Metastatic castration resistant prostate cancer patients' experience with Radium-223 treatment in Japan.

Aim: We aimed to determine Japanese metastatic castration resistant prostate cancer (CRPC) patients' Ra-223 treatment experience. Patients & methods: Patients answered the Cancer Therapy Satisfaction Questionnaire (CTSQ domains: Satisfaction with Therapy [SWT], Expectations of Therapy [ET], Feelings about Side Effects [FSE]), the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) and the FACT-Bone Pain (FACT-BP) Questionnaire at baseline, during (vists 3 and 5) and after treatment (end of observation; EOO). Results: Data from 72 patients were included. Baseline median CTSQ scores SWT: 66.1 (IQR19.7), ET: 75.0 (IQR45), and FSE 68.8 (IQR 34.4) were unchanged during vists 3 and 5, but the SWT (-3.57 [IQR17.9]) and ET (-5.0 [IQR30]) decreased while FSE was unchanged (0.0 [IQR31.25]) at EOO. The median MAX-PC (18.0 [IQR 49]) score was unchanged (0.0, IQR 6) while the median FACT BP (54.0 [IQR13]) score decreased by -1.0 (IQR 8) at EOO. Conclusion: Japanese metastatic castration resistant prostate cancer patients' experience is stable during Ra-223 treatment.

What is this study about? We wanted to know the treatment experience with Radium-223 (Ra-223) among Japanese prostate cancer patients. Ra-223 is a radioactive molecule used for the treatment of metastatic castration resistant prostate cancer. We asked patients to answer different questionnaires on treatment satisfaction, anxiety and quality of life before, during, and after treatment with Ra-223. What were the results? Based on the patients' answers to our questionnaires, treatment satisfaction, anxiety and quality of life remain stable while the patients undergo treatment with Ra-223, but in some aspects may decline after treatment. What do the results mean? The results mean that patients' experience during Ra-223 treatment is stable but patients should share any concerns they have about their treatment with their doctors.

Outcomes in patients with high- and very high-risk localized prostate cancer treated with definitive IMRT and long-term hormone therapy.

BACKGROUND: The aim of this study was to evaluate the effectiveness of intensity-modulated radiation therapy in combination with long-term androgen deprivation therapy for high-risk and very high-risk localized prostate cancer while also investigating factors associated with the therapeutic effect. METHODS: Men who fulfilled criteria for the National Comprehensive Cancer Network high-risk or very high-risk localized prostate cancer and were treated with definitive intensity-modulated radiation therapy (74-78 Gy) of the prostate and the seminal vesicle combined with androgen deprivation therapy in our institution from 2007 to 2016 were identified (n = 197). In principle, patients received androgen deprivation therapy for 3-6 months before radiation, concurrently, and for 2 years after completion of intensity-modulated radiation therapy. RESULTS: The median follow-up period was 96 months. The 5-year and 10-year overall survival rates in the overall population were 96.9% and 89.3%, respectively. The 5-year and 10-year cumulative incidence rates of biochemical failure were 2.5% and 16.3% in the high-risk group, and 8.6% and 32.0% in the very high-risk group, respectively, indicating a significant difference between the two groups (P = 0.023). Grade Group 5 and younger age (cutoff: 70 years old) were independent predictors of recurrence (P = 0.016 and 0.017, respectively). Patients exhibiting biochemical failure within <18 months after completion of androgen deprivation therapy displayed an increased risk of cancer-specific mortality (P = 0.039) when contrasted with those who had a longer interval to biochemical failure. CONCLUSIONS: Patients with the National Comprehensive Cancer Network very high-risk prostate cancer, particularly those with Grade Group 5 and younger age, showed worse outcomes following intensity-modulated radiation therapy and long-term androgen deprivation therapy.

Clinical outcomes of first-line combination therapy with immune checkpoint inhibitor for metastatic non-clear cell renal cell carcinoma: a multi-institutional retrospective study in Japan.

