Cancer Treat Rev
· 2025 May · PMID 40262369
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Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the treatment landscape for metastatic hormone receptor-positive, HER2-negative breast cancer by improving progression-free and Overall Survival (OS)....Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the treatment landscape for metastatic hormone receptor-positive, HER2-negative breast cancer by improving progression-free and Overall Survival (OS). In the adjuvant context, however, results have been discordant and remain immature. The PALLAS and PENELOPE-B trials of palbociclib reported no benefit, while monarchE and NATALEE demonstrated improvements in invasive disease-free survival (iDFS) with abemaciclib and ribociclib, respectively, leading to regulatory approvals despite no demonstrated OS benefit yet. It remains possible that adjuvant CDK4/6 inhibition provides meaningful long-term benefit, but that has not been demonstrated. Concerns related to trial design: risk-enrichment, open-label conduct, high treatment-discontinuation rates, and potential informative censoring complicate interpretation. Although iDFS is a recognized intermediate endpoint with potential psychological validity, it is subject to bias in collection and communication, and has not been validated as a surrogate for OS in this setting. Moreover, early inhibition of CDK4/6 may induce resistance and compromise subsequent efficacy. Reported quality-of-life outcomes were preserved, not improved, which holds limited value considering added toxicity, inconvenience, and cost in a largely curable population. If even half of eligible patients are treated, estimated annual costs in the United States would exceed $7 billion. As these agents are incorporated into clinical guidelines, it is critical to clarify whether they improve long-term outcomes, delay recurrence without affecting survival, or cause unintended harm. Impulse to intervene early is understandable, but emerging data must be carefully assessed to ensure adjuvant CDK4/6 inhibition offers meaningful benefit to patients and health systems.
Kuhlen M, Schmutz M, Kunstreich M
… +2 more, Redlich A, Claus R
Cancer Treat Rev
· 2025 May · PMID 40258305
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Pediatric adrenocortical carcinoma (pACC) is an exceptionally rare and aggressive malignancy, accounting for only 0.2-0.3% of childhood cancers. Characterized by significant endocrine activity and often associated with g...Pediatric adrenocortical carcinoma (pACC) is an exceptionally rare and aggressive malignancy, accounting for only 0.2-0.3% of childhood cancers. Characterized by significant endocrine activity and often associated with genetic syndromes such as Li-Fraumeni syndrome, pACC exhibits distinct clinical and molecular profiles compared to adult adrenocortical carcinoma (ACC). Current treatment approaches, largely adapted from adult protocols, center on surgery and chemotherapy, including mitotane. However, the lack of pediatric-specific data and major clinical trials underscores a pressing need for tailored therapeutic strategies. Advances in molecular profiling have unveiled actionable targets, such as alterations in the Wnt/β-catenin and MAP/ERK pathways, overexpression of IGF2, and epigenetic dysregulation. Emerging therapies, including immune checkpoint inhibitors, CAR T-cell therapy, and radiopharmaceuticals, hold promise but remain largely untested in pediatric populations. Targeting metabolic vulnerabilities, such as steroidogenesis and lipid metabolism, offers additional avenues for therapeutic innovation. Furthermore, improved diagnostic tools like liquid biopsy and steroid profiling may enhance disease monitoring and early detection. Despite progress in understanding pACC biology, significant challenges remain in translating these insights into effective treatments. Collaborative efforts, such as the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), and the development of pediatric-specific clinical trials are vital for advancing the field. Multidisciplinary care and international research initiatives will be pivotal in addressing the unmet needs of pACC patients. By leveraging molecular insights and fostering global collaboration, the field can move toward personalized medicine, improving outcomes and quality of life for children with this challenging disease. Expanding clinical trials, refining diagnostic tools, and integrating novel therapies into treatment regimens will be critical in bridging the gap between pediatric and adult ACC treatment success.
