Expression of Vincristin-induced Peripheral Neuropathy Related to Different Administration Methods.

Vincristine (VCR) is an important drug used in R-CHOP regimens for the treatment of non-Hodgkin's lymphoma. The purpose of this study was to examine whether the administration method affects the incidence of VCR-induced peripheral neuropathy. We investigated the ratio of VCR-induced peripheral neuropathy during rapid intravenous infusion and intravenous drip infusion. A total of 71 patients who had received six or more courses of R-CHOP from January, 2015 to December, 2016 at Komaki City Hospital and Ogaki Municipal Hospital were retrospectively investigated. Peripheral neuropathy was observed in 27/39 patients (69 %) and 24/32 (75 %) in rapid intravenous infusion and intravenous drip infusion of VCR, respectively (P = 0.79). Peripheral neuropathy was observed at a high frequency in this study. Additionally, there was no difference in frequency of peripheral neuropathy due to the difference in administration method. In both groups, the degree of peripheral neuropathy was grade 1 and grade 2 in most patients. However, in rapid intravenous infusion, grade 3 peripheral neuropathy was observed. Some cases required dose reduction and discontinuation in rapid intravenous infusion. In contrast, there were no discontinuing patients in the intravenous drip infusion. Therefore, it was suggested that intravenous drip infusion of VCR reduced serious peripheral neuropathy because the ratio requiring dose reduction and discontinuation was less than that in the rapid group. In conclusion, this study is informative as there are few reports focusing on the administration method of vincristine.

Identifying prognostic factors associated with overall survival in second-line paclitaxel plus ramucirumab treated human epidermal growth factor receptor 2-negative advanced/recurrent gastric cancer.

This study aimed to identify the overall survival prolongation index in patients who received paclitaxel plus ramucirumab as second line chemotherapy for human epidermal growth factor receptor (HER) 2-negative advanced/ recurrent gastric cancer (AGC). We included 77 patients who underwent second line chemotherapy (paclitaxel plus ramucirumab) for AGC at our institution between January 2015 and September 2020. To determine factors associated with survival, univariate and multivariate analyses were performed, and hazard ratios and their 95% confidence intervals (95% CI) were calculated. In the multivariate analysis, grade ≥1 neutropenia (yes) and the number of anti-cancer drugs used (≥5) were independently and significantly associated with survival. Compared to the patients without grade ≥1 neutropenia, patients with grade ≥1 neutropenia had a survival hazard ratio of 0.455 (95% CI: 0.214-0.966; p = 0.040). The median second line treatment durations in patients with grade ≥1 neutropenia (n = 54) and in those without grade ≥1 neutropenia (n = 23) were 133 days (95% CI, 98-190 days) and 70 days (95% CI, 41-128 days), respectively (log-rank test, p = 0.026). This study demonstrated that AGC patients with initial neutropenia may benefit from paclitaxel plus ramucirumab therapy.

A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903.

BACKGROUND: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. PATIENTS AND METHODS: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. RESULTS: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). CONCLUSIONS: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.

Association between immune-related dermatologic adverse events and efficacy of pembrolizumab in non-small cell lung cancer patients.

We retrospectively evaluated the incidence of skin immune-related adverse effects (irAEs) in patients treated with pembrolizumab (PMB) and explored and the relationship between skin irAEs and PMB efficacy. Thirty-two patients with non-small cell lung cancer treated with PMB between April 2017 and May 2018 were enrolled. The patients were separated into two groups, namely, skin irAEs and no-skin irAEs group. We investigated the ratio and degree of express skin irAEs, period of skin irAEs and treatment, and the PFS between the two groups. Additionally, we evaluated the PFS between the irAE and no-irAEs groups. The median patient age was 76.5 (range 56-92) years. The European Cooperative Oncology Group Performance Status (ECOG PS) score of 26, 5, and 1 was 0-1, 2, and 3, respectively. The male/female ratio was 23/9. In terms of clinical stages, 6, 21, and 5 patients were in stages III and IV, and postoperative relapse, respectively. Skin irAEs were observed in 10 patients (31%). The progression-free survival of patients with skin irAEs (median, 390 days) was longer than that of patients without skin irAEs (median, 128.5 days). Overall, we suggested a significant association between skin irAEs and the efficacy of PMB in treating non-small cell lung cancer. As skin irAEs can be an indicator of treatment efficacy, it is important for medical staff, including pharmacists, to closely observe these adverse events.

