Cost-effectiveness Analysis of Monoclonal Antibodies in the First-line Treatment of RAS Wild-type Metastatic Colorectal Cancer: A Systematic Review.

PURPOSE: First-line treatment with monoclonal antibodies (bevacizumab, cetuximab, and panitumumab) for RAS wild-type metastatic colorectal cancer (mCRC) has advanced. The costs of drugs targeted to mCRC are high. This systematic review aimed to summarize the cost-effectiveness of monoclonal antibodies in the first-line treatment of RAS wild-type mCRC. METHODS: We searched 5 databases to find original-research cost-effectiveness analyses of monoclonal antibodies used in the first-line treatment of patients with RAS wild-type mCRC. Three reviewers independently evaluated all of the records to be screened. FINDINGS: A total of 15 articles, 12 cost-effectiveness analyses, and 3 cost-utility analyses were identified. The reporting of identified articles was assessed using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. They were assigned to 1 of 6 categories based on the combination of the intervention and control groups, the most common of which was cetuximab + chemotherapy versus bevacizumab + chemotherapy. The results of the cost-effectiveness analyses may have varied because of the differences in settings, such as country, study population, RAS mutation status, efficacy data, and model structure, in which each study was conducted. IMPLICATIONS: Although treatment with monoclonal antibodies has demonstrated efficacy in terms of life-years gained and progression-free survival, the most cost-effective treatment among monoclonal antibodies remains controversial; however, most of the studies that compared a monoclonal antibody + chemotherapy versus chemotherapy alone reported that chemotherapy alone was a cost-effective strategy. Future studies are needed to evaluate the cost-effectiveness of treating patients with mCRC using biomarker-driven precision medicine.

Clinical usefulness of eribulin as first- or second-line chemotherapy for recurrent HER2-negative breast cancer: a randomized phase II study (JBCRG-19).

BACKGROUND: Anthracycline (A) or taxane T-based regimens are the standard early-line chemotherapy for metastatic breast cancer (BC). A previous study has shown a survival benefit of eribulin in heavily pretreated advanced/recurrent BC patients. The present study aimed to compare the benefit of eribulin with treatment of physician's choice (TPC) as first- or second-line chemotherapy for recurrent HER2-negative BC. METHODS: Patients with recurrent HER2-negative BC previously receiving anthracycline and taxane AT-based chemotherapy in the adjuvant or first-line setting were eligible for this open-label, randomized, parallel-group study. Patients were randomized 1:1 by the minimization method to receive either eribulin (1.4 mg/m2 on day one and eight of each 21-day cycle) or TPC (paclitaxel, docetaxel, nab-paclitaxel or vinorelbine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure (TTF), overall response rate (ORR), duration of response, and safety (UMIN000009886). RESULTS: Between May 2013 and January 2017, 58 patients were randomized, 57 of whom (26 eribulin and 31 TPC) were analyzed for efficacy. The median PFS was 6.6 months with eribulin versus 4.2 months with TPC (hazard ratio: 0.72 [95% confidence interval (CI), 0.40-1.30], p = 0.276). Median TTF was 6.0 months with eribulin versus 3.6 months with TPC (hazard ratio: 0.66 [95% CI, 0.39-1.14], p = 0.136). Other endpoints were also similar between groups. The most common grade ≥ 3 adverse event was neutropenia (22.2% with eribulin versus 16.1% with TPC). CONCLUSIONS: Eribulin seemed to improve PFS or TTF compared with TPC without statistical significance. Further validation studies are needed.

A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer.

PURPOSE: Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC. METHODS: We randomized patients with stage I-III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2. RESULTS: We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years. CONCLUSIONS: Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC. TRIAL REGISTRATION: UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

Baseline neutrophil-to-lymphocyte ratio and c-reactive protein predict efficacy of treatment with bevacizumab plus paclitaxel for locally advanced or metastatic breast cancer.

