International Journal of Clinical Oncology最新文献

Background: Avelumab + axitinib was approved for advanced renal cell carcinoma (aRCC) in Japan in December 2019. We report long-term real-world outcomes with first-line avelumab + axitinib from the J-DART2 study in Japan.

Methods: J-DART2 was a multicenter, noninterventional, retrospective study examining clinical data from patients with curatively unresectable locally advanced or metastatic RCC who started treatment with first-line avelumab + axitinib in Japan between December 2019 and October 2022. Endpoints included patient characteristics, treatment patterns, and outcomes.

Results: Data from 150 patients across 19 sites were analyzed; median follow-up was 18.7 months (95% CI, 16.3-20.6 months). Median age was 70.5 years; 26.0% of patients were aged ≤64 years, 42.7% were aged 65-74 years, and 31.3% were aged ≥75 years. International Metastatic RCC Database Consortium risk was favorable in 26.0%, intermediate in 54.7% (1 risk factor in 30.7%; 2 risk factors in 24.0%), and poor in 19.3% of patients. Median progression-free survival (PFS) was 17.1 months, with 1- and 2-year PFS rates of 57.7% and 37.5%, respectively. Median overall survival (OS) was not reached, with 1- and 2-year OS rates of 90.6% and 84.7%, respectively. Objective response rate was 53.3%; disease control rate was 88.9%. Outcomes were similar across age groups, including patients aged ≥75 years.

Conclusions: J-DART2 is the largest retrospective study to report long-term real-world outcomes in patients with aRCC treated with avelumab + axitinib in Japan. Findings were similar to those observed in previous studies and support the benefit of avelumab + axitinib in clinical practice in Japan.

Background: To improve the outcome in newly diagnosed glioblastoma patients with maximal resection, we aimed to evaluate the efficacy and safety of implantation of carmustine wafers (CWs), radiation concomitant with temozolomide and bevacizumab, and maintenance chemotherapy with six cycles of temozolomide and bevacizumab.

Method: This prospective phase II study enrolled glioblastoma patients considered candidates for complete resection (> 90%) of a contrast-enhanced lesion. The CWs were intraoperatively implanted into the resection cavity after achieving maximal resection. Patients without a measurable contrast-enhanced lesion on magnetic resonance imaging within 48 h after resection received concomitant radiotherapy and chemotherapy with temozolomide and bevacizumab, followed by maintenance treatment with up to six cycles of temozolomide and bevacizumab. The primary endpoint was the 2-year overall survival rate in glioblastoma patients with protocol treatment.

Results: From October 2015 to April 2018, we obtained consent for the first registration from 70 patients across 17 institutions in Japan, and 49 patients were treated according to the protocol. We evaluated the safety in 49 patients who were part of the second registration and the efficacy in 45 glioblastoma patients treated according to the protocol. The profile of hematological and most of the non-hematological adverse effects was similar to that in previous studies, but stroke occurred in 12% of cases (6/49 patients). The estimated 2-year overall survival rate was 51.3%.

Conclusion: Implantation of CWs, followed by concomitant radiation, temozolomide, and bevacizumab, and six cycles of temozolomide and bevacizumab may offer some benefit to survival in Japanese glioblastoma patients with maximal resection.

Trial id: jRCTs021180007.

Background: In Japan, the authorized period (2-4 h) between oral administration of 5-aminolevulinic acid hydrochloride (5-ALA) and transurethral resection for non-muscle invasive bladder cancer (NMIBC) may restrict photodynamic diagnosis (PDD) usage. Therefore, this prospective, single-arm, phase III study aimed to evaluate the diagnostic accuracy and safety of PDD at an extended administration period (4-8 h).

Methods: From January 2022 to May 2023, 161 patients with NMIBC were enrolled from eight hospitals. The primary endpoint was the blue light (BL) sensitivity of pathologically positive biopsies. The secondary endpoints were a comparison of the specificity and positive and negative prediction rates under BL and white light (WL) conditions.

Results: A total of 1242 specimens comprising 337 histological NMIBC specimens were analyzed. BL-sensitivity was 95.3%. Its lower limit of 95% confidence interval (92.4-97.3%) exceeded the threshold (70%) of non-inferiority to authorized usage. Sensitivity and specificity were significantly higher and lower for BL than those for WL (95.3% vs. 61.1%, P < 0.001; 52.7% vs. 95.2%, P < 0.001), respectively. The positive and negative predictive rates were significantly lower and higher for BL than those for WL (42.9% vs. 82.7%, P < 0.001; 96.8% vs. 86.8%, P < 0.001), respectively. Of the 145 patients receiving 5-ALA, 136 (93.8%) and 75 (51.7%) experienced 377 adverse events and 95 adverse reactions, respectively, most of which were grade 1 or 2.

Conclusion: For extended period, the efficacy of PDD for NMIBC was similar to that of authorized period, in terms of higher sensitivity and lower specificity compared with WL, and the safety was acceptable.

