Cell Carcinoma In Japan Research Articles

Real-world outcomes of avelumab plus axitinib in patients with advanced renal cell carcinoma in Japan: long-term follow-up from the J-DART2 retrospective study.

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. 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. Data from 150 patients across 19 sites were analyzed; median follow-up was 18.7months (95% CI, 16.3-20.6months). Median age was 70.5years; 26.0% of patients wereaged ≤64years, 42.7% wereaged 65-74years, and 31.3% wereaged ≥75years. 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 17.1months, 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 ≥75years. 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.

Clinical outcomes and prognostic factors of concurrent chemoradiotherapy for anal squamous cell carcinoma in Japan.

Concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregional anal squamous cell carcinoma (ASCC) in western countries. However, there have been few reports on the clinical outcomes of CCRT in Japan. This study aimed to evaluate the clinical outcomes of CCRT, prognostic factors, and the clinical impact of programmed cell death-ligand 1 (PD-L1) expression of ASCC in Japan. Patients with locoregional ASCC were enrolled between 2007 and 2017. All patients received CCRT consisting of ≥ 45Gy of radiation, 5-fluorouracil, and mitomycin C. Disease-free survival (DFS), overall survival (OS), and adverse events (AEs) were estimated. Expression of p16 and PD-L1 were assessed by immunohistochemical staining (IHC). This study included 36 patients, of whom 30 (83.3%) were female. Among the participants, 32 (88.9%) achieved complete clinical remission, while six (16.7%) experienced recurrence. The five-year DFS and five-year OS were 72.2% and 84.7%, respectively. Grades ≥ 3 serious AEs included neutropenia in 10 (27.7%) and perianal dermatitis in eight (22.2%). In a univariate analysis, male sex, lymph node metastasis, and large tumor size were significantly associated with worse outcome. In a multivariate analysis, tumor size was an independent factor associated with short DFS. Of the 30 patients whose biopsy specimens were available for IHC, 29 (96.7%) were positive for p16, and 13 (43.3%) were positive for PD-L1. However, PD-L1 expression did not show any clinical impact. The comparative etiology, clinical outcomes, and prognostic factors of CCRT observed in Japanese patients with locoregional ASCC were consistent with western data.

Preoperative docetaxel, cisplatin, and 5-fluorouracil for resectable locally advanced esophageal and esophagogastric junctional adenocarcinoma

BackgroundChemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel is the standard perioperative treatment for resectable esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma (EGJ-AC) in Western countries. Meanwhile, preoperative chemotherapy consisting of docetaxel, cisplatin, and 5-fluorouracil (DCF) has been developed for esophageal squamous cell carcinoma in Japan. However, there are few reports on the safety and efficacy of preoperative DCF for resectable EGJ-AC in the Japanese population.MethodsPatients with histologically confirmed resectable EGJ-AC who received preoperative DCF (docetaxel 70 mg/m2 and cisplatin 70 mg/m2 on day 1 and continuous infusion of 5-fluorouracil 750 mg/m2/day on days 1–5 every 3 weeks with a maximum of three cycles) between January 2015 and April 2020 were retrospectively evaluated. We assessed the rates of completion of ≥ 2 courses of DCF and R0 resection, histopathological response, progression-free survival (PFS), overall survival (OS), and adverse events.ResultsThirty-two patients were included. Median follow-up was 28.7 (range, 5.2–70.8) months and median age was 63 (range, 42–80) years. Twenty-one patients (66%) had a performance status of 0. The proportions of clinical stage IIA/IIB/III/IVA/IVB disease were 3%/0%/44%/44%/9%, respectively. The treatment completion rate was 84%. A histopathological response of grade 1a/1b/2/3 was obtained in 58%/26%/13%/3% of cases. Median PFS was 40.7 months (95% confidence interval 11.8-NA). Median OS was not reached (80.8% at 3 years). Grade ≥ 3 adverse events were observed in 63% of cases (neutropenia, 44%; febrile neutropenia, 13%). No treatment-related deaths occurred.ConclusionsPreoperative DCF for resectable EGJ-AC was well tolerated and has promising efficacy.

Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab Combination Therapy as First-line Treatment for Advanced Renal Cell Carcinoma in Japan

ObjectivesThe purpose of this study is to examine the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy (NIVO + IPI) compared with the sunitinib (SUN) therapy for Japanese patients with advanced renal cell carcinoma from the perspective of a Japanese health insurance payer. MethodsA lifetime horizon was applied, and 2% per annum was set as the discount rate. The threshold was set as $ 75 000 per quality-adjusted life-year (QALY) gained. For the analytical method, we used a partitioned survival analysis model to estimate the incremental cost-effectiveness ratio (ICER), which is calculated by dividing incremental costs by incremental QALYs. Progression-free survival, progressive disease, and death were set as health states. Additionally, cost parameters and utility weights were set as key parameters. We set the intermediate/poor-risk population as the base case. Scenario analysis was conducted for the intention-to-treat population and the favorable risk population. Furthermore, one-way sensitivity analysis and probabilistic sensitivity analysis were conducted for each population. ResultsIn the base-case analysis, the QALYs of NIVO + IPI and SUN were 4.32 and 2.99, respectively. NIVO + IPI conferred 1.34 additional QALYs. Meanwhile, the total costs in the NIVO + IPI and SUN were $692 288 and $475 481, respectively. As a result, the ICER of NIVO + IPI compared with SUN was estimated to be $162 243 per QALY gained. The parameter that greatly affected the ICER was the utility weight of progression-free survival in NIVO + IPI. ConclusionsNIVO + IPI for advanced renal cell carcinoma seems to be not cost-effective compared with the SUN in the Japanese healthcare system.

Squamous cell carcinoma of the eyelid.

Eyelid squamous cell carcinoma is a major type of rare eyelid cancer, together with basal cell carcinoma and sebaceous gland carcinoma. It is a painless disease that progresses slowly and is often detected by the appearance of nodules or plaques. Risk factors include exposure to ultraviolet light, fair skin, radiation and human papillomavirus infection. The standard treatment is surgical removal, and in cases of orbital invasion, orbital content removal is required. If sentinel node biopsy reveals a high risk of lymph node metastasis, adjuvant radiotherapy may be considered. Local chemotherapy, such as imiquimod and 5-fluorouracil, may be used for eyelid squamous cell carcinoma in situ. When surgery or radiotherapy is not recommended for distant metastases or locally advanced disease, drug therapy is often according to head and neck squamous cell carcinoma in Japan. The treatment often requires a multidisciplinary team to ensure the preservation of function and cosmetic appearance.

Cost-effectiveness analysis of cabozantinib compared with everolimus, axitinib, and nivolumab in subsequent line advanced renal cell carcinoma in Japan

AimsThe treatment landscape of renal cell carcinoma has changed with the introduction of targeted therapies. While the clinical benefit of cabozantinib is well-established for Japanese patients who have received prior treatment, the economic benefit remains unclear. The objective of this study was to assess the cost-effectiveness of cabozantinib compared with everolimus, axitinib, and nivolumab in patients with advanced renal cell carcinoma who have failed at least one prior therapy in Japan.MethodsA cost-effectiveness model was developed using a partitioned survival approach and a public healthcare payer’s perspective. Over a lifetime horizon, clinical and economic implications were estimated according to a three-health–state structure: progression-free, post-progression, and death. Key clinical inputs and utilities were derived from the METEOR trial, and a de novo network meta-analysis and cost data were obtained from publicly available Japanese data sources. Costs, quality-adjusted life-years, and incremental cost-effectiveness ratios were estimated. Costs and health benefits were discounted annually at 2%.ResultsCabozantinib was more costly and effective compared with everolimus and axitinib, with deterministic incremental cost-effectiveness ratios of ¥5,375,559 and ¥2,223,138, respectively. Compared to nivolumab, cabozantinib was predicted to be less costly and more effective. Sensitivity and scenario analyses demonstrated that the key drivers of cost-effectiveness results were the estimation of overall survival and treatment duration, relative efficacy, drug costs, and subsequent treatment costs.LimitationsMETEOR was an international trial but did not enroll any patients from Japan. Efficacy and safety data from METEOR were used as a proxy for the Japanese population following validation by clinical experts, and alternative assumptions specific to clinical practice in Japan were evaluated in scenario analyses.ConclusionsIn Japan, cabozantinib is a cost-effective alternative to everolimus, axitinib, and nivolumab for the treatment of patients with advanced renal cell carcinoma who have received at least one prior line of therapy.

