Japanese journal of clinical oncology最新文献

Background: Germline pathogenic variants (GPVs) in cancer predisposition genes increase cancer risk, but their population-level prevalence in Japan remains unclear.

Aim: To estimate the prevalence of GPV carriers of hereditary cancer predisposition syndromes (HCPSs) in the Japanese population.

Data source and methods: A cross-sectional analysis of the Tohoku Medical Megabank Organization datasets was conducted to assess allele frequencies of rare GPVs, estimate carrier prevalence, and describe variant distribution.

Results: The cumulative allele frequency of rare GPVs of cancer predisposing genes was 1.47% for autosomal dominant and 3.20% for autosomal recessive diseases. The estimated prevalence of GPV carriers was 2.90% (1 in 35 individuals) and 0.10% (1 in 977 individuals) for autosomal dominant HCPSs and autosomal recessive HCPSs, respectively; ~6.19% of the population (1 in 16 individuals) were carriers. Variant types differed across genes, and hotspot variants had a significant impact on allele frequencies. Moreover, 47 structural variants (0.28%) having the potential to cause structural disruption were identified.

Conclusions: Allele frequency analysis of rare GPVs of cancer predisposition genes offered valuable insight into the prevalence of GPV carriers of HCPSs in the Japanese population. Hotspot variants may represent founder mutations within specific ethnic groups, and their presence or absence could affect gene-specific allele frequencies.

Purpose: To identify independent prognostic factors for recurrence and develop a practical risk stratification system in patients with clinical T1 (cT1) clear-cell renal cell carcinoma (ccRCC) following curative-intent surgery.

Methods: This retrospective multi-institutional study analyzed 1081 consecutive patients with cT1N0M0 ccRCC who underwent partial or radical nephrectomy at 14 Japanese tertiary centers (2016-21). We evaluated six established prognostic factors based on prior literature: pathological T3 upstaging, tumor size, nuclear grade, tumor necrosis, surgical approach, and venous invasion. Cox proportional hazards regression was performed to identify independent predictors of recurrence-free survival.

Results: During a median follow-up of 48 months, 66 patients (6.1%) developed recurrence. Multivariable Cox regression identified two independent prognostic factors: pathological T3 upstaging (HR 4.67, 95% CI 2.40-9.08, P <.001) and tumor necrosis (HR 2.51, 95% CI 1.22-5.13, P = .012). Tumor size showed borderline significance (HR 1.22 per cm, 95% CI 1.00-1.49, P = .055). Based on the significant factors, patients were stratified into low-risk (91.1%, no upstaging/necrosis) and high-risk (8.9%, upstaging or necrosis present) groups with recurrence rates of 4.3% and 25.0%, respectively (log-rank P <.001). The 5-year recurrence-free survival rates were 95.2% and 73.4% for low- and high-risk groups, respectively.

Conclusions: Pathological T3 upstaging and tumor necrosis were identified as the only independent predictors of recurrence in cT1 ccRCC. This simplified two-tier risk stratification effectively distinguishes a small high-risk subset (9% of patients) with 25% recurrence rate from the low-risk majority, enabling tailored surveillance strategies and appropriate selection for adjuvant therapy trials.

Nuclear protein in testis (NUT) carcinoma is an extremely rare and aggressive malignancy characterized by NUTM1 gene rearrangement. It frequently develops in the lungs or the head and neck region as a poorly differentiated squamous cell carcinoma. The prognosis is generally poor and particularly dismal in cases with a pulmonary origin. Given the lack of an established standard treatment and the rapid disease progression, recently, immune checkpoint inhibitors (ICIs) have attracted attention, particularly in combination with platinum-based chemotherapy. We report a case series of four patients with pulmonary NUT carcinoma who received ICI-containing regimens as first-line therapy. Three patients received ICIs in combination with platinum-based chemotherapy and showed transient tumor shrinkage, although all ultimately experienced disease progression and died. One patient received ICI monotherapy owing to poor performance status and showed no clinical response. The median progression-free and overall survival were 53 and 108 days, respectively. Given the limited treatment options for NUT carcinoma, a combination of ICIs with platinum-based chemotherapy may represent a potential first-line treatment option. However, their efficacy remains limited.