BACKGROUND: In metastatic clear cell renal cell carcinoma (ccRCC), recent studies have shown promising efficacy of immune checkpoint inhibitor (ICI) combination therapy. However, there are insufficient evidences about clinical efficacy and safety of ICI combination therapy in metastatic non-ccRCC (nccRCC). METHODS: We retrospectively investigated 44 patients treated with nivolumab plus ipilimumab (ICI + ICI group) or anti-PD-1/PD-L1 inhibitor plus tyrosine kinase inhibitors (TKI) (ICI + TKI group), and assessed clinical efficacy in both groups. RESULTS: Of all patients, overall response rate and disease control rate for ICI combination treatments were 36.3% and 75%, respectively. The median progression-free survival (PFS) and overall survival (OS) was 8.8 and 23.9 months, respectively. Multivariate analysis revealed that the presence of liver metastasis significantly affected worse PFS and OS (p = 0.035 and p = 0.049). Importantly, PFS and OS seemed similar in ICI + ICI group and ICI + TKI group (p = 0.778 and p = 0.559). Although the discontinuation rate of the combination therapy due to adverse effects in patients aged ≥ 75 years was significantly higher compared to that in patients aged < 75 years (45% versus 12%, p = 0.017), there were no significant differences in PFS and OS between two groups (p = 0.290 and p = 0.257, respectively). CONCLUSION: This study confirms clinical benefit of ICI combination therapy for metastatic nccRCC patients in real-world settings. Furthermore, the effectiveness of combination therapy was comparable between patients aged < 75 and those ≥75 years with respect to clinical prognosis.

Management of bone metastasis in prostate cancer.

Progression of bone metastases is the primary cause of death in prostate cancer, and skeletal-related events (SREs), including pathologic fractures, spinal cord compression, radiation, or surgery to bone can impair patients' quality of life. Over the past decade, the development of cytotoxic agents, androgen-receptor-axis-targeted therapies (ARATs), and radioligand therapies has prolonged overall survival of prostate cancer patients with bone metastases and reduced the risk of SREs. The use of bone-modifying agents has also contributed to the reduced risk of SREs. Initial use of a cytotoxic agent, docetaxel, or an ARAT agent with androgen deprivation therapy (ADT) is the current approach to metastatic castration-sensitive prostate cancer. However, there is no consensus on the optimal medication for upfront use in combination with ADT, or on specific patient selection. Recently, next-generation imaging modalities, such as whole-body magnetic resonance imaging and prostate-specific membrane antigen-positron emission tomography have been utilized to detect bone metastases at an early stage. In addition, metastasis-directed therapy, such as stereotactic body radiation therapy, has been attempted. In the future, patients with bone metastatic prostate cancer will be divided into subgroups and their treatment options will be tailored to their specific characteristics.

A phase II randomized trial of metastasis-directed therapy with alpha emitter radium-223 in men with oligometastatic castration-resistant prostate cancer (MEDAL).

BACKGROUND: The significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases. METHODS: This phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI. DISCUSSION: This will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone. Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358.

Final efficacy and safety results and biomarker analysis of a phase 2 study of cabozantinib in Japanese patients with advanced renal cell carcinoma.

BACKGROUND: Cabozantinib was established as the standard of care for the treatment of patients with renal cell carcinoma (RCC) whose disease had progressed after vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in the global randomized trial METEOR. A phase 2 study was conducted to bridge the findings in METEOR to Japanese patients. Here, we report a biomarker analysis and update the efficacy and safety results of cabozantinib treatment. METHODS: Japanese patients with RCC who received at least one prior VEGFR-TKI were enrolled and received cabozantinib 60 mg orally once daily. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory analyses included the relationship between plasma protein hepatocyte growth factor (HGF) levels and treatment responses. RESULTS: In total, 35 patients were enrolled. The median treatment duration was 58.3 (range 5.1-131.4) weeks. The objective response rate was 25.7% (90% confidence interval [CI] 14.1-40.6). Kaplan-Meier estimate of median progression-free survival was 11.1 months (95% CI 7.4-18.4). The estimated progression-free survival proportion was 73.1% (95% CI 54.6-85.0) at 6 months. Median overall survival was not reached. Adverse events were consistent with those in METEOR and the safety profile was acceptable. Nonresponders to cabozantinib showed relatively higher HGF levels than responders at baseline. CONCLUSIONS: Updated analyses demonstrate the long-term efficacy and safety of cabozantinib in Japanese patients with advanced RCC after at least one VEGFR-TKI therapy. Responders tended to show lower baseline HGF levels ClinicalTrials.gov Identifier: NCT03339219.

Efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer: A single-center study in Japan.

