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.
Kaidar-Person O, Weltens CG, Fortpied C
… +22 more, Scheijmans LJEE, Kirkove CY, Budach V, Peignaux-Casasnovas K, Valli M, Peters M, van der Leij F, Rivera S, Weidner N, van den Bongard DHJG, Linsenmeier C, Abdah-Bortnyak R, Hosni S, Koiter E, Engelen AM, Baten A, Champezou L, Fourquet A, Bartelink HGMM, Struikmans H, Poortmans PMP, EORTC Radiation Oncology and Breast Cancer Groups
BACKGROUND: Results from several studies, including our 15-year analysis, showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overa...BACKGROUND: Results from several studies, including our 15-year analysis, showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. Here, we present the scheduled 20-year analysis of the EORTC trial 22922/10925, evaluating the role of internal mammary and medial-supraclavicular (IM-MS) nodal irradiation in patients with stage I-III breast cancer. Patients without confirmed axillary nodal involvement (pathological N stage 0 [pN0]) were eligible for the trial when the primary tumours were centrally or medially located. METHODS: EORTC 22922/10925 was a randomised, open-label, phase 3 trial done across 46 radiation oncology departments from 13 countries. Eligible participants were women up to 75 years of age with unilateral, histologically confirmed, stage I-III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. Only patients without clinically and histopathologically confirmed nodal involvement (pN0) were included in this unplanned subgroup analysis. The primary outcome was overall survival analysed according to the intention-to-treat principle. Safety analyses were conducted in the subset of eligible patients treated per protocol. This trial is registered with ClinicalTrials.gov (on Nov 1, 1999; NCT00002851) and closed after its final analysis. FINDINGS: Between Aug 5, 1996, and Jan 13, 2004, 4004 patients were randomly assigned. 890 (44·5%) of 2002 patients in the IM-MS irradiation group and 888 (44·4%) of 2002 patients in the control group had pN0 disease. The median age of participants was 55 years (IQR 48-63). At a median follow-up of 22·2 years (IQR 20·1-24·5), 276 (31·1%) of 888 patients in the IM-MS irradiation group and 277 (31·1%) of 890 patients in the control group died because of any cause; 87 (31·5%) of 276 and 122 (44·0%) of 277 patients died due to breast cancer, respectively. At 20 years, the overall survival rate was 69·0% (95% CI 65·4-72·3) in the IM-MS irradiation group and 68·4% (64·8-71·6%) in the control group (hazard ratio [HR] 0·98 [95% CI 0·83-1·15], p=0·77). The breast cancer mortality rate was 10·0% (8·0-12·3) in the IM-MS irradiation group and 14·2% (11·9-16·8) in the control group (HR 0·70 [95% CI 0·53-0·92], p=0·010), but cumulative mortality of unknown cause or not breast cancer cause was 20·9% (95% CI 17·9-24·1) in the IM-MS irradiation group and 17·4% (14·7-20·3) in the control group (HR 1·24 [95% CI 1·00-1·53]; p=0·048). In patients with left-sided breast cancer, late cardiac fibrosis occurred in 15 (3·4%) of 445 patients in the IM-MS irradiation group and 12 (2·8%) of 436 patients in the control group. Lung fibrosis at any grade occurred in 55 (6·4%) of 855 patients in the IM-MS irradiation group and 18 (2·1%) of 877 patients in the control group. INTERPRETATION: Breast cancer mortality at 20 years was significantly lower in the IM-MS irradiation group, whereas non-breast cancer mortality was numerically higher in the IM-MS irradiation group after 15 years, resulting in no long-term benefit of IM-MS irradiation on overall survival. Our results emphasise the importance of very long-term follow-up and advanced irradiation techniques to reduce the dose to organs of interest. FUNDING: Ligue Nationale contre le Cancer, KWF Kankerbestrijding, and EORTC Cancer Research Fund.
