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Cancer Science Nov 2019This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic...
This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.
Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Area Under Curve; Asian People; Body Surface Area; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Female; Humans; Japan; Lung Neoplasms; Male; Membrane Transport Proteins; Middle Aged; Neutropenia; Polymorphism, Single Nucleotide; Prospective Studies; Severity of Illness Index
PubMed: 31505087
DOI: 10.1111/cas.14194 -
Cancer Chemotherapy and Pharmacology Nov 2019Amrubicin and cisplatin is one of the active regimens used to treat patients with extensive-disease (ED)-small cell lung cancer (SCLC), whereas combined therapy...
BACKGROUND
Amrubicin and cisplatin is one of the active regimens used to treat patients with extensive-disease (ED)-small cell lung cancer (SCLC), whereas combined therapy involving chemotherapy and concurrent thoracic radiotherapy is the standard treatment for limited-disease (LD)-SCLC.
PURPOSE
This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) for LD-SCLC.
PATIENTS AND METHODS
Patients that fulfilled the following eligibility criteria were enrolled: being aged ≤ 75 years and chemotherapy-naïve and having a performance status (PS) of 0-1, LD-SCLC, and adequate organ function. The patients received escalating doses of amrubicin on days 1, 2, and 3, and a fixed 60-mg/m dose of cisplatin on day 1. Four cycles of chemotherapy were administered, with each cycle lasting 4 weeks. TRT involving 2 Gy/day, once daily, commenced on day 2 of the first cycle of chemotherapy. The initial dose of amrubicin was 20 mg/m (level 1), and the dose was escalated to 25 mg/m (level 2) and then 30 mg/m (level 3).
RESULTS
Eight patients from three institutions were enrolled at three dose levels. The patients' characteristics were as follows: male/female: 3/5; median age (range): 68.5 (60-73); PS 0/1: 4/4; stage IIIA/IIIB disease: 3/5. Both level 3 patients experienced DLT (grade 4 neutropenia and/or leukopenia lasting > 4 days). Level 3 was defined as the MTD, and level 2 was recommended as the dose for this regimen. Seven patients exhibited partial responses, and 1 displayed progressive disease (response rate: 88%). The median progression-free survival and overall survival periods were 11.1 and 39.5 months, respectively. No treatment-related deaths occurred.
CONCLUSIONS
When this regimen was combined with TRT for LD-SCLC, the MTD was 30 mg/m for amrubicin and 60 mg/m for cisplatin. In addition, neutropenia and leukopenia were DLT, and doses of 25 mg/m for amrubicin and 60 mg/m for cisplatin are recommended for this regimen.
Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Progression-Free Survival; Small Cell Lung Carcinoma; Survival Rate
PubMed: 31486872
DOI: 10.1007/s00280-019-03940-0 -
Cancer Management and Research 2019Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line...
Safety and efficacy of amrubicin monotherapy in patients with platinum-refractory metastatic neuroendocrine carcinoma of the gastrointestinal tract: a single cancer center retrospective study.
PURPOSE
Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line treatment, the benefit of amrubicin (AMR) and salvage chemotherapy in those who develop platinum-refractory GI-NEC remains unknown. This study aimed to evaluate the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC.
PATIENTS AND METHODS
Platinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 were retrospectively analyzed. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. PFS and OS were estimated using Kaplan-Meier methods and compared using log-rank tests.
RESULTS
In total, 16 patients were enrolled. Of them, 13 (81.3%), 1 (6.2%), and 2 (12.5%) received cisplatin plus irinotecan, cisplatin plus etoposide, and fluoropyrimidine plus platinum, respectively, before AMR monotherapy. The primary sites of NEC included the esophagus (N=3, 18.8%), stomach (N=10, 62.5%), duodenum (N=1, 6.2%) and colorectum (N=2, 12.5%). Patients were administered a median of 3 (range, 1-15) cycles of AMR. The ORR was 6.3%, and the median PFS and OS were 2.9 months (95% CI: 1.7-7.4) and 13.8 months (95% CI: 7.9-23.5), respectively. Neutropenia was the most serious adverse event. Grade 3 or higher neutropenia and febrile neutropenia occurred in 50.0% and 6.2% of patients, respectively. Other nonhematological toxicities were not severe, and no treatment-related deaths occurred. The 10 patients who received subsequent chemotherapy after AMR had significantly longer OS than those who did not (17.3 months vs 8.9 months; =0.018). The median PFS of those who received organ-specific subsequent chemotherapy after AMR was 3.8 months, which was longer than that of those who received prior AMR.