Tahara M, Lim DW, Keam B
… +4 more, Ma B, Zhang L, Wang C, Guo Y
Cancer Treat Rev
· 2025 May · PMID 40252510
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Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally. For patients with recurrent or metastatic (R/M) HNSCC, immunotherapy represents an important advance in clinical practice as an ef...Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally. For patients with recurrent or metastatic (R/M) HNSCC, immunotherapy represents an important advance in clinical practice as an effective and widely used first-line treatment. However, drug resistance following immunotherapy is an emerging problem and, despite the success of immunotherapy in R/M HNSCC, a proportion of patients will become immunotherapy resistant. The mechanisms of immunotherapy resistance are not yet fully understood and subsequent treatment options are limited. Therefore, there is an unmet need for effective and well tolerated treatments for patients who develop immunotherapy-resistant HNSCC. In this review, we address these challenges by summarizing the current definitions of immunotherapy resistance (primary and acquired resistance) as well as knowledge of the mechanisms of resistance to immunotherapy in R/M HNSCC. We then review available clinical data on treatment strategies, including rechallenge with immunotherapy, chemotherapy ± cetuximab, other targeted treatments, antibody-drug conjugates, and bispecific antibodies. We also investigate future research directions by reviewing ongoing clinical trials. Our review shows that the optimal therapeutic strategy for patients with R/M HNSCC remains unclear. While many therapies have reported promising preliminary results, prospective clinical trials are required to support their adoption in clinical practice. In particular, it appears that immunotherapy and antibody-drug conjugates have high potential in this setting. Our review also highlights the importance of further investigation of the mechanisms underlying immunotherapy-resistant R/M HNSCC, to inform selection of optimal therapeutic strategies on an individual patient basis and improve patient outcomes.
Belge Bilgin G, Lucien-Matteoni F, Chaudhuri AA
… +12 more, Orme JJ, Childs DS, Muniz M, Li GG, Chauhan PS, Lee S, Gupta S, Thorpe MP, Johnson DR, Johnson GB, Kendi AT, Sartor O
Cancer Treat Rev
· 2025 May · PMID 40239461
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Neuroendocrine prostate cancer (NEPC) is rare at the time of initial diagnosis but much more common in patients treated with the combination of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors...Neuroendocrine prostate cancer (NEPC) is rare at the time of initial diagnosis but much more common in patients treated with the combination of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI) such as abiraterone and enzalutamide. NEPC is typically characterized by the loss of prostate-specific membrane antigen (PSMA) expression while exhibiting variable neuroendocrine markers. Recent advancements in nuclear medicine have provided a promising avenue for the development of molecular imaging techniques and targeted therapies tailored to NEPC. This review examines the current and future role of theranostics in the diagnosis and management of NEPC and explores potential future directions in this rapidly evolving field.
Kong WY, Soderholm A, Brooks AJ
… +2 more, Gonzalez Cruz JL, Wells JW
Cancer Treat Rev
· 2025 May · PMID 40233680
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Cytokines are pivotal regulators of cellular functions and immune responses, making them highly promising targets for cancer immunotherapy. Despite their widespread clinical application, the effectiveness of cytokine imm...Cytokines are pivotal regulators of cellular functions and immune responses, making them highly promising targets for cancer immunotherapy. Despite their widespread clinical application, the effectiveness of cytokine immunotherapy is often hampered by their pleiotropic effects, short half-lives, uneven biodistribution, and severe side effects at high dosages. Recent advancements in cytokine biology have led to the development of cytokine-antibody immunocomplexes and cytokine fusion proteins, offering a new paradigm in cancer treatments. These innovations foster the ability of cytokines to selectively activate specific cancer-targeting immune cell populations, such as CD8 T cells and NK cells, effectively inhibiting tumour progression. Furthermore, both therapeutic approaches can mitigate systemic toxicities and prolong the biological activity of cytokines in the body. This review delves into the recent advancements of cytokine immunocomplexes and cytokine fusion proteins, with a particular focus on interleukin-2 (IL-2), IL-7 and IL-15, which are in clinical/preclinical development. Moreover, we discuss the therapeutic benefits of these approaches observed in recent preclinical and clinical studies, along with the challenges that must be addressed to fully unlock their potential in cancer immunotherapy.