The effect of bevacizumab plus paclitaxel therapy on progression-free survival (PFS) is prominent; however, no overall survival (OS) benefit has been demonstrated. Our aim was to study the predictive efficacy of peripheral immune-related parameters, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and c-reactive protein (CRP) in locally advanced and metastatic breast cancers. A total of 179 patients treated with bevacizumab plus paclitaxel were recruited from three institutes in the test cohort. The cut-off values of NLR, ALC, and CRP were set at 3, 1500/µL, and 1.0 mg/dL, respectively, and baseline values of these factors were measured. The PFS of patients with NLR-low was significantly longer than that of patients with -high (median, 12.6 vs. 7.2 months; hazard ratio (HR), 0.48, 95% confidence interval (95% CI), 0.31-0.73; p = 0.0004). OS of patients with NLR-low was significantly better than those with-high (22.2 vs. 13.5 months; HR, 0.57, 95% CI, 0.39-0.83; p = 0.0032). Similarly, improved PFS and OS were recognized in patients with CRP-low as compared with patients with -high (HR, 0.44, 95% CI, 0.28-0.68; p = 0.0001 and HR, 0.39, 95% CI, 0.26-0.61, p < 0.0001, respectively). In the validation cohort from two institutes (n = 57), similar significant improvements in PFS and OS were confirmed for patients with NLR-low (p = 0.0344 and p = 0.0233, respectively) and CRP-low groups (p < 0.0001 and p = 0.0001, respectively). Low levels of NLR and CRP at baseline were significantly associated with improved prognosis in patients treated with bevacizumab plus paclitaxel.

Multicentre, phase II study of eribulin in combination with S-1 in patients with advanced breast cancer.

BACKGROUND: We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis. METHODS: Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m2 on days 1 and 8, every 21 days) and S-1 (65 mg/m2, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS). RESULTS: This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%). CONCLUSIONS: The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis. TRIAL REGISTRATION: Current Controlled Trials UMIN000015049 , date of registration: September 5th 2014.

Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 12 weeks' exemestane exposure in patients with estrogen receptor-positive breast cancer: A multicenter, open-label, phase II study.

Our aim was to investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane alone followed by tailored treatment, either continued exemestane monotherapy or exemestane plus docetaxel-cyclophosphamide (TC) combination therapy, in postmenopausal patients with primary invasive estrogen receptor-positive, human epidermal growth factor receptor 2-negative, stage I-IIIA breast cancer and Ki67 labeling index ≤30%. In this open-label phase II study, patients initially received exemestane 25 mg/d for 12 weeks. Responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 labeling index ≤5% after treatment, or stable disease with Ki67 labeling index ≤5% both before and after treatment. For the subsequent 12 weeks, exemestane monotherapy was continued for responders (group A), whereas nonresponders received exemestane plus four cycles of TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) (group B). Clinical response rate (ie the proportion of patients with CR or PR) at 24 weeks was the primary endpoint. Of 64 patients provisionally enrolled between December 2010 and May 2016, 58 (median age 60 years) started the study treatment. Five patients discontinued treatment in the initial exemestane monotherapy period, and 39 completed the study treatment. Clinical response rates at 8-12 and 24 weeks were 71% (10/14, 95% confidence interval [CI] 41.9%-91.6%) and 57% (8/14, 95% CI 28.9%-82.3%), respectively, in group A, and 16% (4/25, 95% CI 4.5%-36.1%) and 56% (14/25, 95% CI 34.9%-75.6%), respectively, in group B. Grade ≥3 adverse events were reported in 8% (1/15) and 53% (20/38) in group A and group B, respectively. The tailored treatment maintained the favorable clinical response to exemestane alone in responders and improved clinical response in nonresponders. TRIAL NUMBER: UMIN000004752 (UMIN Clinical Trials Registry).

Participants in a randomized controlled trial had longer overall survival than non-participants: a prospective cohort study.

PURPOSE: While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely. METHODS: This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival. RESULTS: The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006). CONCLUSIONS: This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

De-escalated neoadjuvant therapy with nanoparticle albumin-bound paclitaxel and trastuzumab for low-risk pure HER2 breast cancer.