Radical lobectomy, proposed as a curative treatment for lung cancer in 1960, has long been regarded as the standard surgical approach. The findings of two phase III randomized controlled trials comparing limited resection versus lobectomy for non-small cell lung cancer (NSCLC) ≤2 cm have challenged the long-standing evidence supporting lobectomy as the universal surgical option for all patients with lung cancer. The Japanese clinical oncology group (JCOG) and West Japan Oncology Group (WJOG) (JCOG0802/WJOG4607L) demonstrated both the non-inferiority and superiority of segmentectomy, while the Cancer and Leukemia Group B trial (CALGB140503) conducted by the Alliance for Clinical Trials in Oncology in North America, confirmed the non-inferiority of limited resection, including wedge resection for NSCLC measuring ≤2 cm. As both trials demonstrated non-inferiority of limited resection in NSCLC ≤2 cm, their results are often summarized together. However, patient background, radiological findings, prognosis, and extent of resection differ significantly between the two trials and should be interpreted with caution. Previous trials have demonstrated that preserving lung parenchyma helps maintain pulmonary function and improves patient prognosis by enabling appropriate management of subsequent malignancy or other diseases. Limited resection, including segmentectomy, is currently the standard of care for early-stage NSCLC. The JCOG and WJOG are conducting trials to determine whether the indications for limited resection can be expanded to include patients with NSCLC >2 cm or those with stage I NSCLC. This review article outlines the results of previous trials, provides an overview of ongoing trials, and discusses prospects for limited resection.

Objective: Definitive chemoradiotherapy (CRT) is a treatment strategy for localized esophageal squamous cell carcinoma (ESCC). Herein, we aimed to evaluate clinical outcomes of definitive CRT for ESCC.

Methods: We reviewed 127 patients who received definitive CRT for localized ESCC at our institution between January 2004 and December 2022. All patients received elective nodal irradiation with concurrent chemotherapy, primarily comprising cisplatin and 5-fluorouracil, during radiotherapy. Seventeen patients (13%) received intensity-modulated radiation therapy (IMRT) only, and 16 patients (13%) were treated with IMRT as a boost. The median total dose was 61.4 Gy. Approximately 80% of the patients had clinical stage III or higher disease. We analyzed overall survival (OS), progression-free survival (PFS), locoregional recurrence rate (LRR), prognostic factors, and adverse events.

Results: The median follow-up period was 13 months for all patients and 22 months for survivors. The 2-year OS, PFS, and LRR were 40.4%, 27.1%, and 30.8%, respectively. The overall complete response rate was 40.2%. On multivariate analysis, clinical stage 0-III (non-T4) (P < .001) and the use of IMRT (P = .034) were significantly associated with better OS. Pulmonary toxicity was significantly lower in the IMRT group (P = .049).

Conclusions: IMRT for localized ESCC may improve prognosis and reduce pulmonary toxicity.

Background: The Geriatric-8 (G8) is used for the functional status of older adult patients with cancer. However, its role in treatment decision-making for gynecological malignancies has not been established.

Methods: We retrospectively analyzed the data of 180 women aged ≥75 years with gynecological malignancies who underwent initial treatment at our institution between January 2019 and December 2023. Pre-treatment G8 scores were assessed and patients were categorized as fit (G8 > 14) or frail (G8 ≤ 14). Associations between the G8 score and patient background, disease characteristics, treatment options, and treatment tolerability were examined.

Results: Of the 180 women, 53 (29.4%) were classified as fit and 127 (70.6%) as frail. Frail patients required long-term care (P = .008) and used anticoagulants more frequently than fit patients (P = .019). Median G8 scores were highest in endometrial cancer (14) and lowest in vulvar cancer (10). Best supportive care (8) and neoadjuvant chemotherapy (10) had lower G8 scores than surgery and concurrent chemoradiotherapy (14) (P < .001). Postoperative complications occurred in 10/96 surgical cases; these cases had lower scores than those without complications (12 vs. 14, P = .044). During chemotherapy, median scores were lower in women with ≥ grade 3 (12 vs. 14, P = .008) and grade ≥ 4 adverse events (10 vs. 14, P = .002).

Conclusions: The G8 score is associated with patient background, cancer type, and treatment options, and is associated with treatment tolerability in women aged ≥75 years with gynecological malignancies.

Background: Efficacy of available treatments for liposarcoma (LPS), including dedifferentiated liposarcoma (DDLPS) is limited, and detailed real-world clinical data for patients with LPS treated in Japan are scarce. We used the MASTER KEY Registry Database to evaluate the clinical characteristics and outcomes of patients with advanced/metastatic LPS treated with systemic antineoplastic therapy in Japan.

Methods: This non-interventional/observational cohort study included patients with LPS, including DDLPS, and well-differentiated LPS (WDLPS), and a history of systemic antineoplastic therapy, enrolled in the MASTER KEY Project Registry Database from 1 May 2017 to 31 December 2022. Outcomes were analysed by type of treatment. Primary outcomes: progression-free survival (PFS); overall survival (OS). Secondary outcomes: overall response rate; disease control rate. Sensitivity analyses (prospective registry subgroup) were performed to minimize immortal time bias.

