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In Japan, microsatellite instability (MSI) testing for solid tumors was introduced in clinical practice in December 2018. Although immune checkpoint inhibitors (ICIs) are established standards of care for patients with MSI-high tumors, the status of implementing MSI testing in clinical practice remains unclear.We retrospectively reviewed the medical records of patients with solid tumors who underwent MSI testing between January 2019 and December 2020 at our institution.In total, 1,052 MSI tests were performed in 1,047 patients. Regardless of specimen volume and condition, the MSI status was successfully determined in 1,041 (99.0%) tests, encompassing 27 tumor types (microsatellite stable [MSS] or MSI-low: n = 991 [95.2%] and MSI-high: n = 50 [4.8%]). Patients whose specimens were fixed with 20% neutral buffered formalin (NBF) and who had specimens with prolonged storage (98.4% and 95.4%) showed lower success rates than those whose specimens were fixed with 10% NBF and who had specimens with nonprolonged storage (100.0% and 99.6%), respectively. The prolonged turnaround time (TAT) in MSI-high cases (median TAT: 24 days) was a critical issue that directly resulted in treatment delay. Of the 50 patients with MSI-high tumors, 24 (48.0%) received ICIs and 34 (68.0%) were referred to the Department of Clinical Genetic Oncology where 6 (12.0%) patients were diagnosed with Lynch syndrome.MSI testing was successfully performed for various types of tumors and specimens in clinical practice. Our study results identified certain issues associated with the clinical implementation of MSI testing, including optimal specimen selection, extended TAT in MSI-high cases, and awareness of hereditary tumors.

The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients.We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups.A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib.Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

Naomi Hayashi,1 Yasuyoshi Sato,1 Yu Fujiwara,1,2 Naoki Fukuda,1 Xiaofei Wang,1 Kenji Nakano,1 Testuya Urasaki,1 Akihiro Ohmoto,1 Makiko Ono,1 Junichi Tomomatsu,1 Yukiko Sato,3 Hiroki Mitani,4 Takashi Toshiyasu,5 Shunji Takahashi1 1Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York City, NY, USA; 3Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 4Head and Neck Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 5Radiation Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanCorrespondence: Yasuyoshi SatoThe Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, 135-8550, JapanTel +8135200111Fax +81335200141Email yasuyoshi.sato@jfcr.or.jpPurpose: There have been few reports on the evaluation of cancer cachexia based on skeletal muscle mass index (SMI) in patients with head and neck cancer.Patients and Methods: One hundred and ninety-two head and neck cancer patients were enrolled. In definitive and adjuvant chemoradiotherapy settings, clinical outcomes were compared between cachexia and non-cachexia patients.Results: Forty patients were diagnosed with cachexia (20.8%). In the definitive setting, overall survival (OS) was significantly shorter in the cachexia group (3-year OS: 50.0% vs 88.5%; p < 0.01), and multivariate analysis identified UICC stage IV, baseline albumin of < 4 and cachexia as poor prognostic factors. However, cachexia was not significant in the adjuvant setting.Conclusion: Cancer cachexia was negatively associated with prognosis in patients with HNC who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients.Keywords: head and neck cancer, squamous cell carcinoma of head and neck, sarcopenia, cachexia, muscle, skeletal, chemoradiotherapy, prognosis

Milademetan (DS‐3032, RAIN‐32) is an orally available mouse double minute 2 (MDM2) antagonist with potential antineoplastic activity owing to increase in p53 activity through interruption of the MDM2‐p53 interaction. This phase I, dose‐escalating study assessed the safety, tolerability, efficacy, and pharmacokinetics of milademetan in 18 Japanese patients with solid tumors who relapsed after or were refractory to standard therapy. Patients aged ≥ 20 years received oral milademetan once daily (60 mg, n = 3; 90 mg, n = 11; or 120 mg, n = 4) on days 1 to 21 in a 28‐day cycle. Dose‐limiting toxicities, safety, tolerability, maximum tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. The most frequent treatment‐emergent adverse events included nausea (72.2%), decreased appetite (61.1%), platelet count decreased (61.1%), white blood cell count decreased (50.0%), fatigue (50.0%), and anemia (50.0%). Dose‐limiting toxicities (three events of platelet count decreased and one nausea) were observed in the 120‐mg cohort. The plasma concentrations of milademetan increased in a dose‐dependent manner. Stable disease was observed in seven out of 16 patients (43.8%). Milademetan was well tolerated and showed modest antitumor activity in Japanese patients with solid tumors. The recommended dose for phase II was considered to be 90 mg in the once‐daily 21/28‐day schedule. Future studies would be needed to further evaluate the potential safety, tolerability, and clinical activity of milademetan in patients with solid tumors and lymphomas. The trial was registered with Clinicaltrials.jp: JapicCTI‐142693., We are presenting the first report of a phase I study evaluating the safety, tolerability, efficacy, and pharmacokinetics of milademetan in Japanese patients with advanced solid tumors. The plasma concentrations of milademetan increased in a dose‐dependent manner. Milademetan was well tolerated and showed modest antitumor activity in Japanese patients with solid tumors.