Treatment Outcomes of Chemoradiotherapy for Anal Canal Squamous Cell Carcinoma in Japan

肛門管扁平上皮癌の標準治療として化学放射線療法（CRT）が定着しつつある．本報告では当院で経験した肛門管扁平上皮癌7例の治療成績を検討した．各症例の進行度はStageI/II/III/IV＝1例/1例/5例/0例，全例に対してCRTを施行した．CRTは5-FluorouracilおよびMitomycin C（1例に対してはCisplatin）を2コース施行し，骨盤内および両鼠径リンパ節領域に放射線照射した．治療結果は全例がCR，無再発生存中である．Grade 3以上の有害事象として，発熱性好中球減少症などの血液毒性および下痢，放射線性皮膚炎を認めた．晩期障害は，Grade 2の放射線性直腸炎および膀胱炎を認めた．さらに本邦既報の5-FUおよびMMCを用いたCRT症例47例に関しても比較的良好な治療結果が得られていた．血液毒性に注意が必要であるが，CRTは根治が期待できる治療法と考えられた．

407P A post-marketing surveillance of the real-world safety and effectiveness of avelumab in patients with curatively unresectable Merkel cell carcinoma in Japan

Avelumab was conditionally approved in Japan in Sep 2017 for the treatment of patients with curatively unresectable Merkel cell carcinoma (MCC). A mandated all-case surveillance was conducted to confirm the real-world safety and effectiveness of avelumab in Japan. We report the final analysis of this post-marketing surveillance (PMS).

Occurrence of voriconazole-induced cutaneous squamous cell carcinoma in Japan: data mining from different national pharmacovigilance databases.

Long-term voriconazole use may increase the risk of cutaneous squamous cell carcinoma (cSCC), especially in immunocompromised patients. However, relatively little is known regarding voriconazole-induced cSCC in Japan. Thus, the purpose of this study was to evaluate the association between voriconazole use and cSCC in Japan using different national pharmacovigilance databases. First, using the Japanese Adverse Drug Event Report (JADER) database, we evaluated the association between voriconazole use and cSCC in Japan. Second, using the U. S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, we examined regional differences in the occurrence of voriconazole-induced cSCC between Japan and other countries. We calculated reporting odds ratios (RORs) as disproportionality analysis to evaluate voriconazole-induced cSCC. In this study, cases in which one or more of "Bowen's disease", "Carcinoma in situ of skin", "Keratoacanthoma", "Squamous cell carcinoma in skin", or "Squamous cell carcinoma" were reported as adverse events were considered to be cSCC cases. The analysis based on the JADER database showed an association between voriconazole use and cSCC in Japan, with a ROR (95% confidence interval) of 35.37 (25.60-48.87). Further, the analysis based on the FAERS database revealed that signals were detected in Japan as well as in Western countries and Australia. This study is the first in which the association between voriconazole use and cSCC in Japan is assessed using national pharmacovigilance databases. Healthcare providers need to be fully aware of the potential for cSCC development owing to voriconazole use and in all countries, including Japan, ensure careful follow-up of patients' skin.

