Japanese journal of clinical oncology最新文献

Background: Avelumab maintenance therapy is the standard treatment for locally advanced or metastatic urothelial carcinoma (mUC) demonstrating a response to platinum-based first-line therapy. Prognostic markers are necessary to predict the prognostic efficacy of avelumab therapy. This retrospective study investigated prognostic markers to optimize the efficacy of avelumab maintenance therapy.

Methods: This retrospective cohort study enrolled a total of 91 patients diagnosed with locally advanced or mUC and who received avelumab maintenance therapy between February 2021 and September 2024. The impacts of neutrophil-to-lymphocyte ratio (NLR), prognostic nutritional index (PNI), hemoglobin (Hb) level, and Creactive protein (CRP) level on overall survival (OS) were evaluated using Kaplan-Meier method and Cox proportional hazards model.

Results: The patients with pretreatment PNI ≥ 40.2 [hazard ratio (HR) 0.15; 95% confidence interval (CI), 0.04-0.57] and pretreatment Hb ≥ 10.4 g/dl (HR 3.05; 95% CI, 1.53-6.09) were significantly associated with longer OS. In univariate analysis, significant prognostic factors for OS were identified as the number of cycles of avelumab ≥11 (P = .042), pretreatment Hb level ≥ 10.4 g/dl (P = .015), and pretreatment PNI ≥ 40.2 (P = .002). The multivariate Cox regression analysis demonstrated that pretreatment PNI ≥ 40.2 (HR 0.22; 95% CI: 0.56-0.86, P = .03) was identified as a significant prognostic factor for OS.

Conclusions: Pretreatment low PNI was associated with poor survival outcome in avelumab maintenance therapy. This finding provides support for the potential role of PNI as a prognostic factor of avelumab maintenance therapy.

Background: The phase 3 TITAN trial revealed that apalutamide plus androgen deprivation therapy (ADT) has significantly improved outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC). However, the generalizability of these results to Asian and Japanese populations remains unclear. Bayesian methods provide a probabilistic framework offering more clinically meaningful estimates of benefit in such subpopulations.

Methods: We conducted a Bayesian post hoc analysis using reconstructed individual patient data from the published Asian (n = 221) and Japanese (n = 51) TITAN trial subpopulations. Bayesian Cox proportional hazards models were fitted under four prespecified priors representing different skepticism levels. Posterior median hazard ratios (HRs), 95% credible intervals (CrIs), and probabilities of any benefit (Pr[HR < 1.0]) or substantial benefit (Pr[HR < 0.8]) were calculated.

Results: The posterior median HR under the neutral prior for overall survival in the Asian cohort was 0.71 (95% CrI 0.44-1.14), with Pr[HR < 1.0] = 92% and Pr[HR < 0.8] = 69%. Probabilities exceeded 95% under more informative priors. The Japanese cohort demonstrated more pronounced effects (neutral prior HR: 0.55, 95% CrI: 0.22-1.35) with ≥90% probability of benefit across all priors. Posterior median HRs for TTmCRPC were 0.32-0.35 across priors, with ~100% probability of treatment benefit in both cohorts.

Conclusion: This analysis provides strengthened evidence that apalutamide plus ADT offers meaningful clinical benefit for Asian patients with mCSPC. Moreover, our findings support more informed and individualized clinical decision-making, helping clinicians communicate expected outcomes more clearly during shared decision-making.

Background: Apalutamide treatment for prostate cancer may require discontinuation because of adverse events, particularly rashes. We evaluated the real-world outcomes of switching to other androgen receptor signaling inhibitors (ARSI) following such discontinuations.

Methods: This multicenter retrospective cohort study included men with metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) who received apalutamide between July 2019 and August 2025. Those who discontinued apalutamide comprised the switch group. We noted the reasons for discontinuation and compared progression-free survival (PFS) or metastasis-free survival (MFS) and overall survival (OS) between the switch and no-switch groups by disease category. Rash recurrence after switching was also assessed.

Results: Of 117 total patients, 17 (14.5%) comprised the switch group. Rashes accounted for all of the discontinuations, with 40% being grades ≥3. PFS and OS did not differ significantly between the switch and non-switch patients with mCSPC (log-rank P = .225 and P = .785, respectively), and similar MFS and OS results were observed in those with nmCRPC (P = .674 and P = .861, respectively). The rashes recurred after switching to alternative therapies in 5.8% (n = 1) of the patients.