Giugliano F, Giordano E, Gilardi L
… +12 more, Salimbeni BT, Zagami P, Esposito A, Marra A, Trapani D, Berton Giachetti PPM, Malagutti B, Henry T, Deandreis D, Curigliano G, Ceci F, Criscitiello C
Cancer Treat Rev
· 2025 May · PMID 40228448
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Radioligand therapy (RLT) represents a promising advancement in precision oncology and enables the targeted delivery of radiation to cancer cells. This approach has shown success in other tumor types, such as prostate ca...Radioligand therapy (RLT) represents a promising advancement in precision oncology and enables the targeted delivery of radiation to cancer cells. This approach has shown success in other tumor types, such as prostate cancer and neuroendocrine tumors. Its potential in metastatic breast cancer (mBC) is currently under investigation. This review discusses RLT mechanism of action, therapeutic potential, and integration into the existing therapeutic landscape of mBC. While clinical trials have shown promising results, challenges remain regarding target heterogeneity, implementation, and optimizing treatment strategies. Further research is essential to integrate RLT into clinical practice and improve patient outcomes fully.
van Dijk B, Janssen JC, van Daele PLA
… +5 more, de Jonge MJA, Joosse A, Verheul HMW, Epker JL, van der Veldt AAM
Cancer Treat Rev
· 2025 May · PMID 40222269
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PURPOSE: Immune checkpoint inhibitors (ICIs) have improved the survival of patients with different solid tumors and even resulted in cure of metastatic disease. Since the introduction of ICIs, an increasing number of pat...PURPOSE: Immune checkpoint inhibitors (ICIs) have improved the survival of patients with different solid tumors and even resulted in cure of metastatic disease. Since the introduction of ICIs, an increasing number of patients is admitted to the ICU for severe and potentially life-threatening immune related adverse events (irAEs). The outcome of patients who are admitted to the ICU because of severe irAEs is still unknown. The aim of this systematic review is to collect evidence on the outcomes of patients with solid tumors who are admitted to the ICU because of irAEs. METHODS: Medline, Embase, Cochrane central register of controlled trials and Google Scholar were searched systematically from 1975 to 24 September 2024. Articles were only included when describing patients with solid tumors who were admitted to the ICU because of irAEs after treatment with ICIs. Two independent reviewers extracted the data and assessed the risk of bias. RESULTS: A total of 183 articles were included: two prospective ICU population-based studies, four retrospective ICU population-based studies, 25 retrospective studies describing irAEs with incidental ICU admissions, one review of case reports, and 153 articles with a total of 177 case reports. The six ICU population-based studies contained a total of 169 patients who were admitted to the ICU due to irAEs. In these six studies, the most frequently reported irAEs were pneumonitis and neurological irAEs. Of these 169 patients, 26% of the patients died on the ICU and an additional 8% of patients in the three to six months thereafter due to irAEs or disease progression. In all 183 included articles, various irAEs were described and the reported mortality rate varied from 0 to 53%. CONCLUSION: The potential favorable outcomes of both the solid tumors and irAEs will probably result in more need for ICU admissions. Prospective clinical trials are needed to optimize the treatment strategy of severe irAEs at the ICU. Based on the favourable outcomes after life-threatening irAEs, ICU admission should definitely be considered for patients with solid tumors who have life-threatening irAEs.
Cancer Treat Rev
· 2025 May · PMID 40220433
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Primary testicular lymphoma (PTL) is a rare extranodal lymphoma. The majority of cases are of diffuse large B cell lymphoma (DLBCL) histology (PT-DLBCL) with an activated B-cell-like (ABC) gene expression profile. These...Primary testicular lymphoma (PTL) is a rare extranodal lymphoma. The majority of cases are of diffuse large B cell lymphoma (DLBCL) histology (PT-DLBCL) with an activated B-cell-like (ABC) gene expression profile. These are characterised clinically by a high risk of contralateral testis and central nervous system (CNS) relapse, representing an ongoing area of unmet clinical need. Here, we review the epidemiology, clinical presentation and diagnostic evaluation of PT-DLBCL along with the advances in molecular biology that have occurred in the last decade, concerning the now-recognised molecular subtypes of DLBCL and their role of immune escape and sustained signalling in disease pathophysiology. We also appraise the retrospective and prospective clinical trials underpinning modern treatment recommendations, including the updated guidance on the role of radiotherapy and the latest evidence regarding strategies for preventing CNS relapse.
