van den Hoek L, Burgmans M, Tong T
… +18 more, Goeman J, Speetjens F, Zunder S, van Erkel A, van der Meer R, van Rijswijk C, Lutjeboer J, Koolhaas D, Jonker-Bos M, Roozen I, Kropff S, van Meerten EVP, Zoethout R, Sitsen E, Helmerhorst H, Tijl F, Blank C, Kapiteijn E
BACKGROUND: Percutaneous hepatic perfusion can lead to meaningful hepatic tumour control in metastatic uveal melanoma, but its benefit is confined to liver metastases and does not address extrahepatic disease. Immune che...BACKGROUND: Percutaneous hepatic perfusion can lead to meaningful hepatic tumour control in metastatic uveal melanoma, but its benefit is confined to liver metastases and does not address extrahepatic disease. Immune checkpoint inhibitors ipilimumab and nivolumab show limited activity in uveal melanoma, although retrospective studies suggest improved outcomes when combined with liver-directed therapies. This study aimed to evaluate the efficacy and safety of combining percutaneous hepatic perfusion with ipilimumab and nivolumab. METHODS: In this investigator-initiated, single-centre, open-label, randomised, phase 2 trial, adults aged 18-80 years with unresectable liver-only or liver-dominant metastatic uveal melanoma, WHO performance status 0-1, and with no previous systemic therapy were randomly assigned (1:1) to receive percutaneous hepatic perfusion alone (perfusion group) or percutaneous hepatic perfusion combined with ipilimumab plus nivolumab (combination group). Two perfusions with melphalan (3 mg/kg; maximum 220 mg) were scheduled in weeks 1 and 7. The combination group also received intravenous ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) once every 3 weeks in weeks 0, 3, 6, and 9 without maintenance therapy. The primary endpoint, 1-year progression-free survival, was analysed in the intention-to-treat population; the safety analysis included all treated patients and was prospectively collected and graded using Common Terminology Criteria for Adverse Events version 5.0. The trial is registered with ClinicalTrials.gov (NCT04283890) and EudraCT (2018-004248-49) and is ongoing but no longer enrolling. FINDINGS: Between Dec 10, 2020, and Nov 15, 2024, 80 patients were screened, of whom 76 were eligible and assigned to the combination group (n=38) or perfusion group (n=38), including 49 (64%) men and 27 (36%) women. Median follow-up was 24·9 months (IQR 15·4-36·0). 1-year progression-free survival was 54·7% (95% CI 36·8-69·5) with combination therapy versus 15·8% (5·8-30·1) with perfusion alone (adjusted hazard ratio 0·34 [95% CI 0·19-0·60]; p=0·0002). Grade 3-4 treatment-related adverse events occurred in 31 (82%) of 38 patients with combination therapy compared to 15 (41%) of 37 patients with perfusion alone, due to both a higher incidence of severe perfusion-related events and immunotherapy-related adverse events. The most common grade 3-4 adverse events were thrombocytopenia (13 [34%] in the combination group vs five [14%] in the perfusion group), leukopenia (ten [26%] vs five [14%]), γ-glutamyl transferase increase (seven [18%] vs three [8%]), and anaemia (five [13%] vs one [3%]). One treatment-related death (due to triple M syndrome) occurred in the combination group. INTERPRETATION: Adding ipilimumab and nivolumab to percutaneous hepatic perfusion significantly improved progression-free survival, but with a higher rate of adverse events. The combination therapy offers a promising new treatment paradigm for patients with metastatic uveal melanoma. These results would ideally be validated in larger, multicentre randomised trials; however, conducting such studies is challenging due to the low incidence of uveal melanoma. FUNDING: Leiden University Medical Centre, Delcath Systems, and Bristol Myers Squibb.