OBJECTIVES: Cabazitaxel is a next-generation taxane that can prolong overall survival after docetaxel treatment in patients with metastatic castration-resistant prostate cancer. However, the efficacy of cabazitaxel varies among these patients. The clinical indicators of the prognosis after cabazitaxel treatment were analyzed. METHODS: A retrospective review of patients who received cabazitaxel between February 2015 and June 2021 was performed. All patients had metastatic castration-resistant prostate cancer. Prognostic factors for prostate-specific antigen progression-free and overall survival were analyzed by Cox proportional-hazards analysis and the log-rank test. RESULTS: The study comprised 57 patients who received cabazitaxel (median 4 cycles, range 1-27) at a starting dose of 15-25 mg/m2 . The median age and follow-up duration were 70 years and 9.2 months. The median prostate-specific antigen progression-free survival and overall survival were 2.6 and 10.5 months, respectively. Univariate analysis showed that previous androgen receptor-axis-targeted therapy before cabazitaxel treatment was the only significant risk factor (hazard ratio 2.784, p = 0.022) for prostate-specific antigen progression-free survival. Multivariate analysis for overall survival revealed that poor performance status (≥1) (hazard ratio 2.107, p = 0.039), low hemoglobin (hazard ratio 0.142, p = 0.010), and high neutrophil-lymphocyte ratio (hazard ratio 9.150, p = 0.032) at baseline were significantly associated with a poor prognosis. CONCLUSIONS: Previous androgen receptor-axis-targeted therapy was the only risk factor for biochemical progression. Poor performance status, anemia, and high neutrophil-lymphocyte ratio were risk factors for poor prognosis in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel. These risk factors seem useful for identifying patients with survival benefit from cabazitaxel treatment.

Plasma circulating tumor DNA profiling in patients with chemo-refractory germ cell tumors.

OBJECTIVES: Molecular analysis of tumor tissues has been extensively analyzed in germ cell tumors. However, genetic analysis of plasma circulating tumor DNA has been limited. Our objective was to analyze genetic alterations in circulating tumor DNA as well as its impact on prognosis in patients with chemo-refractory germ cell tumors. METHODS: We included 13 patients with chemo-refractory germ cell tumors who relapsed after second-line or higher previous chemotherapy and performed targeted sequencing of plasma cell-free DNA using an AVENIO Expanded kit. RESULTS: Tumor-specific genetic alterations were identified in all patients. The most frequently mutated gene was TP53 (53.4%), followed by PTEN (23.1%), GNAS (15.4%) and MTOR (15.4%). Moreover, EGFR amplification (38.5%) and MET amplification (15.4%) were also identified. We defined two or more single nucleotide variants detected in plasma cell-free DNA as circulating tumor DNA-positive. Kaplan-Meier analysis revealed that overall survival was significantly shorter in circulating tumor DNA-positive patients than circulating tumor DNA negative-patients (median overall survival 3.13 vs. 8.73 months; p = 0.042). CONCLUSION: Analysis of plasma circulating tumor DNA could detect genetic alterations in patients with chemo-refractory GCT. Moreover, detectable circulating tumor DNA in plasma was associated with poor prognosis in those patients. These results suggest that liquid biopsy using analysis of plasma circulating tumor DNA may be clinically useful for germ cell tumor patients.

Sexual function using the EORTC QLQ-TC26 in testicular cancer survivors: A multi-institutional, cross-sectional study.

OBJECTIVE: To evaluate sexual function after treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 (EORTC QLQ-TC26) questionnaire in Japanese testicular cancer (TC) survivors in a multi-institutional, cross-sectional study. METHODS: This study enrolled TC survivors who visited any of eight high-volume institutions in Japan from 2018 to 2019. After obtaining informed consent, participants completed the EORTC QLQ-TC26 questionnaires. We evaluated sexual function after treatment for TC using the EORTC QLQ-TC26 and analyzed the impact of treatment on sexual function in TC survivors. RESULTS: A total of 567 TC survivors responded to the EORTC QLQ-TC26. Median age at the time of response was 43 years (interquartile range [IQR] 35-51 years), and median follow-up period after treatment was 5.2 years (IQR 2.2-10.0 years). Sexual function, particularly ejaculatory function, was significantly lower after post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) than after Surveillance or Chemotherapy groups (p < 0.05). In the PC-RPLND group, nerve-sparing procedure preserved postoperative ejaculatory function after RPLND compared with the non-nerve-sparing and offered improved ejaculatory function with time. On multivariate analysis, RPLND was a significant predictor of post-treatment ejaculatory dysfunction, particularly without nerve-sparing (odds ratio 3.0, 95% CI 1.2-7.7, p < 0.05). In addition, TC survivors with nerve-sparing RPLND had higher sexual activity than those without. CONCLUSION: This survey of the EORTC QLQ-TC26 showed that sexual function and activity in TC survivors after RPLND was reduced in the absence of nerve-sparing techniques.