Xiong X, Zhang S, Du J
… +6 more, Liao X, Yang J, Zheng W, Xu H, Yang L, Wei Q
Cancer Treat Rev
· 2025 May · PMID 40215591
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Despite therapeutic advances, prostate cancer remains lethal for most patients. Accelerated development of novel therapies requires validated surrogate endpoints to circumvent prolonged survival follow-up in phase III tr...Despite therapeutic advances, prostate cancer remains lethal for most patients. Accelerated development of novel therapies requires validated surrogate endpoints to circumvent prolonged survival follow-up in phase III trials. This review systematically evaluates intermediate clinical endpoints (ICEs) in prostate cancer to establish methodologically robust alternatives to overall survival (OS). We first synthesized methodological standards for ICE validation. Subsequent analysis encompassed phase III trials (PubMed/Web of Science, Jan. 2025) in metastatic castration-sensitive (mCSPC) and -resistant prostate cancer (mCRPC), requiring: randomization, therapeutic intervention, OS as primary/co-primary endpoint, ≥1 ICE (radiographic progression-free survival (rPFS), milestone survival), and ≥70 participants. Surrogacy was quantified via two-stage meta-analysis, with R ≥ 0.7 defining validity. Metastasis-free survival (MFS) is validated for localized disease, enabling trial endpoint substitution. In advanced stages, evidence for ICEs remains critically deficient. Our analysis identifies milestone survival as a promising ICE candidate in mCSPC and mCRPC, demonstrating strong trial-level correlation with OS. Current ICE validation in prostate cancer is disproportionately focused on localized disease, leaving advanced-stage therapeutic development constrained. While milestone survival shows surrogacy potential, endpoint validation remains methodologically challenging even in rigorously designed trials. This work underscores the imperative to accelerate ICE standardization through unified methodological frameworks and collaborative cross-trial analyses.
Alonso-Gordoa T, Anguera G, Domínguez-Esteban M
… +5 more, Reig Ò, Martínez-Barros H, Molina-Cerrillo J, Cruz P, Maroto P
Cancer Treat Rev
· 2025 May · PMID 40186886
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Immunotherapy has changed the management of localized clear cell renal cell carcinoma (ccRCC) since the approval of adjuvant pembrolizumab, which demonstrated significant improvements in disease-free survival (DFS) and o...Immunotherapy has changed the management of localized clear cell renal cell carcinoma (ccRCC) since the approval of adjuvant pembrolizumab, which demonstrated significant improvements in disease-free survival (DFS) and overall survival (OS) in patients at intermediate and high risk of recurrence. This new approach impacts rescue strategies in patients who relapse after local treatment and during or after adjuvant pembrolizumab. Nevertheless, there is currently no robust scientific evidence on therapeutic decision-making in this clinical situation, representing an area for further debate and research. In this article, a group of experts from the Genitourinary Alliance for Research and Development (GUARD) have reviewed the available scientific evidence to establish the basis for therapeutic decision-making in patients with ccRCC who progress after adjuvant treatment with immunotherapy. Despite the lack of randomized clinical trials in this setting, this group of experts recommends classifying patients according to relapse volume (oligometastatic vs. polymetastatic), time to relapse and certain molecular characteristics. Rescue treatments beyond relapse should be individualized and might include locoregional treatments such as surgery or radiotherapy as well as antiangiogenic therapies in patients defined as resistant to immunotherapy.