BACKGROUND/AIM Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib. PATIENTS AND METHODS Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions. RESULTS Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. While mitotane is the only agent approved for ACC, clinical data are scarce, especially in the Asian population. We reviewed 10 patients with ACC who received mitotane as a single agent or in combination with other agents in our institution. Patient characteristics, clinical outcomes, and toxicities were analyzed. Mitotane was administered to 2 patients as an adjuvant therapy and to 8 patients for systemic control. In the latter 8 patients, 1 patient had locally advanced disease and 1 had metastatic disease at the time of initial diagnosis, whereas the other 6 patients experienced metastatic relapse at mitotane initiation. The administered regimen was mitotane alone in 7 patients, and mitotane plus cytotoxic chemotherapy in 3 patients. The initial daily mitotane dose was 3.0 g in 2 patients, 1.5 g in 7 patients, and 1.0 g in 1 patient. The median duration of treatment was 3.7 (range, 0.7-22.1) months. In 8 systemic cases, the median overall survival from chemotherapy initiation was 7.2 months, and only 1 patient survived over 1 year. The median interval from mitotane termination to death in systemic cases was 2.8 months, and the cause was progressive disease in 4 patients and toxicity (hallucination, mycobacteriosis, or liver injury) in 3 patients. As a second-line regimen, 2 systemic cases and 1 adjuvant case were enrolled in clinical trials. Our analysis exhibited extremely poor prognosis under mitotane-based regimens, and further treatment strategies are warranted to improve outcomes.

BACKGROUND Eribulin is widely used for the treatment of breast cancer and soft-tissue sarcoma (STS). Previous studies identified the pre-treatment absolute lymphocyte count, baseline neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein concentration as potential prognostic markers in patients with breast cancer treated with eribulin. However, prognostic factors for eribulin treatment in patients with STS have not been identified. PATIENTS AND METHODS This was a retrospective analysis of data collected prospectively from 53 patients who were treated with eribulin for recurrent or metastatic STS between March 2016 and August 2019. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit, progression-free survival, and overall survival. RESULTS L-Sarcoma histology [hazard ratio (HR)=28.20, 95% confidence intervaI (CI)=1.67-476.00; p=0.021] and pre-treatment NLR

Background/aim In the CheckMate-141 trial regarding head and neck cancer (HNC), nivolumab conferred a survival benefit to patients. However, the best treatment sequence of chemotherapy and anti-PD-1/PD-L1 therapy in these cancers is unclear. Patients and methods This was an observational study using data collected prospectively from 97 HNC patients treated with nivolumab at our institutions. Twenty-two HNC patients who received paclitaxel-based chemotherapy before (pre-PTX, n=12) and after (post-PTX, n=10) nivolumab were evaluated. Results The median follow-up time was 15.9 months (range=6.9-35.9 months). There was a significant difference in the overall response rate (ORR) between pre-PTX (17%) and post-PTX (70%) (p=0.027). Similarly, time to progression (TTP) was significantly longer after nivolumab than before nivolumab (post-PTX, 7.4 months; pre-PTX, 4.9 months, p=0.020). Conclusion Paclitaxel-based chemotherapy had a better ORR and TTP after nivolumab than before nivolumab for HNC. The sequential administration of anti-PD-1 therapy followed by paclitaxel-based chemotherapy could be a better strategy for HNC.

Background: Large prospective studies of chemotherapy for metastatic or recurrent adenoid cystic carcinoma (ACC) of the head and neck are lacking due to the rarity of ACC. The aim of this study is to evaluate the efficacy of carboplatin plus paclitaxel toward ACC and perform an exploratory investigation of the prognostic factors to investigate the optimal strategy for metastatic or recurrent ACC.Methods: We retrospectively analyzed recurrent or metastatic ACC patients treated with carboplatin plus paclitaxel between April 2007 and September 2019 in our hospital. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated, and an exploratory analysis of the prognostic factors including tumor growth rate (TGR) was conducted.Results: A total of 26 ACC patients were enrolled. ORR and DCR were 11.5% and 76.9%; the median PFS and OS were 8.1 and 22.3 months, respectively. From the results of the multivariate analysis, higher (≥ 6%/month) TGR was associated with worse PFS (hazard ratio [HR] 7.00, 95%CI 1.34–36.53, p = 0.02) and OS (HR 29.33, 95%CI 3.38–254.80, p Conclusions: Carboplatin plus paclitaxel showed modest efficacy for recurrent or metastatic ACC patients. Watchful waiting may be optimal for ACC patients with lower TGR. Systemic chemotherapy should be considered when TGR increases during active surveillance.