A comparative study on nivolumab and axitinib as secondary treatment in patients with metastatic renal cell carcinoma: A multi-institutional retrospective study in Japan.

OBJECTIVES: When primary treatment has been inadequate, nivolumab and axitinib are often used as a secondary treatments for patients with metastatic renal cell carcinoma (mRCC). However, there have been few reports comparing the efficacy and safety of these drugs. METHODS: We retrospectively investigated 58 patients treated with nivolumab and 57 patients treated with axitinib as secondary treatment between April 2013 and December 2019. We then assessed the clinical efficacy and safety of the treatments in both groups. RESULTS: The most common primary therapy was sunitinib (61.7%). Both nivolumab and axitinib groups showed no significant differences in terms of the objective response rate and disease control rate (p = 0.280 and p = 0.518, respectively). Importantly, progression-free survival (PFS) and overall survival (OS) seemed to be similar in patients treated with nivolumab and axitinib (p = 0.527 and p = 0.266, respectively), irrespective of the objective response to primary therapy. Furthermore, a Cox proportional hazards model showed that pretreatment Karnofsky Performance Status was significantly associated with PFS and OS. Although the incidence of adverse events was significantly higher in the patients treated with axitinib, there was no significant difference in time to treatment failure between the two groups. CONCLUSIONS: Nivolumab and axitinib showed similar clinical benefits as secondary treatment in patients with mRCC; thus, they should be an option in sequential therapy following treatment with tyrosine kinase inhibitors (TKIs). Future studies and feasible therapeutic biomarkers would help predict the clinical response to TKIs or immune checkpoint inhibitors in patients with mRCC.

[A Case of Primary Signet Ring Cell Carcinoma of the Urinary Bladder Showing Effectiveness of Chemotherapy with Gemcitabine and Cisplatin].

A 55-year-old female presented to the hospital with a complaint of gross hematuria. Transurethral resection of bladder tumor was performed. The specimens pathologically showed signet ring cells and no urothelial carcinoma components. Magnetic resonance imaging and computed tomographic (CT) scan revealed bladder tumor, cervical metastasis, bilateral ovarian metastasis, and multiple lymph node metastasis. She was diagnosed with a primary signet ring cell carcinoma of the urinary bladder with cT3bN2M1, and was treated with chemotherapy of gemcitabine and cisplatin combination (GC). After 2 cycles of GC, the value of CEA which was elevated to 106 ng/ml before treatment, became negative. CT scan showed that her disease had successfully responded to the chemotherapy, and remained efficacious till the end of 6 cycles. The patient subsequently received 1 cycle of gemcitabine and nedaplatin and 3 cycles of avelumab due to renal insufficiency. Yet, 14 months after diagnosis, cerebellar metastases appeared and the patient died of meningeal carcinomatosis.

Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis.

BACKGROUND: The Phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control; randomized 2:1 to olaparib or control) in men with homologous recombination repair gene alterations and metastatic castration-resistant prostate cancer whose disease progressed on prior next-generation hormonal agent. METHODS: We present efficacy and safety data from an exploratory post hoc analysis of olaparib in the PROfound Asian subset. Analyses were not planned, alpha controlled or powered. Of 101 Asian patients enrolled in Japan (n=57), South Korea (n=29) and Taiwan (n=15), 66 and 35 patients received olaparib and control, respectively. RESULTS: Radiographic progression-free survival (rPFS) and overall survival (OS) favored olaparib versus control in Cohort A [rPFS 7.2 vs. 4.5 months, HR 0.58, 95% CI 0.29-1.21, P = 0.14 (nominal); OS 23.4 vs. 17.8 months, HR 0.81, 95% CI 0.40-1.74, P = 0.57 (nominal)] and Cohorts A+B [rPFS 5.8 vs. 3.5 months, HR 0.69, 95% CI 0.42-1.16, P = 0.13 (nominal); OS 18.6 vs. 16.2 months, HR 0.96, 95% CI 0.56-1.70, P = 0.9 (nominal)]. Olaparib showed greatest improvement in patients harboring BRCA alterations [rPFS 9.3 vs. 3.5 months, HR 0.17, 95% CI 0.06-0.49, P = 0.0003 (nominal); OS 26.8 vs. 14.3 months, HR 0.62, 95% CI 0.24-1.79, P = 0.34 (nominal)]. Safety data were consistent with the known profile of olaparib, with no new safety signals identified. CONCLUSION: In PROfound, there was a statistically significant improvement in outcomes reported in the global population of patients with metastatic castration-resistant prostate cancer and alterations in homologous recombination repair genes whose disease progressed on prior next-generation hormonal agent compared with control. For the subset of Asian patients reported here, exploratory analysis suggested that there was also an improvement in outcomes versus control. The safety and tolerability of olaparib in Asian patients were similar to that of the PROfound global population. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02987543.