PSY1-3 Combined immunotherapy for advanced renal cell carcinoma

In the field of urological oncology, the progress of drug therapy has been remarkable in recent years, especially in the field of renal cell carcinoma, where research on cytokine therapy, such as IFNα therapy, has been actively conducted, and the development of immunotherapy has been promoted in a competitive manner. As of December 2021, several combination therapies such as PD-1 inhibitor plus anti-CTLA-4 antibody and PD-L1 inhibitor plus VEGFR-TKI are available as first-line treatment for advanced renal cell carcinoma in Japan.

Real-world safety and effectiveness of nivolumab for advanced renal cell carcinoma in Japan: a post-marketing surveillance

BackgroundThis all-case post-marketing surveillance (PMS) evaluated the real-world safety and effectiveness of nivolumab monotherapy in Japanese patients with un-resectable or metastatic renal cell carcinoma (RCC).MethodsThis multicenter, open-label, non-interventional, observational PMS study (registered from August 2016 to January 2017) was conducted in patients who were newly initiated on nivolumab monotherapy. Assessments included treatment-related adverse events (TRAEs) of special interest, patient characteristics affecting safety, and effectiveness over 12 months.ResultsOverall, 580 patients were enrolled; 555 and 554 patients comprised the safety and effectiveness analysis sets, respectively. The median (range) age of the population was 66 (14–90) years. Nivolumab was initiated as 1st-, 2nd-, and ≥ 3rd-line treatment in 0.2%, 42.0%, and 57.8% of patients, respectively. TRAEs were reported in 275 (49.5%) patients. The most common TRAEs of special interest included thyroid dysfunction (9.5%), hepatic dysfunction (8.6%), and interstitial lung disease (6.7%). The incidence of TRAEs was significantly higher in elderly patients (≥ 65 vs < 65 years; ≥ 75 vs < 75 years); patients with lower C-reactive protein levels (< 5 vs ≥ 5 mg/dL); and patients with vs without a past medical history, including hepatic, thyroid, and autoimmune diseases. The 6- and 12-month survival rates were 71.8% and 57.9%, respectively.ConclusionThe safety profile of nivolumab monotherapy in Japanese patients with advanced RCC was similar to that in the phase 3 CheckMate 025 trial. No new safety signals were observed in this study.

Preoperative docetaxel, cisplatin, and 5-fluorouracil for resectable esophagogastric junction adenocarcinoma: A retrospective study.

209 Background: In Western countries, 5-FU plus leucovorin, oxaliplatin, docetaxel (DTX) (FLOT) is the standard perioperative treatment for resectable gastric adenocarcinoma and esophagogastric junction adenocarcinoma (EGJ-AC). Preoperative chemotherapy with DTX plus cisplatin and 5-FU (DCF) has been developed for esophageal squamous cell carcinoma in Japan. However, there have been few reports on the safety and efficacy of preoperative triple therapy for resectable EGJ-AC. Methods: The subjects of this retrospective study were patients (pts) with histologically confirmed resectable EGJ-AC who received preoperative DCF chemotherapy (DTX 70 mg/㎡ and cisplatin 70 mg/㎡ on day 1, and continuous infusion of 5-FU 750 mg/㎡/day on days 1–5, every 3 weeks with a maximum of three cycles) at our hospital from Jan 2015 to Apr 2020. We evaluated the completion rate of &gt;2 courses of DCF and R0 resection in all cases, and also examined histological response, progression-free survival (PFS), overall survival (OS), and adverse events during preoperative chemotherapy. Results: Thirty-two pts were included in this study, and the median observation period was 13.1 months (3.9–57.2). Characteristics were median age (range) 63 (42–80) years, PS 0/1 66/34%, clinical stage I/IIA/IIB/III/IVA/IVB (supraclavicular lymph node) 3/13/3/10/22/32/13%. Treatment completion rate was 84%. Histological response (grade 1a/1b/2/3) was obtained in 18/8/4/1 (58/26/13/3%) pts. Median PFS (95%CI) was 16.8 months (15.0–18.5), and median OS was not reached (3-year OS rate 73.8%). Grade &gt;3 adverse events were observed in 20(63%) pts (neutropenia in 14 [44%], febrile neutropenia in 4 [13%]). No treatment-related deaths occurred. Conclusions: Preoperative DCF chemotherapy for resectable EGJ-AC was well tolerated. Further investigation is required to evaluate the long-term efficacy of this treatment strategy.