PURPOSE: Neoadjuvant trastuzumab combined with anthracycline and taxane is now considered a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A less toxic, non-anthracycline regimen has been considered as a treatment option for patients with node-negative small tumors. Estrogen receptor-negative and HER2-positive (pure HER2) tumors are more likely to achieve a pathological complete response (pCR). This study evaluates the activity and safety of neoadjuvant nanoparticle albumin-bound paclitaxel (nab-PTX) plus trastuzumab for pure HER2 breast cancer in patients with low risk of relapse. METHODS: We treated patients with tumors measuring ≤ 3 cm, node-negative, pure HER2 breast cancer using neoadjuvant nab-PTX 260 mg/m2 with trastuzumab every 3 weeks for four cycles. The primary endpoint was the pCR rate. The secondary endpoints included the clinical response rate, disease-free survival, pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery conversion rate, safety, and disease-free survival. Depending on the pathological findings of surgical specimens, the administration of adjuvant anthracycline could be omitted. RESULTS: Eighteen patients were enrolled. No patient required dose delays or reductions; none showed disease progression, and all patients underwent surgery as scheduled. Of the 18 patients, 66.7% achieved pCR, and the adjuvant anthracycline regimen was omitted for all patients. The incidence of severe adverse events was quite low. CONCLUSION: This less toxic, anthracycline-free regimen appears to be a significantly effective neoadjuvant therapy for patients with pure HER2 breast cancer at low relapse risk.

Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR.

Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre- and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone.

Significance of baseline neutrophil-to-lymphocyte ratio for progression-free survival of patients with HER2-positive breast cancer treated with trastuzumab emtansine.

The efficacy of trastuzumab emtansine (T-DM1) is prolonged for some patients; however, the predictive factors remain unknown. We focused on a peripheral blood biomarker, the neutrophil-to-lymphocyte ratio (NLR), regarding T-DM1 treatment efficacy. Fifty-three advanced or metastatic breast cancers treated with T-DM1 were retrospectively recruited from three institutes. The NLR in the peripheral blood was measured at baseline and after one cycle. The cutoff value of the NLR was set at median value 2.56. The progression-free survival (PFS) of patients with NLR-low at baseline (n = 26; median, not reached) was significantly better than that of patients with NLR-high (n = 27; median, 4.13 months; hazard ratio [HR], 0.226; 95% confidence interval [CI], 0.112-0.493; p = 0.0001). Longer overall survival was significantly associated with a low NLR (HR, 0.384; 95% CI, 0.170-0.910; p = 0.0296). In the subgroup analysis, patients with NLR-low consistently had longer PFS compared to those with NLR-high irrespective of the number of prior chemotherapy regimens, prior trastuzumab, visceral metastasis, estrogen receptor status, and human epidermal growth factor receptor 2 (HER2) score. Although detailed mechanisms remain unknown, treatment efficacy of T-DM1 may be partly mediated by activation of the immune system. Low baseline NLR appears to be beneficial for treatment with T-DM1 in HER2-positive breast cancers.

Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting.