CONCLUSION
AMR is feasible with minimal side effects for platinum-refractory GI-NEC. Organ-specific subsequent chemotherapy after AMR may improve patient survival.
PubMed: 31417315
DOI: 10.2147/CMAR.S201048 -
Mayo Clinic Proceedings Aug 2019Small-cell lung cancer (SCLC) is an aggressive disease with distinct pathological, clinical, and molecular characteristics from non-small-cell lung cancer. SCLC has high... (Review)
Review
Small-cell lung cancer (SCLC) is an aggressive disease with distinct pathological, clinical, and molecular characteristics from non-small-cell lung cancer. SCLC has high metastatic potential, resulting in a clinically poor prognosis. Early concurrent chemo-radiation is the standard of care for limited-stage SCLC (LS-SCLC). Prophylactic cranial irradiation (PCI) is recommended for patients with LS-SCLC without progression of disease after initial therapy. A combination of etoposide and cisplatin or carboplatin remains the mainstay of first-line treatment for ES-SCLC, with the addition of atezolizumab, now becoming standard. Most SCLCs initially respond to therapy but almost invariably recur. Topotecan and amrubicin (in Japan) remain the primary chemotherapy options for relapsed SCLC. Immunotherapy, including nivolumab with or without ipilimumab, is now available for refractory disease. In general, the poor prognosis of SCLC has not improved significantly for more than 3 decades. Recently, next-generation molecular profiling studies have identified new therapeutic targets for SCLC. A variety of proapoptotic agents, compounds capitalizing on DNA-repair defects, immunotherapy agents, and antibody-drug conjugates are being evaluated in SCLC, with a number of them showing early promise.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Disease Management; Disease-Free Survival; Female; Humans; Immunotherapy; Japan; Lung Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Risk Assessment; Survival Analysis
PubMed: 31378235
DOI: 10.1016/j.mayocp.2019.01.034 -
Thoracic Cancer Sep 2019The efficacy of amrubicin for relapsed small-cell lung cancer (SCLC) has been reported in previous studies. Few reports, however, describe the efficacy and survival... (Clinical Trial)
Clinical Trial
The efficacy of amrubicin third-line chemotherapy in patients with relapsed extensive-disease small-cell lung cancer: A retrospective and historical study in a single institute.
BACKGROUND
The efficacy of amrubicin for relapsed small-cell lung cancer (SCLC) has been reported in previous studies. Few reports, however, describe the efficacy and survival benefit of third-line amrubicin chemotherapy in patients with extensive disease (ED)-SCLC.
METHODS
We retrospectively analyzed the clinical records of ED-SCLC patients treated with amrubicin salvage chemotherapy as a third-line chemotherapy between January 2005 and July 2016 (salvage amrubicin group). The efficacy and toxicities of amrubicin were evaluated. Overall survival (OS) in the amrubicin salvage group was compared with OS among ED-SCLC patients treated with at least second-line chemotherapy between May 2000 and July 2016 and without subsequent amrubicin salvage chemotherapy.
RESULTS
A total of 18 patients with a median age of 70 years were analyzed in the amrubicin salvage group. The median number of treatment cycles of amrubicin was four. The response rate was 27.8% (95% confidence interval (CI), 7.1%-48.5%), and the disease control rate (DCR) was 66.7% (95% CI, 44.9%-88.4%). Median progression-free survival was 2.9 months (95% CI, 1.0-4.9 months), and median OS after an initial chemotherapy was 18.1 months (95% CI, 10.2-26.0 months). OS in the amrubicin salvage group was significantly longer than in the no-amrubicin group (n = 19; 12.6 months, 95% CI, 11.5-13.8 months, P = 0.005). The frequency of neutropenia greater than grade 3 was 72.2%, with febrile neutropenia developing in 38.9% of patients in the amrubicin salvage group.