BACKGROUND: Brachytherapy is a key component of cancer treatment, yet global access remains poorly characterised. We aimed to quantify worldwide demand and supply of brachytherapy resources and to identify inequities in...BACKGROUND: Brachytherapy is a key component of cancer treatment, yet global access remains poorly characterised. We aimed to quantify worldwide demand and supply of brachytherapy resources and to identify inequities in access. METHODS: In this population-based observational study, cancer incidence for six cancers (prostate, vaginal, cervical, endometrial, and vulval cancers, and melanoma) in 185 countries was obtained from GLOBOCAN 2022. Data on brachytherapy centres was extracted from the Directory of Radiotherapy Centres (accessed May 7, 2024) and supplemented by a literature review when brachytherapy caseloads exceeded 500 patients per centre. Annual centre capacity was defined as 218 patients, based on HIC capacity. Countries were classified by World Bank income groups. Brachytherapy utilisation rates from the Collaboration for Cancer Outcomes Research and Evaluation model were applied to estimate demand in high-income countries (HICs). An adjusted model accounted for later-stage presentation in low-income countries (LICs) and middle-income countries (excluding prostate cancer since alternative treatments are available). Brachytherapy utilisation for vulval cancer was separately estimated. Euclidean analysis was used to calculate the average population-weighted travel distance to centres in areas with more than 608 people per km·. FINDINGS: 18 528 336 new cancer cases (excluding non-melanoma skin cancer) occurred in 185 countries in 2022, of which 708 948 were estimated to require brachytherapy, corresponding to a global brachytherapy utilisation rate of 3·8%. Cervical cancer accounted for the majority of brachytherapy indications (59·3%, n=420 090), followed by uterine (25·2%, n=178 584) and prostate cancer (11·5%, n=81 849), with smaller numbers for vaginal (2·0%, n=13 996), vulval (1·1%, n=7611), and ocular melanoma (1·0%, n=6817). Brachytherapy demand was met in most HICs (81·5%), some upper-middle-income countries (UMIC; 44·4%), few lower-middle-income countries (LMIC; 11·8%), and in no LICs. The regions with the biggest deficit were sub-Saharan Africa, eastern Asia, and south-eastern Asia. Utilisation rates were higher in LICs (10·4%) compared with LMICs (5·7%), UMIC (3·5%), and HICs (2·9%). Average population-weighted distance to the nearest centre was 68 km in HICs, 167 km in UMICs, 341 km in LMICs, and 551 km in LICs (p<0·0001). INTERPRETATION: Global access to brachytherapy remains profoundly unequal, with adequate coverage largely limited to HICs. Resource gaps are greatest in lower-income settings, where patients also travel farthest. Investment in new centres is urgently needed to reduce geographical and economic barriers to access. FUNDING: None.
BACKGROUND: Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive...BACKGROUND: Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive assessment of the epidemiological trends, disease burden, and risk factors associated with breast cancer globally, regionally, and nationally from 1990 to 2023. METHODS: Breast cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) were estimated by age and sex for 204 countries and territories from 1990 to 2023. Mortality estimates were generated using GBD Cause of Death Ensemble models, leveraging data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Mortality-to-incidence ratios were calculated to derive both mortality and incidence estimates. Prevalence was calculated by combining incidence and modelled survival estimates. YLLs were established by multiplying age-specific deaths with the GBD standard life expectancy at the age of death. YLDs were estimated by applying disability weights to prevalence estimates. The sum of YLLs and YLDs equalled the number of DALYs. Breast cancer burden attributable to seven risk factors was examined through the comparative risk assessment framework. The GBD forecasting framework was used to forecast breast cancer incidence and mortality from 2024 to 2050. Age-standardised rates were calculated for each metric using the GBD 2023 world standard population. FINDINGS: In 2023, there were an estimated 2·30 million (95% uncertainty interval [UI] 2·01 to 2·61) breast cancer incident cases, 764 000 deaths (672 000 to 854 000), and 24·1 million (21·3 to 27·5) DALYs among females globally. In the World Bank low-income group, where a low age-standardised incidence rate (ASIR) was estimated (44·2 per 100 000 person-years [31·2 to 58·4]), the age-standardised mortality rate (ASMR) was the highest (24·1 per 100 000 [16·8 to 31·9]). The highest ASIR was in the high-income group (75·7 per 100 000 [67·1 to 84·0]), and the lowest ASMR was in the upper-middle-income group (11·2 per 100 000 [10·2 to 12·3]). Between 1990 and 2023, the ASIR in the low-income group increased