Japanese journal of clinical oncology最新文献

Objective: To identify pretreatment factors associated with developing primary resistance to nivolumab plus ipilimumab therapy in patients with advanced renal cell carcinoma (RCC).

Methods: We retrospectively reviewed the clinical characteristics, laboratory data, and tumor-related factors in patients with advanced RCC who initiated nivolumab plus ipilimumab as first-line therapy between January 2018 and July 2021. Primary resistance was defined as radiographic or clinical progression within 3 months of treatment initiation. Cases with suspected pseudoprogression were excluded.

Results: Eighty-nine patients met the inclusion criteria; 23 exhibited primary resistance. Univariate analysis identified the following significant predictive factors: body mass index (P = .006), lymph node metastasis (P = .021), sarcomatoid differentiation (P = .035), solitary metastatic organ (P = .051), liver metastasis (P = .056), and serum lactate dehydrogenase (LDH) (P = .094). Receiver operating characteristic curve analysis determined an LDH cutoff value of 174 U/L, which was significantly associated with primary resistance (P = .029). Considering the number of primary resistance cases, multivariable analysis incorporated three candidate variables (lymph node metastasis, sarcomatoid differentiation, and LDH ≥ 174 U/L) and identified sarcomatoid differentiation (odds ratio, 4.264; 95% confidence interval (CI), 1.299-14.825; P = .017) and LDH ≥ 174 U/L (odds ratio, 3.634; 95% CI, 1.143-13.770; P = .028) as independent predictors of primary resistance.

Conclusions: Sarcomatoid differentiation on pretreatment biopsy or elevated serum LDH before treatment initiation may predict primary resistance to nivolumab plus ipilimumab therapy in patients with advanced RCC. Alternative regimens should be considered in such cases, particularly for patients who are likely to experience rapid disease progression or for whom the occurrence of P-res is not clinically acceptable.

Objective: Dasatinib was approved for treating pediatric patients with philadelphia chromosome-positive chronic myeloid leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia. While its efficacy has been proven, comprehensive safety data in pediatric populations remain limited. This study utilizes data from the food and drug administration adverse event reporting system (FAERS) to evaluate and characterize adverse events (AEs) reported in pediatric patients treated with dasatinib.

Methods: Data from the FAERS between 2014 Q1 and 2024 Q4 were analyzed. Disproportionality analysis was performed to identify AEs reported in pediatric patients treated with dasatinib.

Results: A total of 382 pediatric cases involving dasatinib were reported. The most frequent system organ classes included general disorders and administration site conditions, injury, poisoning, and procedural complications, and gastrointestinal disorders. Notably, previously unreported AEs such as hemorrhagic enterocolitis, lymphoid tissue hyperplasia, hydrocephalus, and hemorrhagic cystitis were identified, raising potential new safety concerns. Additionally, instances of off-label use were observed, particularly in regions where dasatinib is not recommended for pediatric patients, underscoring the importance of vigilant AEs monitoring to ensure patient safety.

Conclusion: This study highlights the need for enhanced pharmacovigilance and proactive monitoring in pediatric patients receiving dasatinib to ensure treatment safety and improve clinical outcomes, and provides supporting evidence for the safe use of dasatinib in pediatric populations.

Postmastectomy radiation Therapy (PMRT) reduces locoregional recurrence (LRR) and breast cancer mortality in patients with ≥4 positive lymph nodes. However, evidence supporting PMRT in patients with 1-3 positive nodes remains limited. While the 2014 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis demonstrated benefit in this population, the constituent trials preceded current standard practices including sentinel lymph node biopsy, contemporary systemic therapies, and modern radiation therapy techniques. This analysis examines the applicability of EBCTCG findings to current clinical practice. Historical trials reported elevated LRR rates, potentially attributable to inadequate axillary staging and suboptimal systemic therapy regimens such as cyclophosphamide, methotrexate, and fluorouracil. Contemporary studies demonstrate substantially lower LRR rates in comparable patients managed without PMRT, particularly those with favorable tumor characteristics. Current adjuvant therapies-including anthracyclines, taxanes, trastuzumab, endocrine agents, and targeted therapies such as abemaciclib and olaparib-have markedly reduced recurrence risk. Retrospective analyses yield conflicting results regarding PMRT efficacy, while randomized trials (SUPREMO, TAILOR RT) seek to refine treatment indications. Contemporary practice should not universally recommend PMRT for intermediate-risk patients (1-3 nodes); instead, individualized risk assessment is warranted. The role of PMRT remains undefined in patients without axillary lymph node dissection or those achieving pathologic complete response following neoadjuvant therapy. Clinical decision-making must consider treatment benefits relative to potential late toxicities and reconstructive complications. Personalized, evidence-based approaches informed by emerging trial data represent the optimal strategy for patient management.