BACKGROUND: Indications for postoperative locoregional radiotherapy in cT1-2N1 breast cancer after primary systemic therapy are disputed. The previously published 5-year outcomes of the RAPCHEM study showed excellent loc...BACKGROUND: Indications for postoperative locoregional radiotherapy in cT1-2N1 breast cancer after primary systemic therapy are disputed. The previously published 5-year outcomes of the RAPCHEM study showed excellent locoregional control when radiotherapy was tailored to the nodal response after primary chemotherapy. Here, we present 10-year results. METHODS: In this prospective registry study (RAPCHEM, BOOG 2010-03), patients referred to one of 17 participating Dutch radiation oncology centres between Jan 1, 2011, and Jan 1, 2015, with cT1-2N1 breast cancer (with ≤3 suspicious nodes at imaging) treated with primary chemotherapy, followed by breast and axillary surgery, were included. Three risk groups, with corresponding radiotherapy guideline were defined: the low-risk group received whole breast radiotherapy after lumpectomy and no radiotherapy after mastectomy; the intermediate-risk group received whole breast or chest wall radiotherapy without regional nodal radiotherapy; and the high-risk group received whole breast or chest wall radiotherapy and regional nodal radiotherapy of levels III-IV. The current analysis presents the prespecified secondary endpoints of the study of 10-year isolated locoregional recurrence rate, 10-year recurrence-free interval, and 10-year overall survival. This trial is registered with ClinicalTrials.gov, NCT01279304. FINDINGS: 838 patients were included in the 10-year follow-up analysis: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 10-year locoregional recurrence rate in all patients was 2·9% (95% CI 1·9-4·2), with locoregional recurrence rates of 2·4% (95% CI 1·1-4·7) in the low-risk group, 3·2% (1·8-5·4) in the intermediate-risk group, and 2·8% (1·1-6·1) in the high-risk group. No significant differences were seen in locoregional recurrence between the groups. The 10-year recurrence-free interval for all patients was 79·2% (76·2-81·8), and the 10-year overall survival for all patients was 83·0% (80·3-85·4). INTERPRETATION: Tailoring locoregional radiotherapy in cT1-2N1 breast cancer (with ≤3 nodes at imaging) to the nodal response after primary systemic therapy resulted in a low 10-year locoregional recurrence rate, with promising recurrence-free interval and overall survival. By (partially) omitting radiotherapy based on nodal response after primary systemic treatment, possible morbidity caused by the radiotherapy can be avoided, which could improve patients' quality of life. FUNDING: Dutch Cancer Society.
Seefat RL, Vliek SB, de Jong VMT
… +42 more, Balduzzi S, Mandjes IA, Retèl VP, Eekhout I, Delfos M, Schot M, Holtkamp MJ, van Rosmalen MM, Leeneman B, Blommestein H, Huitema ADR, Rosenberg EH, Nederlof PM, Chan TWS, van Rhenen A, Wondergem MJ, Schaap NPM, Snijders TJF, Van der Poel MWM, Plattel WJ, van Werkhoven E, van Tinteren H, Smidt ML, Wesseling J, Jonkers J, Rottenberg S, Vrancken Peeters MTFD, Voermans C, Maduro JH, Kroep JR, Schroder CP, Kuip EJM, Gonçalves A, Nuver J, Wymenga ANM, Bijlsma RM, van der Wall E, Konings IRHM, Tjan-Heijnen VCG, Jongen-Lavrencic M, Jager A, Linn SC
BACKGROUND: Patients with stage III, human epidermal-growth-factor-receptor 2 (HER2; also known as ERBB2)-negative breast cancer with homologous recombination deficiency (HRD) had a 4-year overall survival of 35% after a...BACKGROUND: Patients with stage III, human epidermal-growth-factor-receptor 2 (HER2; also known as ERBB2)-negative breast cancer with homologous recombination deficiency (HRD) had a 4-year overall survival of 35% after anthracycline-based chemotherapy versus 78% after intensified alkylating chemotherapy with autologous stem cell rescue (IACT) in a post-hoc analysis of an earlier randomised controlled trial. In this study, we aimed to prospectively assess 4-year overall survival with IACT and establish whether this approach remains superior to a contemporary HRD-targeting regimen in patients with HER2-negative breast cancer with HRD. METHODS: This open-label, randomised, controlled, phase 3 trial included patients from eight hospitals and one cancer centre in the Netherlands and one cancer centre in France. Newly diagnosed patients aged between 18-66 years with stage IIIA-C, HER2-negative, HRD breast cancer without distant metastases who had a pathogenic germline BRCA1/2 mutation or evidence of a HRD tumour on testing were randomly assigned (1:1) to receive IACT or conventional chemotherapy using interactive response technology. IACT comprised dose-dense alkylating chemotherapy (ddAC; four cycles of doxorubicin 60 mg/m and cyclophosphamide 600 mg/m every 2 weeks intravenously), supported by 6 mg prophylactic pegfilgrastim subcutaneously every 2 weeks. 