CONCLUSIONS
Despite a high frequency of febrile neutropenia, amrubicin salvage chemotherapy may improve OS in patients with relapsed ED-SCLC.
Topics: Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies; Salvage Therapy; Small Cell Lung Carcinoma; Survival Rate
PubMed: 31350820
DOI: 10.1111/1759-7714.13150 -
Case Reports in Oncology 2019Paraneoplastic limbic encephalitis (PLE) is a rare neurologic disorder that can complicate various malignancies, including lung cancer. PLE is most frequently found the...
Paraneoplastic limbic encephalitis (PLE) is a rare neurologic disorder that can complicate various malignancies, including lung cancer. PLE is most frequently found the initial presentation of lung cancer. In this study, we reported the case of a 74-year-old Japanese woman who developed PLE after partial remission of small cell lung cancer (SCLC) by first-line systemic chemotherapy. Brain magnetic resonance imaging showed no metastatic tumor or cerebrovascular disease. Anti-glutamic acid decarboxylase (GAD) and anti-amphiphysin antibodies were detected in her serum. She was diagnosed as having PLE related to the recurrence of SCLC and received high-dose glucocorticoid, and sequentially systemic chemotherapy with amrubicin. Unfortunately, these treatments did not improve her disease progression and she died 4 months later. Although PLE rarely occurs at the time of SCLC recurrence, physicians should pay attention to PLE onset even after chemotherapy.
PubMed: 31320869
DOI: 10.1159/000501305 -
Thoracic Cancer Sep 2019The first-line treatment for squamous cell lung cancer (SCC) has not necessarily been established; however, our previous exploratory study suggested that the combination...
BACKGROUND
The first-line treatment for squamous cell lung cancer (SCC) has not necessarily been established; however, our previous exploratory study suggested that the combination of nedaplatin and amrubicin would be a promising treatment approach for patients with SCC. Therefore, a phase II study of this chemotherapeutic combination was designed to evaluate its efficacy and safety for treatment-naïve patients with advanced SCC.
METHODS
A total of 21 treatment-naïve patients with stage IIIB/IV or postoperative recurrent SCC were enrolled from six institutions. Nedaplatin (100 mg/m ) on day 1 and amrubicin (25 mg/m ) on days 1-3 were administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR), while the secondary endpoints included overall survival (OS), progression-free survival (PFS), and drug toxicities.
RESULTS
Partial response was observed in seven of 21 cases (ORR, 33.3%; 95% confidence interval [CI], 14.5-52.2). Disease control rate, which includes stable disease, was 71.4%. Median OS and PFS was 14.6 and 4.1 months, respectively. This regimen did not cause any treatment-related deaths. Grade 3/4 neutropenia developed in 8 of 21 cases (38.1%); however, febrile neutropenia developed in only 9.5% of the cases. Grade 3/4 gastrointestinal or neuromuscular toxicities were not observed.
CONCLUSION
The efficacy of the combination of nedaplatin and amrubicin was comparable to that of other conventional chemotherapeutic regimens for treatment-naïve patients with advanced SCC, and no severe gastrointestinal or neuromuscular toxicities were observed. This combination therapy may be an alternative treatment approach, particularly in patients who cannot tolerate gastrointestinal or neuromuscular toxicities.
Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prognosis; Survival Rate
PubMed: 31309738
DOI: 10.1111/1759-7714.13134 -
OncoTargets and Therapy 2019Extensive-disease small-cell lung cancer (ED-SCLC) has been known to be rapid progression and relapse, despite highly sensitive to chemotherapy. Amrubicin (AMR), a...