Platelet-to-Lymphocyte Ratio Multiplied by the Cytokeratin-19 Fragment Level as a Predictor of Pathological Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.

The standard treatment for resectable advanced esophageal squamous cell carcinoma in Japan is surgery followed by neoadjuvant chemotherapy, and it is important to predict the effect of neoadjuvant chemotherapy before treatment. Therefore, this study aims to extract conventional blood examination data, such as tumor markers and/or inflammatory/nutritional index levels, that can predict the pathological response of patients with esophageal squamous cell carcinoma to neoadjuvant chemotherapy. We retrospectively analyzed the medical records of 66 patients with thoracic esophageal squamous cell carcinoma who received neoadjuvant chemotherapy, followed by curative esophagectomy at Tottori University Hospital between June 2009 and December 2019. We demonstrated that the product of the platelet-to-lymphocyte ratio (PLR) multiplied by the cytokeratin-19 fragment (CYFRA) level, which was termed "PLR-CYFRA," is the most accurate indicator that predicts the pathological response to neoadjuvant chemotherapy, with the highest area under the curve [0.795 (95% confidence interval: 0.665-0.925), P < 0.001] in receiver operating characteristic analyses. Therefore, we divided patients into the PLR-CYFRALow (< 237.6, n = 21) and PLR-CYFRAHigh (≥ 237.6, n = 45) groups and found that the percentage of PLR-CYFRALow was significantly higher in patients with a better pathological response (P < 0.001). Furthermore, patients with good pathological response had significantly better prognoses in terms of disease-specific survival (P = 0.014), recurrence-free survival (P = 0.014), and overall survival (P = 0.032). In the multivariate analysis, PLR-CYFRA was an independent predictor of the pathological response of patients with esophageal squamous cell carcinoma to neoadjuvant chemotherapy (P = 0.002). Pretreatment PLR-CYFRA might be a useful and simple tool that predicts the pathological effect of neoadjuvant chemotherapy in esophageal squamous cell carcinoma.

Multicenter phase I/II study of chemoradiotherapy with high-dose CDDP for head and neck squamous cell carcinoma in Japan

Multicenter phase I/II study of chemoradiotherapy with high-dose CDDP for head and neck squamous cell carcinoma in Japan

Post-marketing observational study of everolimus in patients with unresectable or metastatic renal cell carcinoma in Japan.

To confirm the safety and efficacy of everolimus in patients with unresectable or metastatic RCC. Patients with unresectable or metastatic RCC were included and were followed for up to 1 year from the start of everolimus. The study was conducted at 618 investigational sites in Japan from March 2010 through January 2018. Safety endpoints include adverse events (AEs), and efficacy endpoints were presence/absence of tumor response, progression-free survival (PFS), and overall survival (OS) rate. Of 1694 patients, majority were male (76.33%). Overall, 97.64% of patients experienced AEs and 49% reported serious AEs. The most common serious AEs (incidence of ≥ 5%) include malignant neoplasm progression (21.13%) and interstitial lung disease (10.86%). The incidences of adverse reactions of priority investigation items are as follows: interstitial lung disease (27.74%), infections (11.57%), stomatitis (45.45%), increased in serum creatinine (5.61%), hyperglycemia (14.23%), exacerbation of renal impairment (26.14%), and exacerbation of hepatic impairment (1.15%). The overall tumor response rate was 6.81% with 0.08% CR, and 6.73% PR. The SD was reported in 68.74% of patients. The median PFS was 196 days (95% CI: 181-216 days). The 365-day cumulative OS rate was 82.42%. The acceptable safety and efficacy findings in patients with unresectable or metastatic RCC were confirmed in this study, and are similar to those of pivotal study, which led to the approval, and no new issues were detected. There were no safety or efficacy issues in special populations including elderly and patients with renal/hepatic impairment.