Bregni G, Adams R, Bale R
… +48 more, Bali MA, Bargellini I, Blomqvist L, Brown G, Cremolini C, Demetter P, Denecke T, Dohan A, Dopazo C, Elez E, Evrard S, Feakins R, Guckenberger M, Guren MG, Hawkins M, Hoorens A, Huguet E, Intven M, Koessler T, Kunz WG, Lordick F, Lucidi V, Mahnken AH, Malik H, Martinive P, Mauer M, Romero AM, Nagtegaal I, Orsi F, Oyen WJ, Pellerin O, Rengo M, Ricke J, Ricoeur A, Riddell A, Ronot M, Scorsetti M, Seligmann J, Sempoux C, Sheahan K, Stättner S, Svrcek M, Taieb J, West N, Wyrwicz L, Zech CJ, Moehler M, Sclafani F
Cancer Treat Rev
· 2025 May · PMID 40179590
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Patients with colorectal cancer liver metastases have long represented a unique and thoroughly investigated population. Nevertheless, the optimal management of these is still controversial with a number of open questions...Patients with colorectal cancer liver metastases have long represented a unique and thoroughly investigated population. Nevertheless, the optimal management of these is still controversial with a number of open questions which are only partially addressed by available studies and existing guidelines. The European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Group (GITCG) sought to fill this knowledge gap and promoted the development of a European consensus on this subject. By using the Delphi methodology and leveraging a multidisciplinary team of 43 international experts, including gastrointestinal oncologists, hepatobiliary surgeons, interventional radiologists, radiation oncologists, radiologists, nuclear medicine physicians and pathologists from 12 European countries, 34 practical recommendations and two consensus statements were proposed. These cover varying aspects of the optimal management of colorectal cancer liver metastases such as baseline imaging, selection criteria for liver-directed therapies, treatment strategies, assessment of treatment response, follow-up, care delivery, clinical research and future perspectives. This roadmap document is intended to complement national and international guidelines, and to provide practical guidance for clinicians and multidisciplinary teams, ultimately promoting practice standardisation, optimal management and better patient outcomes across Europe. Also, it provides a unique opportunity to highlight grey areas and unmet needs, and to give a strategic direction to future research in the field by identifying topics where there is no consensus among experts.
Antibody-drug conjugates (ADCs) are a rising therapeutic class in oncology and hematology, with eleven drugs approved by the US Food and Drug Administration as of January 2025. These "magic bullets" have a complex struct...Antibody-drug conjugates (ADCs) are a rising therapeutic class in oncology and hematology, with eleven drugs approved by the US Food and Drug Administration as of January 2025. These "magic bullets" have a complex structure, including a monoclonal antibody, a linker, attachment sites, and a payload usually disrupting microtubules, targeting DNA, or inhibiting topoisomerase 1. By targeting specific tumor antigens, they are expected to be exquisitely effective in releasing "supertoxic" payloads inside tumor cells after intracellular trafficking. Additionally, they may exert a bystander effect, wherein the released payloads act on neighboring cells, amplifying their therapeutic impact regardless of target expression. ADCs have been game-changing drugs to treat tumors with once dismal prognoses or with previously considered unactionable targets, such as HER2-low or triple-negative breast cancer. To what extent there is room for personalized medicine to improve the toxicity/efficacy ratio remains unknown. However, there are inherent issues related to the complexity of the pharmacokinetics of ADCs and their assessments: efficacy or toxicity may be influenced by the clearance of the intact ADC, the circulating payload, or the payload-linker complex. Deciphering these multifaceted exposure-outcomes relationships for both efficacy and safety endpoints, is critical for advancing precision medicine and enabling personalized dosing strategies. To improve future developments and broaden their therapeutic scope, several strategies can be developed, including developing adequate combinations with other treatment classes (cytotoxic agents, immune-checkpoint inhibitors, oral molecular-targeted therapies). In this review, we will discuss the PK/PD aspects of ADCs and their dosing to improve their use in current and future indications.
Almuradova E, Izzo D, Gandini S
… +6 more, Gaeta A, Giordano E, Valenza C, Antonarelli G, Trapani D, Curigliano G
Cancer Treat Rev
· 2025 May · PMID 40157116
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Dose optimization in Phase I oncology trials balances therapeutic efficacy and patient safety. Traditional dose-escalation methods, such as the 3 + 3 design, primarily focus on safety, often resulting in prolonged exposu...Dose optimization in Phase I oncology trials balances therapeutic efficacy and patient safety. Traditional dose-escalation methods, such as the 3 + 3 design, primarily focus on safety, often resulting in prolonged exposure to subtherapeutic or excessively toxic doses. Additionally, these methods may fail to account for modern therapies' complex pharmacokinetics and pharmacodynamics, including targeted agents and immunotherapies. Contemporary approaches address these gaps by incorporating biomarkers, pharmacokinetic profiling, and patient-reported outcomes to guide personalized dosing strategies. Such methods improve the precision of dose selection and promote individualized cancer care. This review underscores the importance of distinguishing between dose-finding and dose optimization, advocating for designs that integrate patient perspectives and pharmacologic insights from early-phase trials. Additionally, we highlight the challenges of traditional methodologies and the importance of simplifying complex designs without compromising their scientific rigor. By embracing innovative approaches and patient-centered metrics, Phase I trials can evolve beyond safety assessments to expedite the delivery of effective and tailored cancer therapies.