Extensive-disease small-cell lung cancer (ED-SCLC) has been known to be rapid progression and relapse, despite highly sensitive to chemotherapy. Amrubicin (AMR), a third-generation synthetic anthracycline, was accepted as a feasible alternative compared with the standard first-line chemotherapy for previously untreated ED-SCLC. While, the efficacies of these amrubicin-based regimens are unsatisfactory. Our meta-analysis was performed to assess the efficacy and toxicity of first-line therapy comparing AMR and chemotherapy in patients with ED-SCLC. Electronic databases were searched for eligible trials updated on November 2018. Randomized-controlled trials assessing the efficacy and safety of AMR in ED-SCLC were included, of which the interested results were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). A total of 6 randomized controlled trials were included in this analysis. There are no significant differences in OS (OR=1.03, 95% CI=0.66-1.60, =0.91), PFS (OR=1.2, 95% CI=10.77-1.88, =0.41) or ORR (OR=1.31, 95% CI=0.90-1.92, =0.16) with AMR (OR=0.90, 95% CI=0.76-1.05, =0.17). The most common treatment-related AEs in the AMR group are leukopenia (OR=3.13, 95% CI=1.22-7.99, =0.02) and neutropenia (OR=3.25, 95% CI=1.38-7.65, =0.007). Fatigue, anemia, nausea, vomiting, diarrhea the difference between the two groups had no statistical significance. The results of our analysis indicated that AMR therapy demonstrated non-inferiority to the standard first-line chemotherapy for previously untreated ED-SCLC. Whether it can be accepted as an alternative regimen to the standard first-line chemotherapy is still warranted.
PubMed: 31303766
DOI: 10.2147/OTT.S200601 -
Gan To Kagaku Ryoho. Cancer &... Jun 2019The patient was a 69-year-old woman.Upper gastrointestinal endoscopy showed a protruding tumor in the mid-thoracic esophagus, and biopsy revealed small cell carcinoma in...
The patient was a 69-year-old woman.Upper gastrointestinal endoscopy showed a protruding tumor in the mid-thoracic esophagus, and biopsy revealed small cell carcinoma in November 2012. Four courses of neoadjuvant chemotherapy comprising CDDP and CPT-11 were administered, and radical resection was performed in March 2013.I n March 2014, chest computed tomography revealed the recurrence of mediastinal lymph nodes; thus, we administered chemoradiotherapy comprising 5- FU and CDDP, and the size of the recurrent tumors decreased.However, in February 2015, positron emission tomographycomputed tomography revealed liver metastases.Therefore, we switched to a new chemotherapy regimen containing CDDP and VP-16.Although the treatment was very effective and the liver metastases significantly decreased in size, it was discontinued after 9 courses owing to neurotoxicity.Next, 7 courses of chemotherapy comprising amrubicin, which is administered for treating small cell lung carcinoma, were administered, which suppressed tumor growth for approximately 8 months.However, the tumor then re-grew.Chemotherapy comprising S-1 was administered; however, the tumor gradually progressed.The patient died 51 months after the initial treatment.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Esophageal Neoplasms; Female; Humans; Neoplasm Recurrence, Local
PubMed: 31273174
DOI: No ID Found -
Drugs of Today (Barcelona, Spain : 1998) Jun 2019The theme for this year's meeting of the American Association of Clinical Oncology (ASCO) was 'Caring for Every Patient, Learning from Every Patient'. The meeting...
The theme for this year's meeting of the American Association of Clinical Oncology (ASCO) was 'Caring for Every Patient, Learning from Every Patient'. The meeting consisted of oral, plenary and educational sessions, as well as poster presentations and discussions about important topics in the field of oncology, such as precision medicine, the latest in cancer research impacting patient care, new treatment options and insights for improving access to care. This 55th ASCO annual meeting was held from May 31 to June 4 in Chicago, Illinois, and was attended by over 40,000 cancer experts from around the world who followed a robust program providing opportunities to teach, engage and, most importantly, bring the oncology field together with the aim of improving care for patients with a cancer diagnosis. This report covers some of the later-stage developments and results presented at the meeting.
Topics: Chicago; Humans; Medical Oncology; Neoplasms; Precision Medicine; Societies, Medical
PubMed: 31250844
DOI: 10.1358/dot.2019.55.6.3024181