Association between severe neutropenia and progression-free survival in patients with advanced or recurrent breast cancer treated with palbociclib.

This study aimed to clarify the relationship between neutropenia and progression-free survival (PFS) under palbociclib treatment for advanced/recurrent breast cancer and the risk factors for severe neutropenia. We retrospectively identified 37 patients who received palbociclib for advanced breast cancer at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and June 2020. Kaplan-Meier log-rank test was used to compare PFS (mild [neutrophil count 1,000-2,000/mm 3 ] versus severe [neutrophil count <500-1,000/mm³]). Multivariate analysis was performed to evaluate the relationships between baseline patient characteristics and severe neutropenia development. There were three, four, 25, and five cases with grade 1, 2, 3, and 4 neutropenia, respectively. Median PFS in patients who developed severe neutropenia (n = 30) and those who did develop mild neutropenia (n = 7) was 176 days (range: 62-894 days) and 91 days (range: 19-384 days), respectively (log-rank test, p = 0.005). Severe neutropenia was independently associated with pre-treatment neutrophil count (odds ratio: 27.700; p =0.007). Severe neutropenia is more likely to occur with a pre-treatment neutrophil count of less than 3,680 mm³. Neutropenia prolongs PFS under palbociclib treatment, suggesting management of AEs and patient education as highly important, especially to prevent drug interruption/dose reduction of palbociclib due to these AEs.

Continuity and efficacy of real-world use of azacitidine.

Long-term azacitidine (AZA) treatment is necessary for its maximal therapeutic effect. This study examined the continuity and efficacy of AZA treatment in real-world use. We conducted a retrospective study in 38 patients who had completed AZA treatment at the Ogaki Municipal Hospital between April 2011 and August 2019. The median number of AZA received cycles was 4. The number of AZA treatment cycles received was 1-3 cycles in 15 (39.5%), 4-6 cycles in 15 (39.5%), and ≥ 7 cycles in 8 (21.1%). The most common reason for discontinued AZA treatment was infection. Overall response rate was 33.3% in patients with discontinued AZA use (< 4 cycles) and 56.5% in patients with continued AZA (≥ 4). Median overall survival (OS) was 124 (15-529) days and 391 (132-2,825) days in the respective groups (p<0.01). The presence of peripheral blood blasts (PBs) was a prognostic factor for continuation of treatment (p =0.03). Discontinued AZA treatment due to infection (p <0.01), and PBs (p =0.03) were unfavourable prognostic factors for OS. Long-term AZA use is beneficial for improvement and survival. Infection control and presence of PBs were important factors for continuing AZA. These data support the idea of long-term continued treatment with AZA for optimal benefit to patients.

Cost-effectiveness and safety of palbociclib and everolimus for treating advanced and recurrent breast cancer.

This retrospective study compares the economic superiority of palbociclib versus everolimus for advanced and recurrent breast cancer. Furthermore, we investigated the safety and treatment continuity of palbociclib and everolimus regimens. Expected costs were calculated based on data from patients with advanced and recurrent breast cancer who were treated with palbociclib and everolimus. The progression-free survival (PFS) from the PALOMA-3 clinical trial and BOLERO-2 clinical trial was used to evaluate the therapeutic efficacy of the regimens. The cost-effectiveness ratio of each chemotherapy agent was calculated by dividing the expected cost by the progression-free survival (PFS). The cost-effectiveness ratio per month was JPY 391,551.3/PFS for palbociclib and JPY 488,690.5/PFS for everolimus (p=0.627). The incremental cost-effectiveness ratio per month of everolimus to palbociclib was JPY 100,133.7/PFS. For patients receiving everolimus, adverse drug reactions included stomatitis (77.3%), rash (59.1%) and leukopenia (59.1%). For patients receiving palbociclib, neutropenia (69.2%), leukopenia (69.2%) and anemia (30.8%) occurred. In terms of discontinuation owing to adverse events (AEs), pneumonitis, thrombocytopenia, edema, fatigue, and neutropenia were experienced in the everolimus group. The cost-effectiveness of everolimus and palbociclib are equivalent, but since the prevalence of AEs is high in patients receiving everolimus, its AE management is important.