Real-world use of enzalutamide in men with nonmetastatic castration-resistant prostate cancer in Japan.

BACKGROUND: The purpose of the study is to evaluate real-world effectiveness and safety of enzalutamide in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) in Japan. METHODS: This was a retrospective evaluation of medical records from men in Japan who started enzalutamide treatment from November 1, 2014, to March 31, 2018, and received androgen deprivation therapy throughout. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included PSA response rate, time to first use of new antineoplastic therapy, time to first use of cytotoxic chemotherapy, and enzalutamide treatment duration. An exploratory analysis of metastasis-free survival (MFS) was also performed. Adverse events (AEs) were analyzed to assess safety. RESULTS: Based on data from medical records of 205 men in Japan, median time to PSA progression was 27 months (95% confidence interval [CI] 19-not reached [NR]), with 82.5% and 52.0% of men achieving PSA response rates of ≥ 50% and ≥ 90%, respectively. Median time to first use of new antineoplastic therapy was 36 months (95% CI 27-NR) and median enzalutamide treatment duration was 13 months (interquartile range: 7-24). Median time to first use of cytotoxic chemotherapy was NR (95% CI 41-NR). Median MFS was 29 months (95% CI 23-35). In total, 51.7% of men experienced AEs, with malaise (18.5%), decreased appetite (10.7%), and nausea (4.9%) the most frequently reported. CONCLUSIONS: This is the first study to demonstrate the real-world effectiveness and safety of enzalutamide in men with nmCRPC in Japan, further informing healthcare providers about available treatment options for this patient population.

Real-world efficacy and safety of nivolumab plus ipilimumab in untreated metastatic renal cell carcinoma, and the impact of previous nephrectomy on clinical outcome: Japanese multi-institutional retrospective study.

BACKGROUND: In metastatic renal-cell carcinoma (mRCC), recent clinical trials have shown efficacy of first-line combination therapy, as evidenced by better clinical outcome over target therapy. However, there are insufficient real-world evidences in mRCC patients in Japan. METHODS: We performed a multicenter retrospective study of 72 mRCC patients who received nivolumab plus ipilimumab as first-line treatment between September 2018 and July 2021. Patient's characteristics, clinical outcomes and safety were retrospectively reviewed. We analyzed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in patients treated with combination therapy. RESULTS: Of all patients, the median age was 70 years (range, 36-86) and the major type of histology was clear cell RCC (n = 55; 76.4%). Progressive disease (n = 25; 34.8%) and irAEs (n = 22; 30.6%) were the most common causes for discontinuing treatment. Median PFS and OS seemed similar between patients who discontinued treatment because of irAEs and for patients who did not (p = 0.360 and p = 0.069, respectively). Importantly, for patients with synchronous metastatic disease at diagnosis (n = 56), nephrectomy before initiating nivolumab plus ipilimumab had a significantly positive impact on better OS when compared to that in patients without nephrectomy (p = 0.028). CONCLUSION: This study confirms efficacy and safety of nivolumab plus ipilimumab for mRCC patients in real-world settings. Furthermore, nivolumab plus ipilimumab was associated with a better outcome in patients who had undergone nephrectomy at diagnosis for synchronous mRCC.

Association of financial toxicity with quality of life in testicular cancer survivors.