Conclusions: This real-world multicenter analysis demonstrated that approximately one in seven patients with prostate cancer discontinued apalutamide treatment because they developed rashes. However, switching to other ARSIs preserved oncological outcomes, with no significant differences in PFS, MFS, or OS observed, regardless of prostate cancer subtype. Therefore, this type of switching does not appear to compromise subsequent treatment efficacy if it is done while the disease remains sensitive to ARSIs.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Central nervous system (CNS) relapse is an uncommon yet lethal event in patients with DLBCL. Polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone (pola-R-CHP) is a standard of care for patients with untreated DLBCL. In patients with DLBCL at high risk of CNS relapse, the intrathecal (IT) administration of methotrexate and cytarabine is widely adopted for CNS prophylaxis; however, the optimal treatment is unclear. The aim of this multicenter randomized phase III trial is to confirm the superiority of high-dose methotrexate administered during early cycles of pola-R-CHP in addition to IT chemotherapy for patients with untreated DLBCL at high risk of CNS relapse. A total of 390 patients from 52 institutions will be enrolled across a 4-year period. The primary endpoint is progression-free survival. This trial was registered in the Japan Registry of Clinical Trials as jRCTs031230505 [https://jrct.mhlw.go.jp/latest-detail/jRCTs031230505].

Immune checkpoint inhibitors (ICIs), which target immune regulatory molecules such as cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1, are widely used as standard treatments for various cancer types. However, by overcoming T-cell suppression, they can also trigger immune-related adverse events (irAEs) that may necessitate treatment discontinuation. Rechallenging with an ICI after irAE resolution remains a clinical dilemma. This review evaluates current evidence on the efficacy and safety of ICI rechallenge. Systematic reviews and meta-analyses have demonstrated notable efficacy, with pooled objective response rates (ORR) ranging from 21.8% to 43.1% and disease control rates from 62.0% to 71.9%. Efficacy appears higher among patients who initially discontinued treatment due to an irAE than among those who stopped because of disease progression. For instance, a recent phase II study of nivolumab rechallenge in non-small cell lung cancer patients who relapsed after an initial response reported a modest ORR of 8.5%. Nonetheless, this potential benefit must be balanced against the risk of toxicity recurrence. The recurrence rate of the same irAE is ~32%, with risk varying by organ systems. Safety comparisons between initial treatment and rechallenge yield mixed results, with some studies reporting higher and others similar rates of severe events. Although major guidelines recommend permanent discontinuation for severe (Grade ≥ 3) irAEs, emerging evidence-including class-switching strategies and organ-specific prophylaxis-suggests that rechallenge may be feasible in selected patients. A personalized risk-benefit assessment remains essential, considering the type and severity of the initial irAE and the reason for discontinuation.

Background: DICER1 syndrome is a relatively recently identified hereditary tumor predisposition syndrome, strongly associated with pleuropulmonary blastoma (PPB) and other neoplasms, but its actual status in Japan is unclear.

Methods: We retrospectively performed germline DICER1 gene analysis in patients with suspected PPB at our institute between 2003 and 2022. Relevant clinical data were extracted from the medical records.

Results: Six patients with PPB were identified, of whom four harbored pathogenic germline variants in DICER1. Only one patient had a family history of childhood or juvenile cancer. Genetic testing of unaffected family members was performed in two families, revealing three asymptomatic carriers, including one infant carrier. Two of the three carriers underwent active surveillance, and no new tumors were detected on follow-up at 6 and 2.5 years after diagnosis, respectively.

Conclusions: A high prevalence of DICER1 germline variants was observed in patients with PPB, consistent with previous studies. Family history alone may be insufficient to suspect DICER1 syndrome, and thus, proactive genetic testing of family members is advisable in all cases of PPB.