Cost-effectiveness and safety of the molecular targeted drugs afatinib, gefitinib and erlotinib as first-line treatments for patients with advanced EGFR mutation-positive non-small-cell lung cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib and afatinib are standard first-line treatments for EGFR gene mutation-positive non-small cell lung cancer. The present study aimed to compare the cost-effectiveness of using erlotinib, afatinib or gefitinib. The safety of EGFR-TKIs was also investigated. Expected costs were calculated based on data from patients with advanced EGFR mutation-positive non-small-cell lung cancer who were treated with gefitinib, erlotinib or afatinib. Literature was collected to obtain the necessary clinical information for calculating the probability and the validity of each chemotherapy. Median survival time (MST) was used to evaluate the therapeutic effect of the regimens. The cost-effectiveness ratio was calculated using expected costs and MSTs for the three regimens. The cost-effectiveness ratio per month was JPY 386,859.4/MST for afatinib, JPY 264,788.7/MST for gefitinib and JPY 397,039.9/MST for erlotinib. Significant differences were observed between the three groups (p<0.001). The incremental cost-effectiveness ratio (ICER) of gefitinib compared with afatinib per month was JPY 122,070.7/MST. The ICER of gefitinib compared with erlotinib was JPY -69,605.9/MST. Adverse effects of Grade 3 and higher, including diarrhoea (28.6%) and paronychia (14.3%) were observed in the afatinib treatment group. Paronychia (23.1%) was observed in the erlotinib treatment group, while none were observed in the gefitinib treatment group. These findings demonstrate that gefitinib is more cost effective in comparison with the afatinib and erlotinib regimens, although the afatinib and erlotinib regimens were well-tolerated and produce sufficient effects.

Evaluation of the safety of ramucirumab in Japanese patients with advanced gastric cancer.

As a result of the RAINBOW trial, ramucirumab plus paclitaxel was established as a second-line treatment of advanced gastric cancer. Regarding the safety of ramucirumab plus paclitaxel in the Japanese, a subgroup analysis of the RAINBOW trial was conducted. The incidence of neutropenia was higher in Japanese patients. However, information is lacking concerning the safety of ramucirumab after marketing in Japanese patients. Therefore, the aim of this study was to evaluate the safety of ramucirumab in Japanese patients with advanced gastric cancer. The inclusion criteria were patients diagnosed with advanced gastric cancer who had commenced treatment with ramucirumab plus paclitaxel or paclitaxel only at Ogaki Municipal Hospital (Gifu, Japan) between January 2015 and December 2016. There were 26 patients in the ramucirumab plus paclitaxel group and 22 patients in the paclitaxel only group. Treatment-related adverse events were documented in 100.0% of the patients in the ramucirumab plus paclitaxel group (Grade 3-4, 73.1%) and 90.9 % of the patients in the paclitaxel only group (Grade 3-4, 45.5 %). The most frequently observed adverse event in both treatment groups was anemia. The second common adverse event was neutropenia. The incidence of neutropenia of Grade ≥3 was significantly higher in the ramucirumab plus paclitaxel group than in the paclitaxel only group. In conclusion, the incidence of neutropenia is high. However, we believe that ramucirumab plus paclitaxel can be safely administered.

Risk factors for severe neutropenia induced by combination therapy of S-1 and cisplatin in patients with advanced/recurrent gastric cancer.