BACKGROUND: Regorafenib improved the overall survival (OS) of patients with metastatic colorectal cancer (mCRC) who progress after standard therapies in two phase III trials. The present large-scale prospective observational study evaluated the safety and effectiveness of regorafenib administered to Japanese patients with mCRC in real-life setting. MATERIALS AND METHODS: Patients with mCRC were prospectively registered and initially received ≤160 mg oral regorafenib daily, at the investigator's discretion, for weeks 1-3 of each 4-week cycle. The study's primary aim was to assess safety, particularly unexpected clinically significant adverse drug reactions (ADRs). A Cox's proportional hazards model was used to evaluate the association between OS, hand-foot skin reaction (HFSR), and baseline characteristics. RESULTS: We evaluated 1,227 of 1,301 patients (enrolled from March 2013 to May 2015). ADRs occurred in 89.3% of patients (mostly within the first 4 weeks) and were a major reason for discontinuing treatment. The most frequent ADRs were HFSR, liver injury, and hypertension. The cumulative incidence of HFSR and liver injury was higher in patients who initially received 160 mg than in those who received ≤120 mg. The incidence of hypertension and fatigue was similar between groups. Median OS was 6.9 months (95% confidential interval, 6.4-7.4). OS was associated with early onset of HFSR and good performance status (PS) but not with the initial dose. CONCLUSION: The outcomes of this study were consistent with those of clinical trials. There were no new safety concerns. Regorafenib treatment would not be recommended for patients with higher PS. IMPLICATIONS FOR PRACTICE: Previous clinical trials demonstrated regorafenib improved overall survival in patients with metastatic colorectal cancer who progress after standard chemotherapies. Because the eligibility criteria of the trials were restricted compared with a real-world setting, the data from the trials may not fully represent the profiles of regorafenib in clinical practice. This large-scale observational study showed that the safety and effectiveness of regorafenib in clinical practice were generally consistent with previous trials. The majority of patients reported adverse drug reactions within the first 4 weeks, most commonly hand-foot skin reaction. Regorafenib treatment would not be recommended for patients with higher performance status.

Neoadjuvant endocrine therapy with exemestane followed by response-guided combination therapy with low-dose cyclophosphamide in postmenopausal patients with estrogen receptor-positive breast cancer: A multicenter, open-label, phase II study.

Patients with estrogen receptor (ER)-positive breast cancer are less likely to achieve a pathological complete response (pCR) with neoadjuvant chemotherapy. Neoadjuvant endocrine therapy may be more appropriate than neoadjuvant chemotherapy in these hormone-sensitive patients. Most patients with ER-positive breast cancer are postmenopausal, and therefore, generally older and less able to tolerate chemotherapy. We aimed to investigate the efficacy and safety of tailored neoadjuvant endocrine and chemoendocrine therapy for postmenopausal breast cancer patients. Untreated patients with primary invasive ER-positive, HER2-negative, stage I-IIIA breast cancer, and Ki67 index ≤30% were enrolled. Patients received exemestane 25 mg/d for 12 weeks. Based on clinical response and change in Ki67 index, assessed at 8-12 weeks, patients with complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% before and after treatment were defined as responders. For the subsequent 24 weeks, responders continued exemestane monotherapy (group A), and nonresponders received exemestane 25 mg/d plus cyclophosphamide 50 mg/d (group B). The primary endpoint was clinical response at weeks 24 and 36. A total of 59 patients (median age, 69 years) started initial exemestane monotherapy. After exclusion of three patients who discontinued during this period, 56 remained enrolled to receive subsequent treatment. Clinical response rates (CR and PR) and 95% CI at weeks 24 and 36 were 85% (12/14; 57.2%-98.2%) and 71% (10/14; 41.9%-91.6%), respectively, in group A; and 54% (23/42; 38.7%-70.2%) and 71% (30/42; 55.4%-84.3%), respectively, in group B. At week 36, no significant difference was found in median Ki67 index between the groups (3.5% and 4.0%). There were no treatment-related deaths. We found that clinical response comparable to that of responders was achieved in nonresponders after addition of cyclophosphamide to the initial endocrine therapy.

A multicenter phase II trial of neoadjuvant letrozole plus low-dose cyclophosphamide in postmenopausal patients with estrogen receptor-positive breast cancer (JBCRG-07): therapeutic efficacy and clinical implications of circulating endothelial cells.