OBJECTIVES: Most testicular cancer (TC) survivors have long-term survival. However, the association between financial toxicity (FT), which is an economic side effect of cancer treatment, and the quality of life (QOL) of TC survivors is still unclear. Thus, the impact of FT on the QOL of TC survivors was examined in a multi-institutional cross-sectional study. METHODS: We recruited TC survivors from eight high-volume institutions in Japan between January 2018 and March 2019. A total of 562 participants completed the EORTC QLQ-C30, EORTC QLQ-TC26 and the questionnaires on demographics, including annual income. Financial difficulty in the EORTC QLQ-C30 and low income were used to assess financial distress (FD) and financial burden (FB), respectively. FT was defined as FD and FB. The QOL scores were compared, and a multivariate logistic regression analysis for FT was performed. RESULTS: With severe FD, TC survivors had more treatment side effects, physical limitations, and anxiety concerning employment and future. The TC survivors who reported low income were worried about their jobs and the future. The QOL of the survivors with FT exhibited high impairment, except for sexual activity. In particular, the TC survivors with FT were physically limited and anxious concerning the future. The multivariate logistic regression analysis revealed that four or more chemotherapy cycles were substantial risk factors for FT (4 cycles, odds ratio (OR) = 4.17; ≥5 cycles, OR = 6.96). CONCLUSIONS: TC survivors who received multi-cycle chemotherapy were prone to experience FT, resulting in a decline in their health-related QOL.

Phase II trial of nivolumab monotherapy and biomarker screening in patients with chemo-refractory germ cell tumors.

OBJECTIVES: Germ cell tumors are highly susceptible to chemotherapy; however, there is a lack of established treatments for consistently relapsing germ cell tumor. Therefore, in this phase II study, we evaluated the efficacy and safety of nivolumab for relapsed germ cell tumor. METHODS: Seventeen adult patients (median age 34 years) with refractory primary germ cell tumor after second-line or higher chemotherapy were enrolled. Nivolumab was administered over 30 min at 240 mg/body every 2 weeks until disease progression or intolerable adverse event occurrence. The primary endpoint was the overall response rate. RESULT: We performed a biomarker analysis of programmed death ligand-1 expression and genomic sequencing. Tumor histology revealed nonseminoma and seminoma in 14 and three patients, respectively. Patients were pretreated with a median of three chemotherapy lines, and three patients received high-dose chemotherapy. The median number of nivolumab doses was 3 (range 2-46). One patient showed a partial response and three showed stable disease. Responses were durable in one patient with a partial response and one patient with stable disease (median 90 and 68 weeks, respectively). Nivolumab was well-tolerated, with only two Grade 3 adverse events observed. Programmed death ligand-1 expression was not associated with objective responses. Genomic sequencing revealed a high tumor mutation burden in a patient with a durable partial response. While a small subset of chemorefractory germ cell tumors may respond to nivolumab, programmed death ligand-1 is unreliable to measure response. CONCLUSIONS: Tumor mutation burden is a potential biomarker for future testing of germ cell tumor response.

[A Case of Pleural Empyema with Fistula Caused by Endobronchial Metastasis of Renal Cell Carcinoma].

A 52-year-old man complained of asymptomatic gross hematuria and cough. Chest and abdominal computed tomography (CT) revealed a right renal tumor, mediastinal lymph node metastasis, and right endobronchial metastasis. The right endobronchial metastasis was causing obstructive atelectasis in the lower lobe of the right lung. After tumor biopsy, the pathological diagnosis was clear cell renal cell carcinoma. Combination immunotherapy with ipilimumab and nivolumab was initiated, but CT showed enlargement of the metastatic lesion and lung abscess after two courses of treatment. The therapy was then switched to axitinib. Six days after initiation of axitinib, the lung abscess perforated into the pleural cavity, which resulted in the formation of pleural empyema with fistula. Ten days after initiation of axitinib, obstruction of the bronchus was relieved due to shrinkage of the right endobronchial metastasis, which resulted in development of a pneumothorax. Placement of a thoracic drainage tube and administration of an antimicrobial agent improved the pneumothorax and inflammatory response, but the drainage tube could not be removed. Long-term insertion of the thoracic drainage tube considerably diminished the patient's quality of life, and after 4 months, he was transferred to another hospital to receive the best supportive care.

Antiresorptive agent-related osteonecrosis of the jaw in prostate cancer patients with bone metastasis treated with bone-modifying agents.