by 147·2% (38·1 to 271·7), compared with a 1·2% (-11·5 to 17·2) change in the high-income group. The ASMR decreased in the high-income group, changing by -29·9% (-33·6 to -25·9), but increased by 99·3% (12·5 to 202·9) in the low-income group. The increase in age-standardised DALY rates followed that of ASMRs. Risk factors such as dietary risks, tobacco use, and high fasting plasma glucose contributed to 28·3% (16·6 to 38·9) of breast cancer DALYs in 2023. The risk factors with a decrease in attributable DALYs between 1990 and 2023 were high alcohol use and tobacco. By 2050, the global incident cases of breast cancer among females were forecast to reach 3·56 million (2·29 to 4·83), with 1·37 million (0·841 to 2·02) deaths. INTERPRETATION: The stable incidence and declining mortality rates of female breast cancer in high-income nations reflect success in screening, diagnosis, and treatment. In contrast, the concurrent rise in incidence and mortality in other regions signals health system deficits. Without effective interventions, many countries will fall short of the WHO Global Breast Cancer Initiative's ambitious target of achieving an annual reduction of 2·5% in age-standardised mortality rates by 2040. The mounting breast cancer burden, disproportionately affecting some of the world's most vulnerable populations, will further exacerbate health inequalities across the globe without decisive immediate action. FUNDING: Gates Foundation, St Jude Children's Research Hospital.
Necchi A, Maiorano BA, de Jong JJ
… +18 more, Proudfoot JA, Basile G, Cigliola A, Mercinelli C, Tateo V, Piacentini M, Pastorino G, Latini G, Tomasi E, Davicioni E, Moschini M, Brembilla G, Colecchia M, de Cobelli F, Briganti A, Ross JS, Pavlick DC, Montorsi F
BACKGROUND: Standard-of-care treatment for muscle-invasive bladder cancer is radical cystectomy with neoadjuvant chemotherapy; however, approximately 50% of patients are ineligible for or refuse neoadjuvant chemotherapy....BACKGROUND: Standard-of-care treatment for muscle-invasive bladder cancer is radical cystectomy with neoadjuvant chemotherapy; however, approximately 50% of patients are ineligible for or refuse neoadjuvant chemotherapy. Neoadjuvant pembrolizumab and sacituzumab govitecan have shown activity as monotherapy in muscle-invasive bladder cancer. We aimed to evaluate the clinical activity of neoadjuvant sacituzumab govitecan plus pembrolizumab and adjuvant pembrolizumab, within a bladder-sparing approach. METHODS: SURE-02 is a single-arm, phase 2 study, conducted at IRCCS San Raffaele Hospital in Milan, Italy. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status 0-1, were newly diagnosed with histologically confirmed muscle-invasive bladder cancer (stage cT2-T3bN0M0), were deemed ineligible for or declined cisplatin-based neoadjuvant chemotherapy, and were scheduled for radical cystectomy. Patients received four cycles of intravenous pembrolizumab 200 mg on day 1 and intravenous sacituzumab govitecan 7·5 mg/kg on day 1 and day 8, every 3 weeks, followed by radical cystectomy or redo-transurethral resection of the bladder tumour (re-TURBT; after multidisciplinary tumour board discussion in patients who refused to undergo radical cystectomy) and 13 cycles of postsurgical pembrolizumab 200 mg, every 3 weeks. The primary endpoint was the clinical complete response rate, defined as negative imaging and no viable tumour at re-TURBT in patients not undergoing radical cystectomy. Efficacy was assessed in all patients who received at least one dose of study treatment and had a baseline evaluation (intention-to-treat population). This study is registered with ClinicalTrials.gov, NCT05535218, and is active but not recruiting. FINDINGS: Between Oct 2, 2023, and Feb 26, 2025, 63 patients were screened, 49 patients (median age 66 years [IQR 61-71]; eight [16%] female and 41 [84%] male; 48 [98%] White and one [2%] Black) were enrolled, treated, and evaluated for safety and efficacy. 33 (67%) had a cT2 stage, 21 (43%) had a centrally confirmed variant histology. After a median follow-up of 14 months (IQR 8-18), 19 (39% [95% CI 25-54]) patients had a clinical complete response; all of whom underwent a re-TURBT. All patients with clinical complete response were metastasis-free; two patients developed an intravesical relapse. Grade 3 treatment-related adverse-events occurred in eight patients (16%), the most common being diarrhoea (in four [8%]). There were no treatment-related deaths. Serious treatment-related adverse events were reported in three patients (6%); bullous pemphigoid in two and colitis in one patient respectively. INTERPRETATION: Perioperative sacituzumab govitecan plus pembrolizumab revealed a promising clinical complete response rate, without the occurrence of grade 4 or higher adverse events, allowing a bladder preservation with sustained remission in approximately 40% of patients. FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA and Gilead Sciences.