Neoadjuvant endocrine therapy has been reported to decrease tumor size, which leads to increased breast conservation rates. To improve the clinical response, metronomic chemotherapy with endocrine therapy is a promising strategy. A multicenter phase II single-arm neoadjuvant trial with letrozole and cyclophosphamide was conducted. Eligibility criteria included postmenopausal status, T2-4 N0-1, and estrogen receptor-positive breast carcinoma. Letrozole (2.5 mg) plus cyclophosphamide (50 mg) was given orally once a day for 24 weeks. The primary endpoint was the clinical response rate (CRR). To investigate anti-angiogenic effects, circulating endothelial cells (CECs) were quantified using the CellSearch system. From October 2007 to March 2010, 41 patients were enrolled. The CRR was 67.5% (52.0-80.0%), which was above the prespecified threshold (65%). The conversion rate from total mastectomy to breast-conserving surgery was 64% (18/28). Grade 3 or greater nonhematological toxicity was not reported. Clinical response was associated with improved disease-free survival (DFS) (P = 0.020). The increase in CEC counts at 8 weeks was observed in nonresponders (P = 0.004) but not in responders. Patients with higher CEC counts at baseline or post-treatment showed worse DFS than those with lower counts (P < 0.001 at baseline and = 0.014 post-treatment). Multivariate analysis showed that post-treatment CEC counts but not pretreatment counts were independently correlated with DFS (P = 0.046). In conclusion, neoadjuvant letrozole plus cyclophosphamide showed a good clinical response for postmenopausal patients with estrogen receptor-positive breast cancer. CEC quantification is a promising tool for treatment monitoring and prognostic stratification for metronomic therapy following validation of our results in larger studies. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000001331 Phase II study of neoadjuvant letrozole combined with low-dose metronomic cyclophosphamide for postmenopausal women with endocrine-responsive breast cancer (JBCRG-07).

A phase II, multicenter, single-arm trial of eribulin as first- or second-line chemotherapy for HER2-negative advanced or metastatic breast cancer: evaluation of efficacy, safety, and patient-reported outcomes.

PURPOSE: Although eribulin is a suitable option for early-line treatment of metastatic breast cancer (MBC), data on first- or second-line use of eribulin for human epidermal growth factor receptor 2 (HER2)-negative MBC are still limited. Therefore, we conducted a phase II trial to investigate the efficacy and safety of eribulin for first- or second-line chemotherapy for HER2-negative MBC. MATERIALS AND METHODS: We performed a phase II, open-label, single-arm, multicenter study in Japan. Eligible patients were women with histologically confirmed HER2-negative MBC without chemotherapy or only one chemotherapy line for MBC. The primary endpoint was the overall response rate (ORR) and the secondary endpoints included the clinical benefit rate (ORR + stable disease for 6 months; CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and health-related quality of life (HRQoL). RESULTS: A total of 35 patients with HER2-negative MBC were enrolled between March 2013 and February 2017 (data cut-off July 31, 2017). The ORR was 37.1% (95% CI 21.1-53.2%). The CBR was 54.3% (95% CI 37.8-70.8%). The median PFS was 6.2 months (95% CI 2.7-9.4 months) and median OS was 21.4 months (95% CI 11.5-32.9 months). Common grade 3/4 adverse events were neutropenia (42.9%) but febrile neutropenia (2.9%). Although the majority of non-hematological adverse events were mild in severity, one patient died of pneumonitis. In HRQoL analysis, eribulin appeared to maintain HRQoL of many patients. CONCLUSIONS: Eribulin as first- or second-line chemotherapy is effective and has manageable toxicity for patients with HER2-negative MBC.

Bi-weekly eribulin therapy for metastatic breast cancer: a multicenter phase II prospective study (JUST-STUDY).

BACKGROUND: This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. METHODS: Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated. RESULTS: Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events. CONCLUSION: This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491).

Independent prognostic impact of preoperative serum carcinoembryonic antigen and cancer antigen 15-3 levels for early breast cancer subtypes.