2 weeks after stem cell mobilisation, patients received two IACT cycles 3 weeks apart (3000 mg/m cyclophosphamide on day 1, 250 mg/m thiotepa on day 2, and 400 mg/m carboplatin intravenously on days 1 and 2), followed by autologous stem cell transplantation. Conventional chemotherapy comprised four ddAC cycles, followed by four cycles of intravenous carboplatin area under the curve 6 every 3 weeks, and 80 mg/m paclitaxel every week for 12 weeks (carboplatin-paclitaxel intravenously), followed by 1 year of oral olaparib (300 mg twice daily). All patients proceeded to surgery and radiotherapy according to local practice. Stratification factors were treatment centre, age, stage, and oestrogen receptor status. The primary endpoint was overall survival in the intention-to-treat population (all randomly allocated patients). The trial was registered at ClinicalTrials.gov, NCT02810743, and is ongoing, but is closed for inclusion. FINDINGS: From Jan 25, 2017, through to Oct 5, 2023, 356 patients were screened for eligibility, and 174 patients were randomly assigned to receive IACT (n=87) or olaparib (n=87). All patients were female, and median age was 42 years (IQR 37-50). We did not ask explicit informed consent for collecting data on ethnicity of patients, because we focused on a very rare patient subgroup and therefore used pragmatic eligibility criteria following standard General Data Protection Regulation. 28 (32%) in the IACT group and 22 (25%) patients in the olaparib group had germline BRCA1/2 mutations. With a median follow-up of 41 months (IQR 27-59), the 4-year overall survival was 77·0% (95% CI 67·7-87·7 in the IACT group and 76·4% (66·9-87·4) in the olaparib group (hazard ratio for death 1·11 [95% CI 0·57-2·17]; p=0·37).The most common grade 3-4 adverse events were platelet count decreased (80 [99%] in the IACT group vs 18 [19%] in the olaparib group), neutrophil count decreased (77 [95%] in the IACT group vs 56 [61%] in the olaparib group), and anaemia (50 [62%] in the IACT group vs 37 [41%] in the olaparib group). Treatment-emergent serious adverse events occurred in 38 (47%) of 81 patients in the IACT group versus 24 (26%) of 91 patients in the olaparib group. Febrile neutropenia was the most common serious adverse event in both groups (36 [44%] in the IACT group; 11 [12%] in the olaparib group). No treatment-related deaths were reported. INTERPRETATION: These data demonstrate that targeting HRD yields promising outcomes in stage III, HER2-negative, HRD breast cancer and that intensified chemotherapy with autologous stem cell rescue does not provide any advantage over state-of-the-art chemotherapy plus olaparib. FUNDING: Dutch Cancer Society, the Dutch Ministry of Health, the Netherlands Organization for Health Research and Development, A Sister's Hope, [Z]aan de Wandel, AstraZeneca, MSD, and Eurocept Pharmaceuticals.
Vafaeinik F, Narayanasamy B, Helmueller S
… +7 more, Zhang Y, Gangi A, Lee H, Song C, Figlin R, Sargsyan K, Lee YJ
Mol Ther Oncol
· 2026 Sep · PMID 42371539
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Hepatic colorectal metastases, also termed colorectal liver metastases (CRLM), remain a major clinical challenge, despite advances in surgery and chemotherapy. The complexity of CRLM pathology necessitates novel therapeu...Hepatic colorectal metastases, also termed colorectal liver metastases (CRLM), remain a major clinical challenge, despite advances in surgery and chemotherapy. The complexity of CRLM pathology necessitates novel therapeutic approaches, yet current preclinical models often fail to accurately recapitulate the human tumor microenvironment. To overcome these limitations, we utilized patient-derived three-dimensional (3D) CRLM tumoroids to evaluate the efficacy of DZ-1-DHA, a novel conjugate consisting of the heptamethine carbocyanine dye DZ-1 linked to the anti-malarial derivative dihydroartemisinin (DHA). Data from TUNEL and immunoblotting assays revealed that treatment of CRLM tumoroids with DZ-1-DHA led to significant tumor cell death, accompanied by apoptotic signaling. Fluorescence imaging with MitoTracker, 2',7'-dichlorofluorescin diacetate, MitoSOX, and JC-1 showed that DZ-1-DHA accumulates in mitochondria, where it induces generation of cytotoxic reactive oxygen species (ROS) and causes mitochondrial membrane depolarization. Furthermore, data from treatment with deferoxamine or MitoTEMPO indicated that DZ-1-DHA promotes mitochondrial ROS production through a Fenton-like mechanism. These findings demonstrate that DZ-1-DHA triggers apoptosis through mitochondrial stress and apoptotic signaling pathways. Also, DZ-1-DHA represents a promising second-line therapeutic strategy for CRLM. By inducing selective tumor cell death through mitochondrial-targeted apoptosis in a clinically relevant 3D model. This promising approach needs validation for safety and efficacy.