Objective To report our institutional experience with treatment of primary genitourinary soft tissue sarcoma. Methods We retrospectively reviewed the medical records of adult soft tissue sarcoma patients treated between March 2005 and May 2019. The primary tumor sites included the prostate, kidney, urinary bladder and the paratesticular structures. Results A total of 19 patients - 16 men (84%) and three women (16%) - were enrolled in the study. The median age was 41 years (range 20-79 years). The most common primary site was the prostate (in eight patients; 42%), and prostatic sarcoma patients were younger than patients with sarcomas of other origins. The most common histological subtype was leiomyosarcoma (in five patients; 26%). The overall survival rates after 1, 3 and 5 years were 61.5%, 34.4% and 25.8%, respectively. The median survival time was 20.7 months (95% confidence interval 5.9-35.5 months). Univariate analysis showed that an absence of metastasis at diagnosis and complete surgical resection were predictive of favorable survival. In the chemotherapy group, the objective response rate was 20.5%. Pazopanib was administered to nine patients in the late-line setting, and the objective response rate was 11.1%; six grade ≥3 adverse events were observed in three patients. Conclusions Inoperable metastatic genitourinary soft tissue sarcoma remains difficult to treat, as previously reported. Further investigation on this malignancy, including optimization of currently available antitumor drugs and the development of novel therapeutic agents, is required.

Background In the CheckMate-141 trial, nivolumab conferred a survival benefit in patients with recurrent or metastatic refractory squamous cell carcinoma (SCC) head and neck cancer (HNC). Here, we examined the efficacy of nivolumab in patients with histological subtypes or primary sites of HNC not included in the CheckMate-141 trial. Methods This was a retrospective analysis of data collected prospectively from 97 patients who were treated with nivolumab for recurrent or metastatic HNC at our institution. The patients were assigned to three groups based on HNC primary site: 1) oral cavity, pharynx, and larynx, which were included in CheckMate-141 (n = 68), 2) nasopharynx (excluded in CheckMate-141, n = 7) and 3) other primary sites excluded in CheckMate-141 (n = 22) and assigned to two groups according to histological subtype: 1) SCC (included in CheckMate-141, n = 83) and 2) non-SCC (all sites excluded in CheckMate-141, n = 14). Survival outcomes and nivolumab treatment response were compared between the primary site and histological subgroups. Results The median number of nivolumab treatments was 7 cycles (range, 1-53 cycles) and the median follow-up time was 9.1 months (range, 0.66-33.0 months). There were no significant differences in response rates between the three primary site subgroups (CheckMate-141 sites 22%, nasopharynx 43%, others 18%; p=0) or the two histological subtype subgroups (SCC 25%, non-SCC 7%, p=0). Similarly, overall survival and progression-free survival were comparable for patients stratified by primary site or histological subtype. Conclusion No significant difference in response rates or survival outcomes was detected between nivolumab-treated HNC patients with primary sites and histological subtypes that were included versus excluded in the CheckMate-141 trial. These data provide a potential rationale for nivolumab therapy for all HNC patients in clinical practice.

Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (225 mg/mThe study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

Simple Summary Second-line systematic therapy options for soft-tissue sarcoma (STS) have remained unchanged for decades due to the rarity and various histological types associated with STS. Challenges with molecular-targeted treatments for STS led to the approval of pazopanib and its wide use for STS. However, predictive markers of pazopanib treatment for STS have not been identified. Baseline neutrophil-to-lymphocyte ratio (NLR) is known as a candidate biomarker for several cancers. In this retrospective study, we investigated the use of the NLR as a predictor for the efficacy and prognosis of pazopanib in patients with STS. Our findings could be useful for the development of biomarker-targeted therapies for STS. Abstract Pazopanib with trabectedin and eribulin is widely used to treat soft-tissue sarcoma (STS). We have shown that baseline neutrophil-to-lymphocyte ratio (NLR) may predict the efficacy and patient prognosis of eribulin. Changes in NLR, but not baseline NLR, can predict patient prognosis of trabectedin. However, prognostic factors of pazopanib for STS have not been identified. We present a retrospective analysis of 141 patients treated with pazopanib for recurrent or metastatic non-round cell STS. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit (DCB), overall survival (OS), and progression-free survival. L-sarcoma histology (odds ratio [OR] = 0.31, 95% CI = 0.12–0.79; p = 0.014) and pre-treatment NLR < 3.0 (OR = 2.03, 95% CI = 1.02–6.67; p = 0.045) were independent predictive factors of DCB. Pre-treatment NLR < 3.0 (hazard ratio [HR] = 0.55, 95% CI = 0.36–0.84; p = 0.0057), liposarcoma histology (HR = 1.78, 95% CI = 1.09–2.91; p = 0.022), primary extremity site (HR = 0.48, 95% CI = 0.31–0.75; p = 0.0010), ECOG PS ≥ 1 (HR = 1.62, 95% CI = 1.08–2.42; p = 0.019), and CRP < 0.3 (HR = 0.52, 95% CI = 0.33–0.82; p = 0.0050) were independent predictive factors of OS. These findings indicate that baseline NLR predicts the efficacy and patient prognosis of pazopanib for STS.