Treatment patterns and outcomes in patients with unresectable or metastatic renal cell carcinoma in Japan.

To clarify treatment patterns and outcomes for patients with unresectable or metastatic renal cell carcinoma in the molecular target therapy era in Japan. A multicenter, retrospective medical chart review study was carried out. Patients diagnosed with unresectable or metastatic renal cell carcinoma between January 2012 and August 2015 were enrolled. Data extracted from medical records included treatment duration, grade≥3 adverse events, reason for discontinuation for each targeted therapy and survival data until August 2016. Of 277 eligible patients, 266, 170 and 77 received first-, second- and third-line systemic treatment, respectively. Tyrosine kinase inhibitors were the most common first-line therapy (72.2%), followed by mammalian target of rapamycin inhibitors (14.3%) and cytokines (13.5%). Among 170 patients who received second-line treatment, tyrosine kinase inhibitor-tyrosine kinase inhibitor was the most common sequence (58.8%), followed by tyrosine kinase inhibitor-mammalian target of rapamycin inhibitor (14.1%) and cytokine-tyrosine kinase inhibitor (14.1%). With a median follow-up period of 19.8months, median overall survival was not reached at 48months. Patients who discontinued first-line tyrosine kinase inhibitors in <6months showed poorer overall survival compared with patients who received first-line tyrosine kinase inhibitors for ≥6months. The present analysis illustrates the contemporary treatment patterns and prognosis for patients with unresectable or metastatic renal cancer in a real-world setting in Japan. Tyrosine kinase inhibitor-tyrosine kinase inhibitor represents the most commonly used sequence. Shorter treatment duration of first-line tyrosine kinase inhibitors is associated with poorer prognosis, suggesting the need for better treatment options.

Risk factors and field cancerization of esophageal squamous cell carcinoma in Japan

Risk factors and field cancerization of esophageal squamous cell carcinoma in Japan

RA10.01: TREATMENT STRATEGY OF ESOPHAGEAL CANCER FROM THE EXPRESSION OF HER2 AND EGFR

Abstract Background Neo-adjuvant chemotherapy (NAC) became to be a standard therapeutic strategy for advanced esophageal squamous cell carcinoma in Japan. However the multidrug combination chemotherapy with 5-FU, cisplatin (FP) and docetaxel (DFP) has been well known more effective than FP, biomarker predict efficacy of NAC is not known yet. We have reported that expression of HER2 and EGFR had correlated to the response of neoadjuvant chemotherapy and prognosis. Therefore we started to evaluate them in all cases using biopsy tissue samples from 2012. Methods The tissues were collected from 122 patients with esophageal squamous cell carcinoma before NAC with DFP from August 2012 to August 2017, and expression of HER2 and EGFR were measured with Immunohistochemistry. HER2 positive were 2 + and 3 + expression in immunostaining. The number of the patients were 20 cases in stageII, 91 cases in stageIII, and 11 cases in stageIV. These results were compared with response to NAC and outcome of the patients. Results There were no differences in patient background factors such as sex, age, location and stage.One hundred nineteen of 122 cases (97.5%) were positive for EGFR and HER2 positive cases were 12 cases (9.8%). Expression patterns of EGFR and HER2 were examined, EGFR positive-HER2 negative cases were the most common pattern, and 107 cases (87.7%), both positive were 12 cases (9.8%), and both negative were 3 cases (2.4%), EGFR negative-HER2 positive were not observed. The response rates of chemotherapy was 46.2% in the EGFR positive cases, it was 42.9% in EGFR positive-HER2 negative cases. It was 75% in HER2 and EGFR positive cases, and it was significantly higher than the other pattern (P = 0.034). HER2 expression was suggested to be a biomarker of NAC with DFP especially in stage III. Conclusion HER2 and EGFR expression was shown to be a predictor of NAC response. The patients with both negative pattern showed poorer response. The expression pattern of HER2 and EGFR can be useful biomarker of NAC response with DFP. Disclosure All authors have declared no conflicts of interest.