The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is the standard first-line treatment for hormone receptor-positive (HR + ) and HER2-negative metastatic breast cancer (mBC)....The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is the standard first-line treatment for hormone receptor-positive (HR + ) and HER2-negative metastatic breast cancer (mBC). Despite their efficacy, resistance inevitably develops, necessitating alternative therapeutic strategies post-progression. This review explores current and emerging treatment options following progression on CDK4/6i, focusing on endocrine therapies, targeted therapies, combination approaches, and the continued use of CDK4/6i. Endocrine therapies, including fulvestrant and novel oral selective estrogen receptor degraders (SERDs) like elacestrant, show promise, especially in patients with ESR1 mutations. Targeted therapies such as PI3K/AKT/mTOR inhibitors, exemplified by alpelisib and capivasertib, offer potential by addressing downstream signaling pathways involved in resistance. Additionally, FGFR inhibitors like erdafitinib are under investigation for their role in overcoming specific resistance mechanisms. Combination strategies involving CDK4/6 inhibitors with immune checkpoint inhibitors or other targeted agents are also being explored, with early trials suggesting possible synergistic effects, although further validation is required. Continuation of CDK4/6 inhibitors beyond progression has shown potential benefits in selected patients, but the data are heterogeneous, and further studies are needed to clarify their role. While chemotherapy remains a standard option for patients who progress on these treatments, the goal is to delay its use through the effective utilization of endocrine and targeted therapies. Understanding resistance mechanisms and tailoring treatment to individual patient profiles is crucial for optimizing outcomes. Ongoing clinical trials are expected to provide deeper insights, guiding the development of more effective post-progression therapeutic strategies. This evolving landscape highlights the need for continuous research and individualized patient care to improve survival and quality of life in HR + mBC patients.
AIMS: The primary objective was to assess the impact of HER2 loss after neoadjuvant therapy on the long-term prognosis of patients with HER2-positive breast cancer. METHODS: We extracted relevant studies from PubMed and...AIMS: The primary objective was to assess the impact of HER2 loss after neoadjuvant therapy on the long-term prognosis of patients with HER2-positive breast cancer. METHODS: We extracted relevant studies from PubMed and Cochrane Library and performed systematic review and meta-analysis. The key eligibility criteria for the studies were as follows: included HER2-positive early breast cancer cases undergoing neoadjuvant therapy, available data on HER2 status before and after neoadjuvant therapy, and reported recurrence-related outcomes (disease-free survival/invasive disease-free survival/relapse-free survival) or overall survival. RESULTS: Of 915 studies that were initially identified, 8 met the eligibility criteria and were included in the meta-analysis for the recurrence-related outcomes (1,917 patients with HER2 loss: 411 [21.4 %] or HER2 retained: 1,506 [78.6 %]); 4 of them reported data on overall survival (606 patients with HER2 loss: 243 [40.1 %] or HER2 retained: 363 [59.9 %]). The average follow-up duration, based on data from five out of eight studies that reported this information, was 51.6 months. HER2 loss was significantly associated with worse recurrence-related outcomes (hazards ratio [HR] 1.85, 95 % confidence interval [CI] 1.31-2.61, p = 0.0005) and worse overall survival (HR 2.37, 95 % CI 1.27-4.41, p = 0.0065). No heterogeneity or publication bias was observed in the meta-analysis. CONCLUSIONS: This study demonstrated that compared with patients with HER2 retained, those with HER2 loss had significantly higher risk of disease recurrence and worse prognosis. These findings implied the possible use of HER2 loss as a prognostic factor in patients with HER2-positive early breast cancer. Reassessment of HER2 status after neoadjuvant therapy could be valuable in predicting prognosis and may lead to reconsideration of the rational subsequent treatment.