Immune checkpoint inhibitors (ICIs) play a significant role in therapy for relapsed or refractory cancers due to their excellent efficacy. ICIs, however, frequently induce immune-related adverse events (irAEs) in various tissues and organs, sometimes leading to severe conditions. Thus, early identification and treatment of irAEs are important. Herein, the authors report two cases of a rare type of irAE, severe keratoconjunctivitis with deterioration of eyesight, induced by ICIs. Characteristically, both cases were accompanied by concurrent severe oral mucositis. The patients were treated successfully with both systemic and topical ophthalmic corticosteroids, resulting in complete remission of severe pseudomembranous conjunctivitis and full recovery of eyesight. ICI-induced keratoconjunctivitis progresses rapidly and can lead to blindness. Thus, prompt diagnosis and treatment are necessary.Lay abstract Currently, ‘immunotherapy’ has changed cancer treatments drastically. In this article, the authors use immune checkpoint inhibitors (ICIs) for cancer treatments as ‘immunotherapy’. Generally, cancer puts on the brakes to stop attacking itself via immune checkpoint molecules to survive. ICIs inhibit the mechanism, and patients battle their cancer by using their own activated lymphocytes. However, the activated lymphocytes can attack patients' own normal tissues and organs. ‘Immune-related adverse events’ can occur everywhere in the body. In this article, the authors present an ICI-related severe eye trouble, which is very rare but can put patients at risk of vision loss.

Background: The clinical benefit of systemic chemotherapy for recurrent/metastatic retroperitoneal/intra-abdominal soft tissue sarcoma (STS) compared to its benefits for other primary lesions has not been known or sufficiently evaluated. Methods and Patients: We retrospectively reviewed the cases of the STS patients who consulted a department of medical oncology in Tokyo between June 2011 and March 2018, and we extracted the cases of patients with primary sites at the retroperitoneum/intra-abdomen (cohort R) or extremities/trunk (cohort E) who received systemic chemotherapy in a recurrent/metastatic setting, comparing the cohorts’ characteristics, chemotherapy details, and prognoses. Results: Of all 337 STS patients, we enrolled 49 patients in cohort R and 75 patients in cohort E. Liposarcoma was more frequently observed in cohort R (51.0%) than cohort E (22.7%). The median chemotherapy treatment line was two lines (range: 1–6) in cohort R and three lines (range: 1–9) in cohort E. The doxorubicin usage rates differed in recurrent/metastatic settings (90.0% in cohort R and 55.0% in cohort E), due mainly to the higher rate of a perioperative chemotherapy treatment history in cohort E (52.0% vs. 6.1% in cohort R). The median overall survival from the start of salvage chemotherapy was 31.9 months (cohort R; 95% CI: 20.9–42.8) and 27.1 months (cohort E; 95% CI: 21.6–32.5) (p = 0.549). Conclusion: There were differences in the distributions of pathology and antitumor drugs used in a salvage setting between retroperitoneal/intra-abdominal and extremities/trunk STS patients in recurrent/metastatic settings, but the prognoses with salvage chemotherapy were similar in the two cohorts.