BACKGROUND: Metastasis-directed therapy (MDT) can defer androgen deprivation therapy (ADT) in oligorecurrent prostate cancer, but outcomes vary and there is a paucity of risk stratification tools. We aimed to develop and...BACKGROUND: Metastasis-directed therapy (MDT) can defer androgen deprivation therapy (ADT) in oligorecurrent prostate cancer, but outcomes vary and there is a paucity of risk stratification tools. We aimed to develop and validate a nomogram to predict ADT-free survival. METHODS: In this international, retrospective cohort study across ten hospitals and academic institutions in Europe (Austria, Italy, Latvia, the Netherlands, Poland, and Portugal), we included men aged 18 years and older with histologically confirmed prostate cancer (all subtypes) previously treated with curative-intent local therapy, who developed metachronous oligorecurrent, hormone-sensitive disease (≤5 prostate-specific membrane antigen [PSMA] PET-detected pelvic nodal or distant metastases or both) and received stereotactic body radiotherapy to all lesions without adjuvant systemic therapy. The primary endpoint was the proportion of patients remaining ADT-free at 1 year of follow-up. Ten clinical predictors were evaluated in a multivariable Cox model with backward elimination. Internal validation with bootstrapping assessed model performance (C-index and calibration), followed by external validation. FINDINGS: A total of 1461 men treated between July 1, 2014, and Dec 31, 2023, were screened, of whom 586 were included in the development cohort (307 [52%] pelvic nodal and 279 [48%] distant metastases); median follow-up was 37 months (IQR 24-58). The external validation cohort (henceforth validation cohort) comprised 131 patients (57 [44%] pelvic nodal, 74 [56%] distant), with a median follow-up 43 months (24-57). ADT-free survival at 1 year was 84·3% (95% CI 81·4-87·3) in the development cohort and 92·8% (88·4-97·4) in the validation cohort. Independent predictors of earlier ADT initiation were higher pre-MDT PSA (hazard ratio 1·05 [95% CI 1·03-1·08]), shorter PSA doubling time (0·97 [0·95-0·98]), three to five lesions (HR 1·74 [1·33-2·28]), and distant metastases (HR 1·45 [1·18-1·78]). Model discrimination was 0·66 (95% CI 0·65-0·68) in the development cohort and 0·65 (95% CI 0·55-0·75) in the external validation cohort. Risk stratification separated patients into three prognostic groups-low risk, intermediate risk, and high risk (p<0·0001). INTERPRETATION: This nomogram predicts ADT-free survival after MDT in oligorecurrent prostate cancer. While individual-level discrimination was modest, risk-group stratification showed meaningful separation, supporting its potential use in treatment selection. FUNDING: None.