Multicenter phase I/II study of chemoradiotherapy with high-dose CDDP for head and neck squamous cell carcinoma in Japan

ObjectiveRecent data indicated that concurrent chemoradiotherapy (CCRT) using high dose cisplatin (CDDP) is the most useful treatment for advanced head and neck squamous cell carcinoma (SCC). Regarding the dose of CDDP, 100mg/m2 is most recommended in Western countries. However, in terms of a balance of efficacy and adverse events, appropriate dose of cytotoxic drugs such as CDDP may be different among the different ethnic groups. In this multicenter phase I/II study, we aimed to identify the optimal dose of CDDP in CCRT for patients with advanced head and neck SCC in the Japanese. MethodsPatients were eligible for inclusion if they had head and neck SCC that was treated with radical CCRT comprising whole-neck irradiation of the primary lesion and level II–IV lymph nodes on both sides. For the phase I study, a CDDP dose was 70mg/m2 for level 0, 80mg/m2 for level 1, and 100mg/m2 for level 2. Maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) were examined by phase I trial, by which CDDP dose for phase II was determined. The primary endpoint for the phase II was CCRT completion rate, and the secondary endpoint was full-dose-CCRT completion rate, the percentage of patients receiving a total CDDP dose of ≥200mg/m2, response rate, and incidences of adverse events. ResultsA CDDP dose of 100mg/m2 was the MTD for phase I, and the recommended dose for phase II was 80 mg/m2. Forty-seven patients were evaluated in the phase II trial. CCRT completion rate, full-dose-CCRT rate, and the percentage of patients receiving a total CDDP dose of ≥200mg/m2, were 93.6%, 78.7%, and 93.6%, respectively. One patient (2.1%) developed grade 2 renal dysfunction, and no patient developed febrile neutropenia or a grade 4 adverse event. ConclusionThe present phase I study indicated that a CDDP dose of 80mg/m2 is the optimal dose in terms of safety. The phase II study revealed that CCRT completion rate, response rate, and rates of adverse events were not inferior for a CDDP dose of 80mg/m2 as compared with a dose of 100mg/m2, and a dose of 80mg/m2 is therefore recommended in CCRT for the Japanese.This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification No. UMIN000010369).

Efficacy and safety of sunitinib alternate day regimen in patients with metastatic renal cell carcinoma in Japan: Comparison with standard 4/2 schedule.

Sunitinib is a standard agent for metastatic renal cell carcinoma (mRCC). The standard schedule, 4 weeks-on followed by 2 weeks-off (4/2 schedule), often does not maintain an adequate dosage because of the severe adverse events (AEs). We compared the efficacy and safety of an alternative every other day (q.a.d.) dosing with that of the 4/2 schedule in mRCC patients. Of the 55 Japanese patients, 32 and 23 were administered 4/2 (standard group) and q.a.d. schedules (50 or 37.5 mg, every other day; experimental groups), respectively. The AEs, anticancer effects, and trough plasma concentrations of sunitinib were compared between them. The most common AE in the standard group was thrombocytopenia (43.2%), but it was observed in only two patients in the experimental group (8.7%). Although leukopenia and hand-foot syndrome were both detected in six patients (18.8%) in the standard group, no patients had these AEs in the experimental group. The incidence of dose interruption in the experimental group (21.7%) was significantly lower than that in the standard group was (59.4%, P = 0.005). Time to progression (TTP) and overall survival (OS) of the experimental group were better than those of the standard group (P < 0.001 and P = 0.002, respectively). Mean plasma levels in the experimental group (64.83 ng/mL) were significantly lower than those in the standard group (135.82 ng/mL, P < 0.001) were. Sunitinib administered q.a.d. was safe and effective for mRCC patients. We speculate that the persistent optimal drug plasma concentrations contributed to these effects.