S-1 and cisplatin therapy (SP therapy) is widely used as the first-line of advanced/recurrent gastric cancer. However, severe neutropenia is often observed (40%) during this therapy. Therefore, the risk management of neutropenia is important. From September 2014 to April 2017, we investigated 76 patients who underwent SP therapy as primary treatment for advanced/recurrent gastric cancer at Ogaki Municipal Hospital. Risk factors for grade 3/4 neutropenia were examined by univariate and multivariate analyses. In SP therapy, 19 patients (25%) experienced grade 3/4 neutropenia. The results of multivariate analysis of factors with p <0.05 in the univariate analysis indicated that less than 10.6 g/dL of the haemoglobin value before the course at the lowest neutrophil count (odds ratio: 7.900; 95% CI: 1.280-48.60; p = 0.026), more than six courses of the total course (odds ratio: 9.13; 95% CI: 2.13-39.1; p = 0.003), and less than 3140 m2 neutrophil counts (odds ratio: 5.33; 95% CI: 1.47-19.3; p = 0.011) before chemotherapy were risk factors of grade 3/4 neutropenia. A low haemoglobin value before the course at the lowest neutrophil count was revealed as a risk factor causing severe neutropenia in SP therapy.

Risk factors contributing to the development of neutropenia in patients receiving oral trifluridine-tipiracil (TAS-102) chemotherapy for advanced/recurrent colorectal cancer.

Elucidating the factors influencing severe neutropenia could aid in earlier management of neutropenia during oral trifluridine-tipiracil (TAS-102) chemotherapy in advanced and recurrent colorectal cancer (CRC). This study was conducted to assess the risk of TAS-102-induced grade 3 or more neutropenia. Between August 2014 and July 2017, 60 patients underwent oral TAS-102 monotherapy at Ogaki Municipal Hospital, Japan. The patients were divided into two groups based on the development of grade 3 or more neutropenia (9 patients) or not (51 patients). Risk factors for grade 3 or more neutropenia were examined by univariate and multivariate analyses. Creatinine clearance rate (CrCl) before TAS-102 administration significantly correlated with the incidence of Grade 3 or more neutropenia after TAS-102 administration (odds ratio 6.5, 95% confidence interval 1.14-30.00; p = 0.02). Multivariate analysis revealed that a CrCl of lower than 57.1 mL/min before TAS-102 administration (odds ratio 54.06, 95% confidence interval 2.14-1364.2; p = 0.02) was an independent risk factor significantly contributing to the development of grade 3 or more neutropenia, induced by TAS-102. CrCl < 57.1 mL/min in patients with advanced and recurrent CRC who underwent TAS-102 chemotherapy was associated with grade 3 or more neutropenia.

Prognostic factors in patients with advanced and recurrent colorectal cancer receiving last-line chemotherapy.

For patients with advanced/recurrent colorectal cancer, the trifluridine/tipiracil combination tablet (TAS 102) and regorafenib are last-line treatments. This study aimed to clarify prognostic factors in patients receiving last-line chemotherapy. Between April 2014 and December 2016, 47 patients received last-line chemotherapy at Ogaki Municipal Hospital, Japan. The primary outcome was overall survival. To determine factors associated with survival, those considered significant in the univariate analysis (p <0.10), were entered into a multivariate Cox proportional hazards model. KRAS type and the use of opioid formulations were independently and significantly associated with survival in the multivariate analysis. For patients with KRAS-wild relative to KRAS-mutation cancers, the hazard ratio for death was 0.478 (95% CI, 0.249-0.919; p = 0.03). For patients taking opioid formulations, relative to those not, the hazard ratio for death was 3.557 (95% CI, 1.032-12.257; p = 0.04). The median overall survival duration for patients with KRAS-wild (n = 24) and KRAS-mutation (n = 23) cancers were 223.5 days (range: 115-703) and 154 days (range: 51-503), respectively (p = 0.05). This finding provides a useful index to make an early decision on discontinuation of treatment and to guide decisions around agents to use in last-line chemotherapy.

Age is a significant predictor of early and late improvement in semen parameters after microsurgical varicocele repair.