Background: Olanzapine is an atypical antipsychotic drug used for chemotherapy-induced nausea and vomiting. It is particularly effective in preventing delayed nausea and vomiting induced by highly emetogenic chemotherapy (HEC). However, it has side effects, such as hyperglycemia and somnolence, the efficacy and safety of adding olanzapine to triplet antiemetic therapy (5-HT₃ receptor antagonist, NK₁ receptor antagonist, and dexamethasone) must be verified.

Methods: We performed a systematic review and meta-analysis to compare the effectiveness of olanzapine combined with triplet antiemetic therapy and triplet antiemetic therapy in preventing nausea and vomiting for HEC. We set five items (hyperglycemia, prevention of vomiting, prevention of nausea, adverse events, and cost (drug costs)) as outcomes and conducted a systematic review.

Results: Five randomized controlled trials was extracted and they showed that the addition of olanzapine was effective in control of nausea and vomiting, especially in the delayed phase. Complete response of acute and delayed phase were significantly higher in the olanzapine group. Risk difference was - 0.14 [95% CI - 0.26, - 0.03; p = 0.02] and - 0.14 [95% CI - 0.19, -0.09; p < 0.00001], respectively. Additionally, we evaluated hyperglycemia and somnolence, which are typical side effects of olanzapine. However, the incidence of grade ≥ 2 was low in both events, and there was no significant difference between olanzapine and control groups.

Conclusions: Adding olanzapine to triplet antiemetic therapy is useful in preventing nausea and vomiting induced by HEC and there would be minimal adverse effects from the combination use.

Background: The expenses related to fertility preservation or subsequent assisted reproductive treatments are significant for adolescents and young adult patients in Japan's current healthcare system. With fertility preservation becoming more widespread in developed countries, it is expected that these costs will be covered by insurance or subsidies. It is critical for patients, healthcare providers, and the government to know the costs that patients will be responsible for. In Japan, the costs of fertility preservation and subsequent assisted reproductive technology are not covered by insurance, but patients can apply for subsidies from the local and central governments if certain conditions are met. Presently, the above-mentioned costs, as well as the amount paid by the patient, vary by facility. Therefore, it is essential to ensure patients' continued access to necessary medical care despite the associated costs.

Methods: In this study, questionnaires were mailed to 186 certified fertility preservation facilities in Japan to assess patients who had undergone fertility preservation or assisted reproduction. The questionnaires were sent between October 27, 2023 and March 31, 2024, with 140 of the 186 facilities responding (response rate: 75.3%).

Results: Our findings show that approximately one-third of the costs was borne by the patients.

Conclusion: Given these circumstances, sustainable pricing and insurance coverage are necessary for both patients and facilities.

Background: Cutaneous melanoma (CM) is the most common type in Caucasians, while acral melanoma (AM) and mucosal melanoma (MM), which are resistant to immunotherapies and BRAF/MEK-targeted therapies, are more common in East Asians. Genomic profiling is essential for treating melanomas, but such data are lacking in Japan.

Methods: Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed.

Results: A total of 380 melanomas was analyzed, including 136 CM, 46 AM, 168 MM, and 30 uveal melanoma (UM). MM included conjunctival, sinonasal, oral, esophageal, anorectal, and vulvovaginal melanomas. No significant difference in the median tumor mutational burden (TMB) of CM (3.39 mutations/megabase), AM (2.76), and MM (3.78) was the key finding. Microsatellite instability-high status was found in one case. BRAF V600E/K was found in only 45 patients (12%). Key driver mutations in CM were BRAF (38%), NRAS (21%), NF1 (8%), and KIT (10%), with frequent copy number alterations (CNAs) of CDKN2A, CDKN2B, and MYC. AM was characterized by altered KIT (30%), NRAS (26%), and NF1 (11%) and CDKN2A, CDKN2B, CDK4, MDM2, and CCND1 CNAs. MM was characterized by altered NRAS (24%), KIT (21%), and NF1 (17%) and MYC, KIT, and CDKN2A CNAs, with differences based on anatomical locations. UM bore GNAQ or GNA11 driver mutations (87%) and frequent mutations in SF3B1 or BAP1.

Conclusion: The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents.

Background: Previously reported results from phase III KEYNOTE-048 demonstrated similar or improved overall survival (OS) with pembrolizumab or pembrolizumab-chemotherapy versus cetuximab-chemotherapy (EXTREME) in Japanese patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). We report results in Japanese patients from KEYNOTE-048 after 5 years of follow-up.

Methods: Patients with R/M HNSCC of the oropharynx, oral cavity, hypopharynx, or larynx were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Primary endpoints were OS and progression-free survival. Efficacy was evaluated in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, PD-L1 CPS ≥ 1, and total Japanese populations.