Background: Ewing sarcoma (ES) is a malignant type of bone and soft tissue tumor with EWSR1-ETS gene fusions as the primary driver alteration. Incidence is higher in White populations compared to Black and Asian populations. Researchers use next-generation sequencing to identify alterations as potential therapeutic targets. We compared the data from the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets in the USA with the data from Center for Cancer Genomics and Advanced Therapeutics in Japan.

Methods: We sequenced tumor DNA from 81 ES samples using the FoundationOne® CDx for multigene panel testing. Genetic alterations were interpreted via the Cancer Knowledge Database (CKDB) and potentially actionable alterations were classified into levels A-F.

Results: Analysis of 81 ES samples revealed 556 mutations in 197 genes and 126 copy-number alterations in 58 genes. Potentially actionable alterations were detected in 10 patients (12.3%) at CKDB levels A or C. STAG2 mutations accounted for 3.7%, TP53 mutations for 17.3%, and CDKN2A deletions for 13.6%. There was no significant difference in overall survival after genomic profiling test enrollment for STAG2 and TP53 mutations (P = .663 and P = .767), but those with CDKN2A and CDKN2B deletions had poor prognosis (P = .024 and P = .012).

Conclusion: Compared to previous reports, Japanese ES cases showed lower STAG2 and higher TP53 mutation frequencies. CDKN2A and CDKN2B deletions may serve as prognostic biomarkers indicating unfavorable outcomes.

Background: The impact of the starting dose of tyrosine kinase inhibitors (TKIs) following combination therapy of immune checkpoint inhibitors with TKIs (i.e. IO-TKI) for advanced renal cell carcinoma (RCC) remains unclear.

Methods: We retrospectively evaluated clinical data from 155 patients treated with first-line IO-TKI for RCC. Patients were categorized into full-dose and reduced-dose groups based on their starting dose of TKIs. Effectiveness and safety profiles were compared between groups.

Results: A reduced starting dose was administered to 52 patients (34%). These patients were older (P = 0.0137) and received pembrolizumab plus axitinib more frequently, while lenvatinib plus pembrolizumab was less used (P = 0.0258) compared to the full-dose group. Progression-free survival and overall survival did not significantly differ between the full-dose and reduced-dose groups (P = 0.202 and P = 0.309, respectively). Although the objective response rate appeared higher in the full-dose group, the difference was not statistically significant after adjusting for other covariates (P = 0.0588). Safety profiles were comparable, with no significant differences in TKI dose reduction, drug interruption or discontinuation, or glucocorticoids use (P > 0.05). However, adverse events of grade ≥3 were more frequent in the full-dose group, although not statistically significant (P = 0.121).

Conclusion: The starting dose of TKIs did not significantly impact clinical outcomes following IO-TKI for RCC. These findings suggest a potential for the optimization of the starting dose of TKIs; however, prospective studies are warranted to confirm these findings.

The ARASENS trial demonstrated a significant overall survival (OS) benefit for a triplet regimen in metastatic castration-sensitive prostate cancer (mCSPC). We aimed to determine whether this benefit is synergistic or additive. Using a mathematical model of independent drug action and published data from the ARASENS and ARANOTE, we compared the observed OS of the triplet regimen to a predicted OS curve. Reconstructed individual patient data were compared using a Cox model. The observed OS was statistically superior to the predicted OS (hazard ratio [HR] 0.82, 95% CI 0.68-0.99; P = .047), indicating a clinical benefit ~18% greater than the expected additive effect. To address confounding by subsequent therapies, we analyzed time to initial subsequent anticancer therapy, which showed an even more pronounced greater-than-additive benefit (HR 0.57, 95% CI 0.44-0.74; P < .001). These findings suggest the triplet regimen provides an early therapeutic advantage that exceeds additive expectations, supporting an upfront combination strategy in mCSPC.