Objectives: This retrospective observational study is conducted to evaluate the association between cancer cachexia and prognosis in head and neck cancer patients treated with chemoradiotherapy using skeletal muscle mass index at the level of the third lumbar vertebra with computed tomography.Methods: Two hundred forty-two patients were enrolled and categorized into the following four groups based on cancer cachexia criteria and treatment setting: definitive chemoradiotherapy with cachexia, definitive chemoradiotherapy without cachexia, adjuvant chemoradiotherapy with cachexia, and adjuvant chemoradiotherapy without cachexia. Progression-free survival (PFS) and overall survival (OS) between cachexia and non-cachexia groups were compared by treatment setting using the long-rank test. Prognostic factors were evaluated using the Cox proportional hazards model.Results: Fifty patients were diagnosed with cancer cachexia (20.7%). In the definitive setting, both PFS and OS were significantly shorter in the cachexia group (median PFS, 15.5 months vs. not reached, p < 0.01; median OS, 48.4 months vs. not reached. p < 0.01). Conversely, there was no significant difference between the two groups in the adjuvant setting. UICC Stage IV, base of albumin of Conclusion: Cancer cachexia was negatively related with prognosis in patients with head and neck squamous cell carcinoma who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients. Further research is warranted.

Background/Aim: Trabectedin is a synthetic antineoplastic agent approved for advanced soft tissue sarcoma (STS) in Japan. The aim of this study was to evaluate the efficacy and safety of the Japan-approved dose of trabectedin for advanced STS. Patients and Methods: We retrospectively reviewed 38 patients with advanced STS who received salvage chemotherapy with trabectedin. Results: The overall response and disease control rates were 16% (5 patients) and 67% (20 patients), respectively. The median progression-free and overall survival were 7.3 and 17.8 months, respectively. There were no significant differences between patients with liposarcoma or leiomyosarcoma and those without, or between patients with TRS and those without. The most common grade 3-4 AEs were elevated transaminases and neutropenia. Conclusion: Trabectedin 1.2 mg/m(2), as the approved dose in Japan, showed similar efficacy to the dose of 1.5 mg/m(2) used in Western countries. Trabectedin could be an option for advanced STS in Japan, regardless of histological subtype.

Background/Aim: Trabectedin and eribulin are widely used for the treatment of soft-tissue sarcoma (STS). Previously it was shown that the baseline neutrophil-to-lymphocyte ratio (NLR) predicts the efficacy of eribulin for STS. However, prognostic factors for trabectedin on STS have not been identified to date. Patients and Methods: We conducted a retrospective study of data collected prospectively from 39 patients treated with trabectedin for recurrent or metastatic STS between October 2012 and December 2019. To determine the predictive factors of overall survival (OS) and progression-free survival (PFS), univariate and multivariate analyses were performed. Results: Age ≥40 (HR=0.33, 95% CI=0.15-0.71; p=0.0050) and changes in NLR (ΔNLR)

Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983-2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10-42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21-74%) and median overall survival was 4.4 years (95% CI, 2.4 years-not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.

Background Head and neck squamous cell carcinoma (HNSCC) is a geriatric cancer. However, older adult patients are frequently underrepresented in large clinical trials. Aims The aim of this study is to assess the efficacy and safety of the EXTREME regimen (platinum + fluorouracil + cetuximab) in older and younger adult patients with HNSCC. Methods and results Patients with recurrent or metastatic HNSCC treated with the EXTREME regimen were retrospectively analyzed. We compare the efficacy and safety in older (aged ≥70 years) younger (aged

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

Background/Aim: Lenvatinib is one of the few options for patients with anaplastic thyroid cancer (ATC). However, tumor markers for ATC treated with lenvatinib is lacking. The aim of this study was to explore whether the neutrophil-to-lymphocyte ratio (NLR) can be a tumor marker for ATC treated with lenvatinib. Patients and Methods: We retrospectively analyzed the prognostic significance of the NLR in 13 ATC patients treated with lenvatinib. Results: The disease control rate was better in patients with lower NLR (

Clinical evidence regarding eribulin treatment for patients with soft tissue sarcoma (STS) is limited to those with L-sarcoma (leiomyosarcoma and liposarcoma) who have completed at least two chemotherapies. Whether histological subtypes and treatment lines affect the efficacy and safety of eribulin for patients with STS has yet to be elucidated. The current study retrospectively reviewed patients with STS receiving eribulin at the Cancer Institute Hospital of JFCR and evaluated the prognostic factors affecting its efficacy and safety by histological diagnoses and treatment lines. A total of 41 patients with STS, including 26 with L-sarcoma, underwent eribulin treatment. Additionally, a total of and 14 patients, including 12 with L-sarcoma, received eribulin as a second-line treatment. The results revealed that patients with L-sarcoma demonstrated longer progression-free survival (PFS) rates compared with patients without L-sarcoma (4.5 vs. 2.3 months; P=0.005). Furthermore, differences in treatment line significantly affected PFS (4.5 months in second-line treatment vs. 2.4 months in later lines; P=0.037). A high number of patients with L-sarcoma received eribulin as a second-line treatment. Regarding safety, several adverse events were reported, such as neutropenia, which were more frequently observed in patients with L-sarcoma or other patients receiving eribulin as a second-line treatment. However, most adverse events were tolerable. The clinical efficacy of eribulin was increased in patients with L-sarcoma, which was similar to previous clinical trials. However, treatment lines could also affect its efficacy. When evaluating the clinical value of eribulin to STS, it is important to consider treatment lines.