Results: Since 2017, 100 patients with LPS were prospectively enrolled in the database; of these, 62 had DDLPS and 11 had WDLPS. In patients with LPS, median PFS was 11.1 months after first-line (1 L) pharmacotherapy and 6.9 months after 1 L doxorubicin. In patients with DDLPS, median PFS was 6.9 months after 1 L pharmacotherapy and 4.4 months after 1 L doxorubicin. Median OS after 1 L pharmacotherapy was 45.8 months in patients with LPS, and 40.7 months in those with DDLPS. Median OS in the sensitivity analysis was not reached for patients with LPS and was 13.9 months for the DDLPS subgroup.

Conclusions: These data investigating DDLPS in Japanese patients highlight the poor outcomes and lack of effective treatment options in the real-world clinical practice setting.

RNA therapeutics, including antisense oligonucleotides (ASOs), have emerged as a promising class of drugs, with several already approved for clinical use. To date, most approved ASO-based RNA therapies target non-malignant disorders such as neurodegenerative diseases, and only a single therapy in this class has been approved for cancer. Notably, nearly half of existing RNA therapeutics act by modulating RNA splicing. Given the growing evidence implicating aberrant RNA splicing in cancer pathogenesis, the development of ASO-based therapeutics for oncologic indications is expected to accelerate. More than 250 clinical trials have evaluated oligonucleotide agents targeting diverse cancer-associated molecules, with several showing encouraging early results. In this review, we summarize recent advances in understanding cancer biology relevant to ASO-based therapies and highlight ongoing progress in the development of RNA-targeted approaches for cancer treatment.

Background: Total gastrectomy (TG) is commonly performed as the standard treatment for upper third advanced gastric cancer (AGC). Proximal gastrectomy (PG) may be a potential alternative procedure for upper-third AGC. However, its oncologic safety remains uncertain. This study aimed to compare the long-term outcomes of PG and TG for upper-third AGC and to evaluate the oncological safety of PG.

Methods: We retrospectively analyzed the data of patients who underwent PG or TG for clinical T2-T4aNanyM0 upper-third gastric cancer at six institutions between 2018 and 2022. To minimize selection bias, propensity score matching (PSM) was performed at a 1:1 ratio. The primary endpoint was overall survival (OS).

Results: A total of 208 patients with upper-third AGC were included. After PSM, 104 patients were selected for analysis, with 52 patients in each group. The 3-year OS rates were 81.8% in the PG group and 70.8% in the TG group, with no statistically significant difference between the two groups (P = .167), with a hazard ratio for PG of 0.58 (95% confidence interval, 0.27-1.27; P = .173). Subgroup analysis revealed that the hazard ratio for OS was significantly lower in the PG group than in the TG group among patients with tumor diameters <50 mm.

Conclusions: The long-term survival outcomes of PG and TG for upper-third AGC patients are comparable, suggesting that PG may be an oncologically acceptable option in carefully selected patients.

Background: Triplet therapy with darolutamide, androgen deprivation therapy, and docetaxel (DOC) has emerged as an intensified treatment option for metastatic castration-sensitive prostate cancer (mCSPC). This study evaluated real-world prostate specific antigen (PSA) responses and adverse events (AEs) associated with triplet therapy, with a focus on age-specific differences.

Methods: We performed a retrospective cohort study across six academic institutions in Japan between February 2023 and February 2025. A total of 137 patients with mCSPC who received triplet therapy were analyzed. PSA responses and AEs were assessed, including subgroup analyses by age (<75 vs ≥75 years).

Results: The median age was 71 years, and 40 patients (29.2%) were aged ≥75 years. Six cycles of DOC were completed at similar rates in patients aged <75 years (66.0%) and ≥ 75 years (57.5%) (P = .435). The median baseline PSA was 298 ng/ml, and 107 patients (78.1%) met the CHAARTED high-volume criteria. At three months, the median [interquartile range] PSA decline was 99.8% [99.0-99.9]; 113 patients (92.6%) achieved a PSA decline >90%, and 35 patients (28.7%) achieved a PSA <0.2 ng/ml. During follow-up, the proportion achieving a PSA nadir <0.2 ng/ml did not differ significantly between patients aged <75 years (63.9%) and ≥ 75 years (55.0%) (P = .341). Grade ≥ 3 AEs occurred in 56 patients (40.9%), including febrile neutropenia in 29 patients (21.2%). The incidence of AEs did not differ significantly by age.

Conclusions: In this real-world cohort, triplet therapy showed substantial PSA declines and acceptable tolerability, with no significant differences in short-term efficacy or safety between patients aged <75 and ≥ 75 years. These findings suggest that chronological age alone should not preclude consideration of triplet therapy in appropriately selected patients.