mg/m for 48 h) followed by either four 3-week adjuvant cycles of oral capecitabine (1000 mg/m twice per day on days 1-14) or six 2-week adjuvant cycles of 5-fluorouracil and leucovorin (intravenous leucovorin 400 mg/m, followed by bolus intravenous 5-fluorouracil 400 mg/m, and continuous intravenous 5-fluorouracil 2400 mg/m for 48 h). Intravenous bevacizumab was added to the first three neoadjuvant cycles of CAPOX (7·5 mg/kg) or the first four neoadjuvant cycles of FOLFOX or FOLFIRI (5 mg/kg). The primary outcome was overall survival assessed in a prespecified modified intention-to-treat population, excluding patients who withdrew consent before treatment or violated major eligibility criteria. Major postoperative morbidity was defined as Clavien-Dindo grade 3-5 and assessed up to 90 days postoperatively. Major systemic therapy-related toxicity was defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 3-5 and assessed up to 30 days after its last administration. The Dutch patient organisation for colorectal cancer was involved in the trial design. The trial is registered with Clinicaltrials.gov (NCT02758951) and is active but not recruiting. FINDINGS: Between June 15, 2017, and April 29, 2024, 1922 patients were screened for eligibility. Of these, 358 patients were enrolled and randomly assigned to perioperative systemic therapy (n=180) or surgery alone (n=178). 351 patients were included in the modified intention-to-treat population (173 patients randomly assigned to perioperative systemic therapy and 178 patients to surgery alone; 181 [52%] male and 170 [48%] female). After a median follow-up of 41 months (IQR 21-62), median overall survival was 44 months (95% CI 30-54) in the perioperative systemic therapy group versus 39 months (95% CI 31-46) in the surgery alone group (hazard ratio [HR] 0·85, 95% CI 0·62-1·15; p=0·28). In 292 patients who underwent macroscopic complete or near complete CRS-HIPEC, major 90-day postoperative morbidity occurred in 49 (36%) of 138 patients in the perioperative systemic therapy group and in 40 (26%) of 154 patients in the surgery alone group. The most common Clavien-Dindo grade 3-4 postoperative adverse events were intra-abdominal abscess (16 [12%] of 138 patients in the perioperative systemic therapy group vs 16 [10%] of 154 patients in the surgery alone group), anastomotic leakage (12 [9%] vs six [4%]), and fascia dehiscence (13 [9%] vs six [4%]). 90-day postoperative mortality occurred in two (1%) patients in the perioperative systemic therapy group (anastomotic leakage and cerebrovascular accident) and in one (1%) patient in the surgery alone group (anastomotic leakage). Major systemic therapy-related toxicity occurred in 92 (57%) of 161 patients who started perioperative systemic therapy. The most common CTCAE grade 3-4 systemic therapy-related adverse events were hypertension (13 [8%] patients), diarrhoea (12 [7%] patients), neutropenia (11 [7%] patients), and thromboembolic events (ten [6%] patients). Systemic therapy-related death occurred in one (1%) patient (hyperglycaemia). INTERPRETATION: Perioperative systemic therapy cannot be recommended in all patients with resectable colorectal peritoneal-only metastases. FUNDING: Dutch Cancer Society, F Hoffman-La Roche.
Francolini G, Di Cataldo V, Caini S
… +21 more, Garlatti P, Aquilano M, Bertini N, Bruni A, Ingrosso G, D'Angelillo RM, Tagliaferri L, Jereczek-Fossa BA, Augugliaro M, Triggiani L, Parisi S, Masieri L, Campi R, Valicenti RK, Simontacchi G, Greto D, Bonomo P, Loi M, Tang C, Livi L, ARTO Working Group
BACKGROUND: The ARTO trial showed improved early clinical outcomes by adding metastasis-directed therapy (MDT), through stereotactic body radiotherapy (SBRT), to abiraterone acetate and ADT in oligometastatic castrate-re...BACKGROUND: The ARTO trial showed improved early clinical outcomes by adding metastasis-directed therapy (MDT), through stereotactic body radiotherapy (SBRT), to abiraterone acetate and ADT in oligometastatic castrate-resistant prostate cancer. The aim of this analysis is to explore the long-term impact of MDT on overall survival. METHODS: ARTO was a multicentre, phase 2, randomised trial conducted in 16 academic and community centres across Italy. All patients included were aged 18 years or older and had a diagnosis of prostate adenocarcinoma with metastatic castrate-resistant prostate cancer, no more than three metastatic sites, and no previous systemic therapy for metastatic castrate-resistant prostate cancer status. Patients were randomly assigned (1:1, using random permuted blocks; stratified by treating centre, Eastern Cooperative Oncology Group performance status, and number of metastases) in an open-label design to androgen deprivation therapy plus oral abiraterone acetate 1000 mg daily with or without SBRT to all sites of metastatic disease (one to five fractions providing a biologically effective dose ≥100 Gy). The primary endpoint was 6-month biochemical response (PSA decrease of ≥50% compared with baseline) and has been reported previously. After meeting its primary endpoint, the power calculation was updated post-hoc to assess overall survival, finalised before data unmasking. We present an unplanned long-term follow-up focusing on overall survival. All analyses were performed on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov (NCT03449719) and is now closed. FINDINGS: Between Jan 2, 2019, and Sept 7, 2022, 157 patients were randomly assigned to the control (n=82) and experimental (n=75) groups. No data about race or ethnicity were collected. After a median follow up of 53 months (IQR 43-60), median overall survival was 50 months (95% CI 36-not reached [NR]) in the control group versus NR (55-NR) in the experimental group (HR 0·55, 95% CI 0·33-0·92, p=0·021). Most common grade 3-4 adverse events recorded were infectious complications (five in the control group vs zero in the experimental group) and cardiovascular disorders (three in the control group vs three in the experimental group). One treatment-related death occurred in the control group due to myocardial failure. INTERPRETATION: The ARTO trial showed significant benefit in overall survival with the addition of MDT to systemic therapy versus systemic therapy alone. FUNDING: Fondazione Radioterapia Oncologica.