BACKGROUND: Although the prognosis for operable breast cancers is reportedly worse if serum carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels are above normal, the usefulness of this prognosis is limited due to the low sensitivity and specificity; in addition, the optimal cutoff levels remain unknown. METHODS: A total of 1076 patients who were operated for breast cancers (test set = 608, validation set = 468) without evidence of metastasis were recruited, and their baseline and postoperative serum CEA and CA15-3 levels were analyzed. The optimal cutoff values of CEA and CA15-3 for disease-free survival (DFS) were 3.2 ng/mL and 13.3 U/mL, respectively, based on receiver operating characteristic curve and area under the curve analyses. RESULTS: The DFS of patients with high CEA levels (CEA-high: n = 191, 5-year DFS 70.6%) was significantly worse (p < 0.0001) than that of CEA-low patients (n = 885, 5-year DFS 87.2%). There was a significant difference in DFS (p < 0.0001) between CA15-3-high and CA15-3-low patients (n = 314 and n = 762, respectively; 5-year DFS 71.8 vs. 89.3%). Significant associations between DFS and CA15-3 levels were observed irrespective of the subtypes. Multivariable analysis indicated that tumor size, lymph node metastasis, tumor grade, and CEA (p = 0.0474) and CA15-3 (p < 0.0001) levels were independent prognostic factors (hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.005-2.245 for CEA; HR 2.088, 95% CI 1.457-2.901 for CA15-3). CONCLUSIONS: These findings suggest that CEA and CA15-3 levels might be useful for predicting the prognosis of patients with operable early breast cancer irrespective of the subtype. Serum levels at baseline may reflect tumor characteristics for metastatic potential even when these levels are within the normal ranges.

Short-term outcomes following single-port laparoscopic surgery in elderly patients with colon cancer compared with younger patients.

Surgeons are increasingly being faced with the challenge of treating elderly patients with colon cancer. The present study therefore aimed to compare the short-term outcomes of single-port laparoscopic surgery (SILS) for elderly patients with colon cancer (≥70 years) with those in younger patients (41-69 years; control group). Among 100 patients with colorectal cancer who had been treated with single-port laparoscopic surgery between January 2011 and December 2014, 56 (56.0%) were ≥70 years of age. The results of treatment and short-term outcomes in the elderly group (n=56) were retrospectively compared with the younger patients in the control group (n=44). The sex distribution, body mass index, history of prior surgery and the American Society of Anesthesiologists physical status classification were similar between the groups. Onodera's prognostic nutritional index demonstrated significant differences between the elderly and control groups (38.3 vs. 49.8; P<0.05). No significant differences were observed in the mean length of surgery (219.5±73.5 vs. 201.4±76.5 min; P=0.43), estimated blood loss (32.2±74.5 vs. 36.1±90.2 ml; P=0.10), postoperative complications (10.9 vs. 7.1%; P=0.78), length of postoperative hospital stay (9.6±12.5 vs. 7.3±3.0 days; P=0.23) or number of harvested lymph nodes (21.8±24.3 vs. 22.5±11.3; P=0.87) between the elderly and control groups. In conclusion, the results of the present study demonstrate that SILS may be carried out feasibly in elderly patients with colon cancer.

[A Case of Synchronous Double Cancers of the Liver and Pancreas Treated Using Pancreaticoduodenectomy and Liver Resection].

A 50-year-old woman had a 12mm liver tumor at segment 4 and was diagnosed with hemangioma. Two years later, the liver tumor had grown to 27mm in diameter, and a new pancreatic tumor was detected using CT examination. The pancreatic tumor was suspected of being pancreatic carcinoma, based on the results of endoscopic-ultrasound-guided fine-needlebiopsy( EUS-FNA)of the pancreas. The liver tumor was diagnosed as adenocarcinoma using liver biopsy. Because of its slow growth and the solitary liver tumor, synchronous pancreatic cancer and intrahepatic cancer were suspected. We therefore performed pancreaticoduodenectomy with portal vein resection and partial liver resection of segment 4. Upon histological analysis, carcinoma in situ was detected in the liver tumor and the patient was diagnosed with synchronous double cancers of the liver(cholangiocellular carcinoma)and pancreas(invasive ductal carcinoma). Our case indicated that it is very difficult to distinguish cholangiocellular carcinoma from metastatic liver tumor using diagnostic images. We should therefore consider the possibility of cholangiocellular carcinoma when a solitary tumor in the liver is detected at the same time as pancreatic cancer.