Louis FM, van der Voort A, van Ramshorst MS
… +17 more, Daletzakis A, Mandjes IA, Kemper I, Agterof MJ, van der Steeg WA, Heijns JB, van Bekkum ML, Siemerink EJM, Kuijer PM, Scholten A, Wesseling J, Vrancken Peeters MTFD, Egeler MD, van de Poll-Franse LV, Mann RM, Sonke GS, Dutch Breast Cancer Research Group (BOOG)
BACKGROUND: Neoadjuvant treatment comprising six to nine cycles of anti-HER2 based chemotherapy yields high pathological complete response rates and excellent survival outcomes in patients with stage II-III HER2-positive...BACKGROUND: Neoadjuvant treatment comprising six to nine cycles of anti-HER2 based chemotherapy yields high pathological complete response rates and excellent survival outcomes in patients with stage II-III HER2-positive breast cancer but comes with noteworthy side-effects. The TRAIN-3 study investigated if patients treated with this regimen who have a rapid complete radiological response on MRI are candidates for early surgery. The study showed that one-third of patients with hormone receptor-negative tumours and one-sixth of patients with hormone receptor-positive tumours had a pathological complete response after only three cycles of chemotherapy. Here, we report the results of the primary endpoint, 3-year event-free survival. METHODS: TRAIN-3 is a multicentre, single-arm, phase 2 study conducted across 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and with a WHO performance status of 0 or 1 were eligible for inclusion. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m, day 1 and 8 of each 21-day cycle, intravenous), trastuzumab (6 mg/kg on day 1 of each cycle [loading dose 8 mg/kg on day 1 of cycle 1], intravenous), carboplatin (area under the curve 6 mg/mL per min on day 1 of each cycle, intravenous) and pertuzumab (420 mg on day 1 of each cycle [loading dose 840 mg on day 1 of cycle 1], intravenous) for up to nine cycles, and were referred for surgery once a complete radiological response was observed on MRI. Patients who had a pathological complete response post-surgery completed 1 year of adjuvant trastuzumab and pertuzumab. Patients with residual invasive disease in the resection specimen continued chemotherapy for a total of nine cycles, followed by 14 cycles of trastuzumab emtansine (3·6 kg/mg, day 1 of each 21-day cycle, intravenous). Adverse events of grade 3 or worse and grade 2 or worse left ventricular ejection fraction and neuropathy were registered until 30 days after the last adjuvant treatment cycle. The primary endpoint was 3-year event-free survival; analyses were done in hormone receptor-negative and hormone receptor-positive patients separately on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT03820063); recruitment is closed, and follow-up for secondary endpoints is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative tumours and 232 with hormone receptor-positive tumours were enrolled. All participants, except one, were female. Median follow-up was 40·1 months (IQR 35·3-45·6). 3-year event-free survival was 92·2% (95% CI 88·7-95·9) in patients with hormone receptor-negative tumours and 92·0% (88·5-95·6) in patients with hormone receptor-positive tumours. In total, 40 (9%) patients had experienced an event (19 [8%] patients in the hormone receptor-negative group and 21 [9%] in the hormone receptor-positive group). 3-year event-free survival rates among patients treated with one to three cycles were 96·1% (95% CI 91·8-100) in the hormone receptor-negative group and 98·6% (95·8-100) in the hormone receptor-positive group. Event-free survival rates for patients receiving four to six cycles were 89·2% (82·4-96·6) and 94·2% (88·8-99·9), and for those receiving seven to nine cycles, 90·6% (83·8-98·1) and 85·4% (78·3-93·1%), respectively. The most common grade 3-4 adverse events were neutropenia (187 [40%] of 467), anaemia (82 [18%]), diarrhoea (60 [13%]), thrombocytopenia (46 [10%]), and hypokalaemia (35 [7%]), and treatment-related serious adverse events occurred in 56 (12%) patients. The frequency of grade 3-4 adverse events and grade 2 or worse neuropathy increased with the increasing number of neoadjuvant chemotherapy cycles. No treatment-related deaths were reported. INTERPRETATION: MRI-guided optimisation of neoadjuvant chemotherapy duration was associated with favourable 3-year event-free survival outcomes in patients with stage II-III HER2-positive breast cancer. This approach represents a novel strategy that reduces treatment burden, minimises toxicity, and preserves quality of life in a subset of patients with early HER2-positive breast cancer. FUNDING: Roche Netherlands.