INTRODUCTION: Locally advanced cervical carcinoma (LACC) remains a significant global health issue, particularly in low- and middle-income countries (LMICs), where disease burden is highest. While cisplatin-based chemora...INTRODUCTION: Locally advanced cervical carcinoma (LACC) remains a significant global health issue, particularly in low- and middle-income countries (LMICs), where disease burden is highest. While cisplatin-based chemoradiotherapy (CTRT) has long been the cornerstone of first-line treatment, its toxicities, including nephrotoxicity and hematologic adverse events, limit its use in certain patients. Advances in systemic therapies, including immune checkpoint inhibitors and induction chemotherapy, offer new avenues for improving outcomes. This study aimed to evaluate the efficacy of various first-line regimens for LACC through a systematic review and Bayesian network meta-analysis (NMA), focusing on overall survival (OS) and progression-free survival (PFS). MATERIALS AND METHODS: This analysis adhered to PRISMA guidelines and included Phase III randomized controlled trials (RCTs) evaluating first-line treatments for LACC. The primary outcome was OS, expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), while PFS was secondary. A comprehensive search of PubMed, EMBASE, and Cochrane Library was conducted through November 2024. Statistical analysis used a Bayesian NMA framework, with treatments ranked by surface under the cumulative ranking curve (SUCRA). RESULTS: Pembrolizumab + CTRT improved OS (HR, 0.67; 95 % CI, 0.50-0.90), while induction chemotherapy with carboplatin/paclitaxel followed by CTRT showed significant benefit (HR, 0.60; 95 % CI, 0.40-0.90). RT + cisplatin and 5-fluorouracil (5-FU) also improved OS (HR, 0.66; 95 % CI, 0.44-0.99), ranking highest in SUCRA analysis (98 %). CONCLUSION: Three promising strategies-pembrolizumab-based regimens, induction chemotherapy followed by CTRT, and RT + CDDP + 5-FU-offer substantial survival benefits, advancing treatment options for LACC.
Delcuratolo MD, Crespi V, Saba G
… +13 more, Mogavero A, Napoli VM, Garbo E, Cani M, Ungaro A, Reale ML, Merlini A, Capelletto E, Bironzo P, Levis M, Ricardi U, Novello S, Passiglia F
Despite PACIFIC set a new milestone in the clinical management of unresectable stage III non-small cell lung cancer (NSCLC), it left some critical questions pending for clinical research: the efficacy of durvalumab in th...Despite PACIFIC set a new milestone in the clinical management of unresectable stage III non-small cell lung cancer (NSCLC), it left some critical questions pending for clinical research: the efficacy of durvalumab in the real-world setting; the activity of less intensive regimens for frail populations; the role of targeted therapies in oncogene-addicted tumors; the selection of subsequent strategies at immunotherapy failure; the efficacy of novel and intensified treatments; the role of molecular biomarkers for patients' selection. This review aims to describe the evolving landscape of unresectable stage III NSCLC and provides an updated overview of the available evidence, analyzing lights and shadows emerging from recent clinical trials and discussing the most relevant challenges of post-PACIFIC era.
Treatment options for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have evolved over the past decade and have helped improve survival outcomes for patients. Most nati...Treatment options for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have evolved over the past decade and have helped improve survival outcomes for patients. Most national and regional guidelines recommend first-line therapy with an immune checkpoint inhibitor (with or without chemotherapy) or a cetuximab-based regimen, by assessment of expression levels of the biomarker programmed cell death-ligand 1 (PD-L1). However, patient- and tumor-specific factors, including the patient's age, comorbidities, performance status, and tumor burden, kinetics and spread also need to be considered to optimize treatment in the first line. Additionally, with increasing availability of newer therapies globally, it is crucial to customize the subsequent second- or later-line therapy based on patient characteristics, including the previous therapy received. This review highlights the factors that should be considered for treatment decision-making in patients with R/M SCCHN. It also summarizes the current evidence for clinical outcomes based on treatment sequencing and provides guidance on choosing an optimal treatment regimen for patients in the first-line treatment setting and beyond.