INTRODUCTION: The incidence rate and risk factors of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in prostate cancer patients with bone metastasis are not clear. MATERIALS AND METHODS: We retrospectively reviewed patients' records of prostate cancer patients with bone metastasis who were treated with zoledronic acid or denosumab between 1/Dec/2008 and 31/Mar/2019. ARONJ-free survival rate was analyzed with Kaplan-Meier analysis, and risk factors for ARONJ were analyzed with Cox proportional hazard model. RESULTS: We identified 124 and 67 patients treated with zoledronic acid and denosumab, respectively. Seventy-six patients were hormone sensitive, and 115 patients were castration resistant when they started bone-modifying agents (BMA). Twenty-eight patients developed ARONJ during the observation period (median: 23 months, range 1-130 months). Their number of doses of BMA ranged 3-69 (median: 21.5). The 2-year ARONJ-free survival rate was 91.1%, and the 5-year ARONJ-free survival rate was 72.5%. There was no significant difference in the incidence rate of ARONJ between zoledronic acid and denosumab. However, multivariate analysis revealed that use of denosumab (hazard ratio [HR] 3.67, 95% confidence interval [CI] 1.01-13.31; p = 0.0484), serum calcium < 9.2 mg/dL (HR 3.16, 95% CI 1.10-9.13; p = 0.033)), and concomitant or prior use of chemotherapeutic agents (HR 4.71, 95% CI 1.51-14.71; p = 0.0076) were independent risk factors for the development of ARONJ. CONCLUSION: Almost one-quarter of patients had a risk of developing ARONJ within 5 years after starting BMA. Low serum calcium, use of chemotherapeutic agents, and use of denosumab might contribute to the development of ARONJ.

Clinical indicators for predicting prognosis after radium-223 administration in castration-resistant prostate cancer with bone metastases.

BACKGROUND: Radium-223 (Ra-223) is a targeted alpha therapy that has been shown to prolong overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. However, prognosis after Ra-223 administration varies among patients. The aim of the present study was to assess risk factors associated with the poor prognosis of patients treated with Ra-223. METHODS: We retrospectively reviewed patients' records of treatment with Ra-223 between October 2016 and December 2019. All patients had mCRPC, bone metastasis, and no known visceral metastases, and received up to six cycles of Ra-223 (55 kBq/kg). Prognostic factors for OS were analyzed by Cox proportional hazards model and log-rank test. RESULTS: We identified 42 patients who received at least one cycle of Ra-223 (median six cycles, range 1-6). Approximately two-thirds of patients had received at least two lines of therapy for mCRPC. The median age was 74 years, and the median follow-up duration was 13.6 months. The median OS time was 16.6 months. On multivariate analysis, PSA doubling time (PSADT) (0-3 months) at baseline, number of bone metastases (≥ 20), and treatment line of Ra-223 (4th-5th line) remained significantly correlated with the poor OS (HR 4.354, P = 0.003; HR 2.855, P = 0.020; and HR 4.871, P = 0.001, respectively). CONCLUSIONS: Our study demonstrated that a shorter PSADT, a heavier volume of bone metastases, and a later treatment line before Ra-223 are poor prognostic factors for mCRPC patients. These newly discovered risk factors may help select patients who potentially have long-term OS after Ra-223 treatment.

The prognostic impact of immune-related adverse events in metastatic renal cell carcinoma patients treated with nivolumab: a real-world multi-institutional retrospective study.

BACKGROUND: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were correlated with favorable clinical outcome in patients with melanoma. However, in metastatic renal cell carcinoma (mRCC) patients, there have been few reports about the correlation between irAEs and clinical efficacy of anti-programmed cell death protein-1 (PD-1) therapy. METHODS: We retrospectively investigated 160 mRCC patients who started nivolumab monotherapy between September 2016 and July 2019. IrAEs were defined as patients' AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy. We compared the data of patients who received nivolumab into two groups based on the occurrence of irAEs and assessed clinical efficacy in both groups. RESULTS: Of all mRCC patients, 47 patients (29.4%) developed irAEs. In patients who developed irAEs, the objective response rate and disease control rate were 38.8% and 77.6%, which were significantly higher when compared to that in patients without irAEs (p = 0.012 and p < 0.001, respectively). Furthermore, the incidence of irAEs was significantly associated with an increase in progression-free survival (PFS) [Hazard ratio (HR) = 0.4867; p = 0.0006] and overall survival (OS) (HR = 0.526; p = 0.0252). Importantly, PFS and OS seemed to be similar in patients who discontinued treatment because of irAEs and in those who did not discontinue because of irAEs (p = 0.36 and p = 0.35, respectively). CONCLUSION: Development of irAEs strongly correlates with clinical benefit for mRCC patients receiving nivolumab monotherapy in real-world settings.