Accumulating evidence indicates that varicocele repair improves sperm quality. However, longitudinal changes in sperm parameters and predictors of improved semen characteristics after surgery have not been fully investigated. We retrospectively reviewed data from 100 men who underwent microsurgical subinguinal varicocele repair at a single centre. Follow-up semen examinations were carried out at 3, 6 and 12 months post-operatively. Logistic regression was used to identify predictors of early (3 months) and late (≥6 months) improvement in semen parameters after varicocele repair. At 3 months post-operatively, 76.1% of the patients had improved total motile sperm counts, which continued to improve significantly up to 12 months post-operatively (p = .016). When comparing changes in semen parameters between younger (<37 years) and older (≥37 years) men, post-operative improvements in sperm concentration and motility were greater among younger men. Multivariate analysis showed that younger age was associated with early (p = .043) and late (p = .010) post-operative improvement in total motile sperm count. Our findings indicate that early varicocele repair improved semen parameters after surgery.

Severe neutropenia: a prognosticator in patients with advanced/recurrent colorectal cancer under oral trifluridine-tipiracil (TAS-102) chemotherapy.

BACKGROUND/AIM: The effect of oral trifluridine-tipiracil (TAS-102)-induced neutropenia on survival of patients with advanced/recurrent colorectal cancer was investigated. PATIENTS AND METHODS: Between August 2014 and May 2016, 41 patients underwent TAS-102 monotherapy at Ogaki Municipal Hospital. Risk factors for survival were examined by univariate and multivariate analyses. RESULTS: In 41 patients, mild neutropenia (grade 1-2) occurred in 10 patients (24.4%), severe neutropenia (grade 3-4) occurred in 13 (31.7%), and 18 (43.9%) did not experience neutropenia. The median overall survival times in the absent, mild, and severe groups were 120 days (95% confidence interval [CI], 67-179), 184 days (95% CI, 94-274), and 299 days (95% CI, 192-404), respectively (p = 0.045). In patients with severe neutropenia, the death hazard ratio was 0.442 (95% CI, 0.201-0.974; p = 0.042). CONCLUSION: In patients with advanced/recurrent colorectal cancer, TAS-102-induced severe neutropenia was associated with superior survival.

Risk factors for neutropenia with lenalidomide plus dexamethasone therapy for multiple myeloma.

Neutropenia may develop as an adverse event in patients with multiple myeloma receiving lenalidomide (LEN) plus dexamethasone (DEX) therapy. In the present study, we examined the risk factors associated with grade 3/4 neutropenia during the first cycle of LEN plus DEX therapy. We observed that hemoglobin level (≤ 8.5 g/dl) was a significant risk factor for grade 3/4 neutropenia during the first cycle of therapy (odds ratio: 19.40; 95% confidence interval: 2.68-141.00; p < 0.01). thus, our findings suggest that determining the hemoglobin level could be useful in the risk management for neutropenia in patients receiving LEN plus DEX therapy.

Safety of an oral anticancer agent (trifluridine/tipiracil combination tablet) in patients with advanced and recurrent colorectal cancer.

We retrospectively studied the safety of trifluridine/tipiracil combination tablet (TAS-102) monotherapy in patients with advanced and recurrent colorectal cancer. Adverse events to TAS-102 monotherapy were observed in 22 out of 23 cases (95.7%). The most frequent adverse events were neutropenia (69.6%), nausea (53.2%), and malaise (30.4%). Treatment was postponed in 54 (59.3%) out of 91 courses, and in 34 (66.7%) of these 54 courses, the delay in treatment was due to bone marrow suppression. Seven patients with peritoneal metastases suffered from nausea, whilst none of the patients without peritoneal metastases had nausea (p = 0.0139). Nausea and vomiting during a previous chemotherapy cycle was significantly associated with nausea after TAS-102 treatment (p = 0.0007), and the treatment cycles were significantly longer in patients with grade 3 or 4 neutropenia (p = 0.0061). Our results suggest that the incidence of nausea was higher in patients treated with TAS-102. Therefore, it is important to inform patients of the risk of these toxicities and to provide enhanced supportive care. Moreover, we recommend that, for patients with repeated treatment postponement due to neutropenia, the dosage should be fixed based on therapeutic efficacy and prognosis.