Results: In Japan, 67 patients were enrolled (pembrolizumab, n = 23; pembrolizumab-chemotherapy, n = 25; EXTREME, n = 19). Median follow-up was 71.0 months (range, 61.2-81.5); data cutoff, February 21, 2022. 5-year OS rates with pembrolizumab versus EXTREME were 35.7% versus 12.5% (hazard ratio [HR] 0.38; 95% CI 0.13-1.05), 23.8% versus 12.5% (HR 0.70; 95% CI 0.34-1.45), and 30.4% versus 10.5% (HR 0.54; 95% CI 0.27-1.07) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively. 5-year OS rates with pembrolizumab-chemotherapy versus EXTREME were 20.0% versus 14.3% (HR 0.79; 95% CI 0.27-2.33), 10.5% versus 14.3% (HR 1.18; 95% CI 0.56-2.48), and 8.0% versus 12.5% (HR 1.11; 95% CI 0.57-2.16) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively.

Conclusion: After 5 years of follow-up, pembrolizumab and pembrolizumab-chemotherapy showed long-term clinical benefits; results further support these treatments as first-line options for Japanese patients with R/M HNSCC.

Clinical trial registration: NCT02358031.

Background: Tumor-infiltrating lymphocytes-ultrasonography (TILs-US) score is used to predict lymphocyte-predominant breast cancer (LPBC) in surgical specimens. We aimed to compare diagnostic performance of TILs-US score for predicting pathological complete response (pCR) with that of LPBC in biopsy specimens.

Methods: TILs ≥ 50% in biopsy specimens was defined as biopsy-LPBC, and TILs-US score ≥ 4 was categorized as TILs-US score-high. Basic nomogram for pCR was developed using stepwise logistic regression based on the smallest Akaike Information Criterion, and biopsy-LPBC and TILs-US score nomograms were developed by integrating biopsy-LPBC or TILs-US scores into a basic nomogram. The diagnostic performance of the nomograms for pCR was compared using area under the curve (AUC), categorical net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

Results: This retrospective study evaluated 118 patients with breast cancer, including 33 (28.0%) with biopsy-LPBC, 52 (44.1%) with TILs-US score-high, with 34 (28.8%) achieving pCR. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and AUC for predicting pCR were 0.53, 0.82, 2.96, 0.57, and 0.68, respectively, for biopsy-LPBC, and 0.76, 0.69, 2.47, 0.34, and 0.73, respectively, for TILs-US score. The biopsy-LPBC nomogram showed significant improvements in categorical NRI (p = 0.023) and IDI (p = 0.007) but not in AUC (p = 0.25), compared with the basic nomogram. The TILs-US nomogram exhibited significant improvements in AUC (p = 0.039), categorical NRI (p = 0.010), and IDI (p < 0.001).

Conclusions: The TILs-US score may serve as a novel marker for prediction of pCR in patients with breast cancer. An external validation study is warranted to confirm our findings.

Background: Cisplatin (CDDP) is an anticancer drug used to treat several types of cancer. CDDP-induced nephrotoxicity (CIN) is a serious adverse effect of CDDP treatment. Although magnesium sulfate (Mg) premedication has been proven to prevent CIN, the relationship between Mg dosage and its preventive effects on CIN are unknown. Therefore, we have evaluated this relationship using meta-analysis and meta-regression analysis to optimize cancer chemotherapies, including CDDP.

Methods: We selected candidate studies, generated a forest plot to evaluate the preventive effects of Mg on CIN, and performed subgroup analyses. Moreover, a meta-regression analysis was conducted to reveal the relationship between Mg dosage and its preventive effects on CIN.

Results: We identified 17 related studies and the total odds ratio (OR) of Mg premedication on CIN was 0.26 and the 95% confidence interval (95% CI) was 0.17-0.41 (p < 0.00001) although funnel plot suggested asymmetry. In subgroup analysis by forest plot, total OR with 95% CI of low Mg dosage administration (less than 10 mEq) and high Mg dosage administration (10 mEq or higher) was 0.35 (0.16-0.77, p = 0.0169) and 0.12 (0.07-0.21, p < 0.0001), respectively. In addition, meta-regression analysis was performed on Mg dosage and the OR of related studies, indicating a relationship between Mg dosage and OR (p = 0.0349).

Conclusion: This study has revealed that premedication with Mg prevented CIN in a dose-dependent manner.

As a result of the recent advances in first-line treatment including chemotherapy, radiation therapy, targeted therapy, and immune checkpoint inhibitor immunotherapy (ICI) for locally advanced/metastatic initially unresectable esophageal and esophagogastric junction cancer, surgery aiming at cure after initial treatment, so-called "conversion surgery" has become more common in this field. Several studies have indicated encouraging survival outcomes for patients after conversion surgery with R0 resection. However, various issues, such the utility and the safety of conversion surgery remain unclear. In this review, we will focus on the surgical treatment for initially unresectable esophageal and esophagogastric junction cancer after first- or later- line treatment and review recent evidence regarding the safety and the efficacy of conversion surgery. Multidisciplinary treatment including surgery may serve as a novel treatment strategy for esophageal and esophagogastric junction cancer, thus provide a curative treatment option and potentially contribute to better prognosis for initially untreatable diseases.