Taselisib is a potent and selective phosphatidylinositide 3‐kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2‐stage, phase I, multicenter, open‐label, dose‐escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)‐positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28‐day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose‐limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment‐related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half‐life was 12.9‐32.0 hours in stage 1 and 16.1‐26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA‐mutated solid tumors or HR‐positive advanced breast cancer.

Objective: In a phase III trial, Western patients with medullary thyroid cancer (MTC) treated with the oral multikinase inhibitor vandetanib showed significantly improved progression-free survival (PFS) and objective response rate (ORR) compared with placebo. The biology of MTC and pharmacokinetics (PK) are similar for Japanese and Western patients; therefore, similar clinical benefit is anticipated in the Japanese population. This study evaluated the safety and tolerability of vandetanib in Japanese patients with unresectable locally advanced or metastatic MTC. Methods: This was a phase I/II, open-label, nonrandomized study. Patients received vandetanib (300 mg daily) until objective disease progression. The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and PK. Final data analysis was conducted once all patients with measurable baseline disease had been followed to progression, or for 56 weeks. Results: Fourteen patients received vandetanib. All patients experienced at least one adverse event (AE), and 7 patients (50%) experienced grade ≥3 AEs. Common AEs included diarrhea (79%), hypertension (64%), and rash (43%). Four patients reported a total of five serious AEs (SAEs). Eleven patients (79%) had dose interruptions, and 8 patients (57%) had dose reductions. One patient discontinued treatment because of an SAE (interstitial lung disease). No patients met the prespecified criterion for QTc prolongation. The ORR was 38% and PFS at 12 months was 85%. Conclusion: Safety and efficacy data were comparable to those previously reported, and AEs were generally manageable by standard clinical practice or dose modifications. Overall, vandetanib was considered to be beneficial for Japanese MTC patients. Abbreviations: AE = adverse event CI = confidence interval Css,max = maximum steady-state plasma concentration DCR = disease control rate EGFR = epidermal growth factor receptor ILD = interstitial lung disease MTC = medullary thyroid cancer ORR = objective response rate PFS = progression-free survival PK = pharmacokinetics RECIST = Response Evaluation Criteria in Solid Tumors RET = re-arranged during transfection SAE = serious adverse event VEGFR = vascular endothelial growth factor receptor

Humoral hypercalcemia due to parathyroid hormone-related peptide (PTHrP) elevation is a well-known complication of various malignancies, but the situation is rare concerning hematological malignancies except for adult T-cell leukemia/lymphoma. We report a case of Richter’s syndrome with humoral hypercalcemia, and demonstrate by reverse transcription polymerase chain reaction (RT-PCR) that peripheral blood PTHrP levels were 2,500-fold higher compared to healthy controls. PTHrP production by tumor cells in chronic lymphocytic leukemia (CLL) and Richter’s syndrome has been previously demonstrated by nonquantitative methods such as immunohistochemistry and northern blot analysis, but this is the first report using the RT-PCR method. The presented case did not have hypercalcemia when initially diagnosed as small lymphocytic lymphoma (SLL), and as reported earlier, the development of hypercalcemia may be an indication of the transformation to Richter’s syndrome in patients with CLL/SLL.

Purpose Ipatasertib is a selective inhibitor of Akt, a frequently activated protein kinase in human cancers. The current study assessed the safety, tolerability, and pharmacokinetics of ipatasertib in Japanese patients with solid tumors. Methods This was a phase I, open-label, 3 + 3 dose-escalation study conducted in two stages. In stage I, Japanese patients with solid tumors were administered ipatasertib 200, 400, or 600 mg/day for 21 days of a 28-day cycle. In stage II, Japanese patients with castration-resistant prostate cancer were administered ipatasertib 200 or 400 mg/day in combination with abiraterone and prednisolone in 28-day cycles. Dose-limiting toxicity (DLT) was assessed at each dose before enrolling patients at a higher dose; DLT was used to determine the maximum tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic parameters were assessed after a single dose and at steady state. Results Fifteen patients were enrolled in Stage I and six in Stage II. The ipatasertib MTD was 600 mg as monotherapy and MAD was 400 mg in combination with abiraterone and prednisolone. Ipatasertib plasma exposure was dose proportional across the dose range, and was not markedly affected by concurrent administration of abiraterone plus prednisolone. Stable disease (SD) was observed in eight patients treated with ipatasertib monotherapy (53.3%); four patients had SD and one had complete response with ipatasertib plus abiraterone and prednisolone. Conclusions Ipatasertib, at the monotherapy MTD of 600 mg/day and MAD of 400 mg/day in combination with abiraterone and prednisolone, was safe and tolerable in Japanese patients with solid tumors. Electronic supplementary material The online version of this article (10.1007/s00280-019-03882-7) contains supplementary material, which is available to authorized users.