OBJECTIVES: Newer cancer treatments, such as small molecule tyrosine kinase inhibitors and monoclonal antibodies that restore anti-tumour immunity, lead to improved survival when delivered as adjuvant or neoadjuvant trea...OBJECTIVES: Newer cancer treatments, such as small molecule tyrosine kinase inhibitors and monoclonal antibodies that restore anti-tumour immunity, lead to improved survival when delivered as adjuvant or neoadjuvant treatments with surgery or chemoradiotherapy for early and locally advanced non-small cell lung cancer (NSCLC). However, these novel drugs are costly, posing a funding challenge for most health systems. A Markov modelling-based cost-utility analysis was conducted to determine its cost-effectiveness in Sri Lanka from a health system perspective. DESIGN: A decision-analytic model was developed to evaluate the incremental costs and quality-adjusted life-years (QALYs) associated with treating patients diagnosed with stage II-III NSCLC for the following treatments: adjuvant osimertinib following surgery and after curative chemoradiotherapy, adjuvant alectinib after surgery, neoadjuvant nivolumab prior to surgery, adjuvant pembrolizumab and atezolizumab after surgery, perioperative durvalumab and pembrolizumab and consolidation durvalumab after chemoradiotherapy. The study employed 1-month simulation cycles over a lifetime. Sex-specific analyses were conducted and parameter uncertainty was addressed using probabilistic analysis. A willingness-to-pay threshold of US$6700 per QALY was applied. A 5-year budget impact analysis was performed for therapies identified as cost-effective. RESULTS: At the primary threshold, adjuvant osimertinib after surgery and after curative chemoradiotherapy, adjuvant alectinib after surgery and neoadjuvant nivolumab were cost-effective in both males and females. However, conclusions were sensitive to lower opportunity-cost-informed thresholds. At US$3000 per QALY, only osimertinib-based strategies remained robustly cost-effective. Other therapies were not cost-effective at current prices and would require substantial price reductions. The 5-year cumulative budget impact of adopting cost-effective therapies under full implementation was approximately US$11.8 million. CONCLUSIONS: Using a common modelling approach and Sri Lanka-specific costing assumptions, we present comparative cost-effectiveness results across multiple novel perioperative, adjuvant and neoadjuvant strategies for stage II-III NSCLC. These findings are intended to support prioritisation of which therapies could be considered first for public funding and to indicate the price reductions required for other agents to represent value for money.
Cervical cancer is a largely preventable disease, yet over 90% of its global mortality occurs in low and middle income countries(LMICs), reflecting profound inequities in access to screening and treatment. Traditional mu...Cervical cancer is a largely preventable disease, yet over 90% of its global mortality occurs in low and middle income countries(LMICs), reflecting profound inequities in access to screening and treatment. Traditional multivisit cervical cancer prevention models have been inadequate in these settings, largely due to high rates of loss to follow-up and insufficient health system infrastructure. In response, the WHO recommends the screen-and-treat (SAT) approach, which offers treatment based on a positive screening result, without requiring histological confirmation, preferably within a single visit. This narrative review synthesises evidence on the clinical effectiveness and operational feasibility of SAT in resource-constrained settings, with a focus on screening modalities, visual inspection with acetic acid (VIA) and human papillomavirus (HPV) testing and treatment options including cryotherapy, thermal ablation (TA) and large-loop excision of the transformation zone (LLETZ). While VIA is low-cost and provides immediate results, its accuracy is limited by provider-dependent subjectivity. HPV testing, particularly through point-of-care platforms and self-sampling, offers higher sensitivity and improved acceptability and is now the WHO-recommended primary screening modality. For treatment, portable TA devices have emerged as a logistically superior alternative to cryotherapy in LMICs, eliminating the need for compressed gas while maintaining comparable efficacy. Recent evidence further confirms that TA is non-inferior to LLETZ in real-world SAT settings, challenging the long-held perception that ablative therapies are clinically inferior. Concerns about overtreatment persist but must be weighed against the considerably greater risk of undertreatment in fragmented health systems. Women living with HIV require particular attention, given higher HPV prevalence, lower test specificity, more rapid disease progression and substantially lower post-treatment cure rates, necessitating tailored management protocols. The SAT approach represents a pragmatic, evidence-based strategy for achieving cervical cancer elimination in LMICs, but its effectiveness will depend on contextually appropriate implementation, integration within existing primary healthcare services and dedicated strategies for high-risk populations.