Galli E, Patelli G, Villa F
… +11 more, Gri N, Mazzarelli C, Mangoni I, Sgrazzutti C, Ghezzi S, Sartore-Bianchi A, Belli LS, De Carlis L, Vanzulli A, Siena S, Bencardino K
BACKGROUND: Relapse after radical treatment remains a major concern in hepatocellular carcinoma (HCC), affecting 50-75 % of early-stage cases within 5 years. Early recurrence prediction is a clinical unmet need. Circulat...BACKGROUND: Relapse after radical treatment remains a major concern in hepatocellular carcinoma (HCC), affecting 50-75 % of early-stage cases within 5 years. Early recurrence prediction is a clinical unmet need. Circulating blood biomarkers could provide a minimally invasive approach to detect minimal residual disease (MRD) post-intervention. Although alpha-fetoprotein has been the primary biomarker in this setting, its MRD sensitivity is limited to 50-70 %. This systematic review aims to summarize available evidence regarding the clinical validity and potential utility of emerging circulating blood biomarkers for MRD detection in HCC patients. METHODS: We searched PubMed and Embase for peer-reviewed articles and abstracts published up to 2025, and ClinicalTrials.gov for ongoing trials on circulating blood biomarkers for MRD in HCC. RESULTS: A total of 91 studies (74 with results and 17 ongoing, out of 2,386) were retrieved. We evaluated various blood biomarkers, including circulating DNA (cDNA, N = 24), circulating tumor cells (CTCs, N = 20), circulating RNA (cRNA, N = 8), and other miscellaneous (N = 22) for MRD detection in HCC. These biomarkers demonstrated encouraging results, albeit with notable heterogeneity. In particular, circulating tumor DNA (ctDNA) and CTCs stand as the most robust novel approaches, with 50-80 % sensitivity and specificity up to 94 %. Nonetheless, none of the 17 ongoing studies involve biomarker-driven intervention to prove clinical utility. CONCLUSIONS: Novel circulating blood biomarkers are mature for MRD detection in HCC. However, variability in methodologies and results highlights the need for further validation. We encourage the investigation of CTCs and/or ctDNA in interventional trials to assess clinical utility. This biomarker-driven approach may enhance adjuvant treatment effectiveness in MRD-positive cases while minimizing toxicity in MRD-negative patients.
BACKGROUND: The implementation of patient-reported outcome measures (PROMs) in the clinical identification of immunotherapy toxicities is a complex intervention. There has been very little work evaluating the clinical ut...BACKGROUND: The implementation of patient-reported outcome measures (PROMs) in the clinical identification of immunotherapy toxicities is a complex intervention. There has been very little work evaluating the clinical utility and generalisability of PROMs used after immune checkpoint inhibitor (ICI) treatment to date. We reviewed evidence on the use of PROMs assessing toxicities and health-related quality of life in patients treated with ICIs. METHODS: PubMed, EMBASE, MEDLINE, PsycInfo, CINAHL, Web of Knowledge, the Cochrane Library were searched (January 2008 - October 2024). Quantitative studies reporting the use of PROMs to identify, assess and manage toxicities at any timepoint and HRQoL associated with ICI treatment in adult patients with cancer were included. A narrative synthesis describes the key characteristics of the PROMs identified. RESULTS: 43 studies were included; 12 on melanoma/skin, 12 on lung and 19 on other cancers. Study designs included 20 randomised controlled trials, 14 cohort studies, six cross-sectional studies and three non-randomised interventional trials. The lack of ICI-specific PROMs was highlighted, particularly as the PROMs used lacked sufficient sensitivity for ICI treatments. CONCLUSIONS: There is need for an ICI-specific PROM for effective assessment of toxicities and a tailored PROM for assessment of HRQoL. Some suggested key domains by certain studies for ICI-specific PROMs include: (a) ICI-specific items (e.g. certain USD-I and PRO-CTCAE items) to capture symptoms associated with ICI treatments such as rash, myalgia, (b) role, psychological, emotional and social functioning domains within HRQoL assessments and (c) additional patient-reported toxicities not included in existing PROMs. Findings emphasize the importance of using a disease-specific PROM that is applicable, acceptable and sufficiently sensitive to identify toxicities and HRQoL issues across all stages.