e18007 Background: Concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) is a standard treatment for locally advanced head and neck cancer (LAHNC) in the definitive setting. Three cycles of 100 mg/m2 CDDP for every three weeks (Q3W) are now recommended but compliance with CCRT is relatively low due to its severe toxicity. Therefore, the potential de-escalation strategies for LAHNC have been discussed to decrease the therapeutic toxicity. Methods: Patients with LAHNC who underwent definitive CCRT with CDDP between 2012 and 2018 at The Cancer Institute Hospital of Japanese Foundation for Cancer Research were analyzed. Patients were classified into two groups based on the planned CDDP dose: (A) 100 mg/m2 and (B) 80 mg/m2 Q3W for three times. One-to-one propensity score matching was performed to minimize bias between two groups. After patients in two groups were matched by using propensity score, the overall survival (OS), recurrence-free survival (RFS), local recurrence-free survival (LRFS), and metastatic recurrence-free survival (MRFS) were analyzed by the Kaplan-Meier method with the Cox proportional hazards model. The follow-up term was set as two years to evaluate the early survival benefit. The dose and density of CDDP and the objective adverse events were also assessed. Results: A total of 304 patients were included with the median age of 62 (Interquartile range [IQR]: 54-67) years. Among them, 249 patients (82%) were male. Patients were treated with 100 mg/m2 CDDP (n = 145) and 80 mg/m2 CDDP (n = 159) regimens. After the propensity score matching, 119 patients were included in each group, respectively. There were no significant differences in baseline characteristics between two propensity-matched cohorts. The median follow-up time was 24 months in each group. Two-year OS was 93.0% (95% confidence interval [CI]: 88.4-97.8) in group A and 94.9% (91.0-99.0) in group B. Two-year RFS was 86.5% (80.6-92.9) in group A and 83.1% (76.6-90.1) in group B, respectively. No significant difference was observed in OS (Hazard ratio [HR] = 1.42, 95% CI: 0.49-4.08, p = 0.52), RFS (HR = 0.81, 95% CI: 0.42-1.57, p = 0.54), LRFS (HR = 0.57, 95% CI: 0.24-1.36, p = 0.20), and MFS (HR = 1.32, 95% CI: 0.52-3.35, p = 0.56). The median cumulative dose of CDDP was significantly higher in group A (300 mg, interquartile range [IQR]: 240-300) than in group B (240 mg, IQR:160-240) but the frequency of hematological, hepatic, renal, electrolytic, and grade 3-5 any adverse events was not significantly different between two groups. Conclusions: Our study showed no survival difference at 2-year follow-up between 100 mg/m2 and 80 mg/m2 CDDP regimens of definitive CCRT for LAHNC. This result could support the tide of the de-escalation strategy in head and neck cancer treatment. Longer follow-up is necessary and further prospective trials comparing CDDP dosage are warranted.

Purpose Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients. Methods LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status. Results The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11–14 days. No anti-LJM716 antibodies were detected. Conclusions LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed. Clinical trial information ClinicalTrials.gov NCT01911936.

Background. Doxorubicin is the key drug for treatment of advanced soft tissue sarcoma (STS). The appropriate dosage of doxorubicin, regarding monotherapy or the role of combination therapy, is unclear. Methods. We retrospectively reviewed patients with advanced or metastatic STS of nonextremities who were treated with doxorubicin-based chemotherapies in our institution. Time to treatment failure (TTF), overall survival (OS), overall response, and prognostic factors for OS were evaluated. Results. Seventy-five patients were enrolled. The median TTF was 4.7 months, and the median OS was 20.1 months. The overall response rate was 20%. Doses of doxorubicin monotherapy did not show significant difference either in TTF or in OS. There were no significant differences in OS between combination therapy and monotherapy, but the TTF with combination therapy was better than monotherapy. The overall response for combination therapy indicated a better response rate. Less number of involved organs, no bulky mass, and a normal CRP level were independent favorable prognostic factors for OS. Conclusions. Combination therapy showed better response and TTF than monotherapy but did not show better OS. Possible prognostic factors for OS were indicated. This retrospective study was approved by the institutional review board. This trial is registered with UMIN000028787.