Messenger RNA (mRNA) offers a powerful platform for therapeutic cancer vaccines. Several clinical trials targeting tumor-associated antigens and neoantigens have demonstrated promising immunological and clinical responses. For effective cancer vaccination, technologies for in vivo mRNA delivery and mRNA molecular design are essential. mRNA delivery systems, typically based on synthetic nanoparticles, are designed to protect mRNA from enzymatic degradation, facilitate its delivery to lymphoid organs and antigen-presenting cells, and stimulate innate immune responses to serve as adjuvants. To maximize the potential of these delivery systems, molecular design of the delivered mRNA is also critical. Strategies such as nucleoside modification, self-amplifying RNA, circular RNA, and hybridization-based mRNA engineering are employed to modulate the immunostimulatory properties of mRNA, extend the duration of antigen presentation, and introduce additional functionalities to the delivery systems. While technological advances in these areas have significantly contributed to the recent progress of mRNA cancer vaccines, current formulations, including widely used lipid nanoparticles (iLNPs), still have considerable room for improvement in terms of safety and efficacy. This has prompted vigorous research efforts to redesign iLNPs and explore non-lipid-based approaches. In this context, this review outlines the established foundational technologies and highlights ongoing research in mRNA delivery and engineering, with a focus on their biological and functional aspects.

Objective: This multicenter, single-arm, Phase II study aimed to evaluate the efficacy and safety of fluorouracil, levofolinate, and irinotecan (150 mg/m2, standard dose in Japan) (FOLFIRI) plus ramucirumab (RAM) as second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients.

Methods: On Day 1 of each 2-week cycle, patients with unresectable mCRC who were refractory to oxaliplatin and fluoropyrimidine in combination with bevacizumab or anti-epidermal growth factor receptor antibodies as first-line treatment received 8 mg/kg RAM, followed by the FOLFIRI regimen with low-dose irinotecan (150 mg/m2). The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), treatment compliance, and safety.

Results: A total of 62 patients were enrolled from 15 institutions between January 2018 and August 2021. The intent-to-treat and safety populations included 61 and 58 patients. Median PFS and OS were 5.9 months (95% CI, 4.8-6.9 months) and 17.0 months (95% CI, 12.0-21.0 months), respectively. The objective response rate and disease control rate were 8.2% and 74%, respectively. The median time to treatment failure was 4.8 months (95% CI, 3.2-5.9 months). The median relative dose intensities of irinotecan, 5-fluorouracil, and RAM were 73.8% (range, 40.3%-102.4%), 58.5% (range, 22.8%-102.4%), and 80.8% (range, 36.1%-102.4%), respectively. Frequencies of Grade ≥ 3 hematologic, non-hematologic, and RAM-associated adverse events were 43%, 24%, and 17%, respectively. The observed Grade ≥ 3 adverse events included neutropenia (40%), diarrhea (8.6%), decreased appetite (10%), hypertension (6.9%), and proteinuria (3.4%).

Conclusion: FOLFIRI with low-dose irinotecan plus RAM is a feasible second-line treatment in Japanese patients with mCRC.

Background: While nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) showed higher efficacy than 5-FU/LV in controlled settings, whether the availability of this regimen has truly improved real-world survival outcomes in unresectable pancreatic cancer remains unclear.

Methods: We retrospectively analyzed consecutive patients with metastatic or recurrent pancreatic cancer, who received second-line chemotherapy after gemcitabine with nab-paclitaxel (GnP) between April 2015 and September 2024 at our hospital. The patients were divided into two cohorts: patients treated before (Group A) and after (Group B) the availability of nal-IRI plus 5-FU/LV in Japan. Time to treatment failure (TTF) of first-line GnP, overall survival (OS), and progression-free survival (PFS) were compared between groups. OS from the beginning of first-line treatment (OS-1) and from the beginning of second-line treatment (OS-2) were evaluated.

Results: A total of 426 patients (Group A/B: 230/196) were included. Median TTF were comparable (6.4/6.6 months, P = .75). However, median second-line PFS and OS-2 were significantly longer in Group B (PFS: 3.0/4.8 months, P = .03; OS-2: 6.3/8.2 months, P = .047). Median OS-1 tended to be longer in Group B (13.9/17.2 months, P = .07). Multivariate analysis revealed that treatment after the introduction of nal-IRI plus 5-FU/LV was an independent prognostic factor for OS-2 (hazard ratio, 0.75; P < .01).

Conclusion: The introduction of nal-IRI plus 5-FU/LV was associated with improved second-line treatment outcomes, providing a new combination regimen with acceptable toxicity in metastatic or recurrent pancreatic cancer.