The rising incidence of oropharyngeal cancer (OPC), primarily driven by human papillomavirus (HPV), presents a significant public health challenge. Given the markedly better prognosis associated with HPV-positive OPC, th...The rising incidence of oropharyngeal cancer (OPC), primarily driven by human papillomavirus (HPV), presents a significant public health challenge. Given the markedly better prognosis associated with HPV-positive OPC, there is a compelling need to balance oncologic efficacy and reduce treatment morbidity. Although early de-escalation trials did not change standards, selective, biomarker-informed strategies show promise. This review synthesises evidence across transoral robotic surgery (TORS), reductions in RT dose and elective volumes, systemic therapy modification and the integration of circulating HPV DNA, immune profiling and functional imaging to guide truly personalised de-escalation. Ultimately, successful deintensification will require integration of biomarkers, multidisciplinary collaboration and patient-centred decision-making, moving beyond stage and HPV status alone.
King E, Saha C, Saleem R
… +5 more, Jiang B, O'Donoghue E, Cottone F, McCarthy HO, Piskareva O
Mol Ther Oncol
· 2026 Jun · PMID 42369018
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Neuroblastoma is an aggressive pediatric solid tumor that arises during embryonic development and contributes to 15% of cancer-related deaths in children. To date, neither experimental nor clinical trial data on an mRNA...Neuroblastoma is an aggressive pediatric solid tumor that arises during embryonic development and contributes to 15% of cancer-related deaths in children. To date, neither experimental nor clinical trial data on an mRNA vaccine for neuroblastoma have been published, highlighting a significant gap in the anticancer vaccine development pipeline. This study presents the first mRNA vaccine for the treatment of neuroblastoma. We explored the self-assembling peptide RALA for delivering mRNA encoding glypican 2 (GPC2), a potent tumor-associated antigen in neuroblastoma. These data outline rigorous characterization of vaccine nanoparticle formulations, cellular uptake, and functionality. Immunization of mice with RALA/ generated an antigen-specific cellular immune response against GPC2, with significant increases in IFN-γ and IL-2 expression by splenocytes and TNF-α expression by CD4 and CD8 T cells. Immunization delayed tumor development by 10-11 days and reduced tumor volume by 70% compared with unvaccinated controls in a subcutaneous murine model of -amplified neuroblastoma. This work demonstrates the therapeutic potential of the RALA/ vaccine for treating neuroblastoma. Additionally, GPC2 is upregulated across multiple adult and pediatric cancer subtypes, establishing this vaccine as an attractive immunotherapy with far-reaching potential.
Hong Y, Zhang P, Jin J
… +6 more, Liang W, Chen J, Liu J, Guan H, Huo Z, Li H
Clin Med Insights Oncol
· 2026 · PMID 42368681
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BACKGROUND: Diabetes mellitus (DM) is a common comorbidity in patients undergoing neurosurgical procedures and has been associated with adverse surgical outcomes. However, the extent to which DM, particularly the presenc...BACKGROUND: Diabetes mellitus (DM) is a common comorbidity in patients undergoing neurosurgical procedures and has been associated with adverse surgical outcomes. However, the extent to which DM, particularly the presence of chronic diabetic complications, affects perioperative outcomes and healthcare utilization in patients undergoing craniotomy for brain tumors remains unclear. Clarifying this relationship is essential for perioperative risk stratification and optimization. METHODS: We conducted a retrospective cohort study using the National Inpatient Sample (NIS) database, identifying adults (≥18 years) who underwent craniotomy for brain tumors between 2016 and 2022. Patients were stratified into three groups: non-DM, DM without chronic complications, and DM with chronic complications. Outcomes included in-hospital mortality, postoperative complications, length of stay (LOS), discharge disposition, and hospitalization costs. RESULTS: A total of 49,100 patients were included, of whom 8,822 (18.1%) had DM. Overall, DM patients experienced higher rates of postoperative complications, longer LOS, increased non-routine discharge, and greater hospitalization costs compared with non-DM patients. Notably, patients with DM without chronic complications had outcomes comparable to those of non-DM patients. In contrast, DM patients with chronic complications demonstrated significantly higher risks of adverse outcomes across all measured endpoints. CONCLUSIONS: DM alone does not significantly worsen outcomes after craniotomy for brain tumors. However, the presence of chronic diabetic complications is strongly associated with increased perioperative morbidity, mortality, prolonged hospitalization, and higher healthcare costs. These findings underscore the importance of incorporating diabetic complication status into preoperative evaluation and targeted perioperative management strategies.