Objective: In Japan, pazopanib has been made available to soft tissue sarcoma patients, also to patients histologically diagnosed as ineligible for the international Phase 3 study (PALETTE). However, clinical evidence for the use of pazopanib in PALETTE-ineligible patients is currently insufficient. Methods: We retrospectively reviewed medical records of soft tissue sarcoma patients treated with pazopanib at our institute. By pathological review, the patients’ eligibility for the PALETTE was evaluated and the differences in their responses to pazopanib and incidences of adverse events were investigated. Results: From November 2012 to August 2014, a total of 47 patients received pazopanib, 38 (81%) of whom were histologically eligible for the PALETTE, and 9 of whom (19%) were not. The median follow-up time was 7.5 months (range 1.4–20.3 months). An objective response was observed in both groups, but the patients’ survival tended to be longer in the PALETTE-eligible patients; median progression-free survival was 4.5 months vs. 2.9 months (P= 0.15) and overall survival was 10.7 months vs. 7.8 months (P = 0.55), though these differences were not statistically significant. There were no significant differences in the incidence of adverse events by PALETTE eligibility, but dose skipping or dose reduction was more likely to be observed in PALETTE-ineligible patients. Conclusion: Pazopanib is tolerable to soft tissue sarcoma patients ineligible for the PALETTE and some of them respond to pazopanib, but the prognoses of patients ineligible for the PALETTE might be worse than those of PALETTE-eligible patients. The indication of pazopanib for soft tissue sarcoma patients with PALETTE-ineligible histologies should be decided carefully.

Background The effectiveness of the combination chemotherapy of weekly paclitaxel and cetuximab has not yet been compared to that of the current standard regimen, EXTREME (combination of 5-fluorouracil, cisplatin and cetuximab). Methods We retrospectively reviewed the clinical records of R/M SCCHN patients who received cetuximab-containing chemotherapy as a first-line therapy; from these, patients receiving a weekly paclitaxel and cetuximab regimen (cohort A) and the EXTREME regimen (cohort B) were extracted. The responses, prognoses and adverse events of these two cohorts were evaluated. Results A total of 86 patients were included (cohort A, 49; cohort B, 36). Patients with histories of platinum-based chemotherapy were more frequently given the cohort A treatment. Though the response rates were similar in the two cohorts (45% in cohort A and 51% in cohort B; p = 0.83), the progression-free survival (PFS) was significantly more favorable in cohort A by the log-rank test (6.0 months vs 5.0 months; p = 0.027). In the Cox-regression hazard analyses, male gender (hazard ratio [HR] = 2.1, p = 0.010), older age (≥ 70 yo) (HR = 5.0, p = 0.018), PS 0 (HR = 2.2, p = 0.027), no history of platinum chemotherapy (HR = 3.2, p = 0.003) and the presence of a tracheostomy (HR = 2.3, p = 0.039) were favorable factors within cohort A. Conclusion In selected R/M SCCHN patients, the combination of weekly paclitaxel and cetuximab could be the better treatment option than the EXTREME regimen.

Background Precision medicine using next gene sequencing (NGS) of tumor tissues has become mainstream of cancer therapy. Liquid biopsy is minimally invasive Method of sampling to assess tumor genotypes, and would be useful for detecting targetable mutations, follow-up during therapy, and detecting relapse, but more data are needed to clarify its significance. We show some preliminary data for liquid biopsy to detect actionable mutations in various cancer patients. Method We analyzed peripheral blood (14 ml) of patients with various cancers resistant to or without standard therapy and purified circulating cell-free DNA and RNA, then sequenced with customized Oncomine Pan-cancer cell free assay to detect actionable mutations in 95 genes. Data would be confirmed with sequencing of cancer tissues if possible, and be followed during therapy. Results From September 2018 to February 2019, 41 patients were analyzed. Of the 41 patients, primary loci of cancer are breast (n = 12), pancreas (n = 7), soft tissue sarcoma (n = 6), uterine (n = 5), head and neck (n = 3), ovary (n = 3), urothelial (n = 2), others (n = 3). The median age was 57 (25-78) years, performance status was 0-1 in all patients. No actionable mutation was detected in 7 patients. In other 34 patients, some significant mutations could be detected. Of those mutations, TP53 mutations were detected in 20 patients, PIK3CA mutations in 10, KRAS mutations in 7, AKT1 mutation in 1, BRAF mutation in 1, MTOR mutation in 1, FGFR3 amplification in 3. Conclusion The results suggest that actionable or druggable mutation can be detected by liquid biopsy using NGS. Further validation with tumor tissue examination and targeting therapy is needed.