Objectives: This article aims to describe the newly developed Japanese practice guidelines for psychological distress of adult individuals with cancer who have elevated levels of psychological distress.

Methods: We conducted systematic reviews and Delphi consensus rounds to determine the levels of certainty of evidence and strength of recommendation.

Results: In our proposed flow of care, all individuals with cancer should initially be provided with general support, comprising supportive communication, detection of psychological distress, attendance to their needs, and differentiating physical conditions that mimic psychological distress. If a patient still has significant psychological distress despite such support, more specific care for psychological distress should be considered. Collaborative care has strong evidence base and is strongly recommended. Evidence for psychotherapy for psychological distress and fear of cancer recurrence is moderate to strong, however, recommendations for these interventions were weakened because of the heterogeneity of interventions and lack of formal training system. Evidence of pharmacotherapy was weak. Thus, anxiolytics are weakly recommended only for short term and should be accompanied with psychosocial support. Antidepressants are weakly recommended when a patient is diagnosed with depression. Early specialized palliative care, care for caregivers and peer support are not recommended as a sole means to alleviate psychological distress, due to the scarce supporting evidence. Provision of these interventions is not hindered when they aim to improve the outcomes other than psychological distress, such as quality of life, symptom burden and self-efficacy.

Discussion: New practice guidelines for psychological distress of adult individuals with cancer have been developed.

Background: Recent studies have demonstrated that patients with hematological malignancies (HM) exhibit significantly impaired humoral immune responses after coronavirus disease 2019 (COVID-19) vaccination. Although booster doses and cellular immune responses have been increasingly studied, few analyses have concurrently evaluated both humoral and cellular immunity in patients receiving bendamustine, bispecific antibodies, or CAR-T therapies. We aimed to assess the humoral immunogenicity, T-cell immune response, and booster effect after COVID-19 vaccination in patients with B-cell lymphoma undergoing immunochemotherapy or novel agent treatment.

Methods: Serum antibodies to the severe acute respiratory syndrome coronavirus 2 spike protein (S-IgG) were measured after the second and booster (third) mRNA vaccinations, and specific T-cell responses were measured using the enzyme-linked immunosorbent spot method.

Results: Forty-six of 114 patients (40%) acquired antibodies. Age < 65 years (odds ratio 8.99) and CD19 ≥ 50/μL (odds ratio 19.7) were independent predictors of response. To support the selection of this threshold, operating characteristic curve analysis was performed and confirmed CD19 ≥ 50/μL as a clinically meaningful discriminator despite a lower statistical cutoff. Even in some patients who did not develop antibodies, T-cell responses were observed (36% after two doses; 45.5% after the booster). The booster vaccine enhanced antibody (40% to 62.9%) and T-cell (47.2% to 57.6%) responses.

Conclusions: This study provides confirmatory real-world evidence that CD19 recovery is a key determinant of humoral response, while vaccine-induced T-cell immunity may be preserved even in antibody-nonresponders, supporting continued vaccination efforts in this high-risk population.

Background: Olfactory neuroblastoma (ONB) is a rare malignant tumor of the nasal cavity and paranasal sinuses. In this study, we aimed to analyze ONB cases registered in the nationwide Head and Neck Cancer Registry of Japan.

Methods: Among 90 885 head and neck cancer registrations (2011-19), we identified 346 patients with ONB. We summarized demographics, tumor-node-metastasis (TNM) classification, and treatment modalities (surgery, radiotherapy, chemotherapy) and compared patterns between an early (2011-15) and a late (2016-19) period. Survival was analyzed in 95 patients with standardized 5-year outcomes available.

Results: T4 lesions were frequent, and 234 patients (67.6%) received surgery-based treatment, typically combined with postoperative radiotherapy. Over time, endoscopic approaches increased markedly and became predominant over open skull base surgery. Among the 95 patients with evaluable follow-up, the 5-year overall survival (OS) and 5-year recurrence-free survival (RFS) were 85.1% and 62.7%, respectively. Patients <60 years old and female patients exhibited better OS compared to younger patients and males. Postoperative radiotherapy was associated with improved RFS but not OS. Chemotherapy was used more often with open skull base surgery than with other surgical approaches.

Conclusions: Endoscopic surgery for ONB rose substantially, while younger age and female sex were associated with better OS, and postoperative radiotherapy was correlated with improved RFS.