Multicenter prospective phase II trial of nivolumab in patients with unresectable or metastatic mucosal melanoma.

BACKGROUND: Mucosal melanoma is a rare and aggressive malignancy with poorer response compared with cutaneous melanoma. Prospective trials of immune checkpoint inhibitors in unresectable or metastatic mucosal melanoma have not been reported. PURPOSE: This phase II trial assessed the efficacy and safety of nivolumab monotherapy for unresectable or metastatic mucosal melanoma. PATIENTS AND METHODS: Eligibility criteria were as follows: histological diagnosis of unresectable or metastatic mucosal melanoma; age ≥ 20 years; ECOG performance status 0 or 1; and with measurable lesions. Patients received nivolumab 2 mg/kg every 3 weeks. The primary endpoint was the response rate (RR) according to Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were overall survival, progression-free survival, disease control rate, and toxicity. RESULTS: Twenty patients were enrolled between December 2014 and July 2017. Two patients without measurable lesions and one patient with uveal melanoma were excluded from analysis of efficacy. The best overall RR was 23.5%. One patient achieved a complete response, three partial response, and five stable disease as their best response. The median progression-free survival was 1.4 months (95% CI 1.2-2.8). The median overall survival was 12.0 months (95% CI 3.5 to not reached). The 1-year overall survival was 50.0% (95% CI 25.9-70.0%). Treatment-related adverse events of grades 3 or 4 occurred in 15% (3/20) of the patients. Grade 3 adverse events were resolved by corticosteroid treatment. CONCLUSION: Although this trial met the primary endpoint, the RR was still unsatisfactory. Therefore, further treatment development is required.

A single-arm, phase 2 study of steroid-containing mouthwash for the prevention of everolimus-associated stomatitis in multiple tumor types.

BACKGROUND: Everolimus is a mammalian target of rapamycin inhibitor used in the treatment of multiple tumor types, and its most common toxicity, stomatitis, can affect patient quality of life. Recent studies in breast cancer have supported the efficacy of steroid mouthwash for the prevention of everolimus-associated stomatitis. However, a few studies have been reported to date, and none have examined this effect in other tumor types. METHODS: This single-arm phase 2 study was designed to evaluate the efficacy of steroid-containing mouthwash for the prevention of stomatitis in patients with multiple tumor types receiving everolimus. The primary outcome was incidence of grade ≥ 2 stomatitis at 8 weeks of everolimus with steroid-containing mouthwash prophylaxis. We also assessed the stability of steroid-containing mouthwash components. RESULTS: Twenty-nine patients were evaluated, of which 76% had breast cancer and 24% had neuroendocrine tumors originating in the lung, gastrointestinal tract, pancreas, or of unknown primary origin. Grade ≥ 2 stomatitis incidence at 8 weeks was 28.1% (90% CI 16.2-46.1); the higher confidence limit exceeded the prespecified threshold of 30%. No patients developed grade ≥ 3 stomatitis. Most stomatitis occurred behind the oral cavity, with no lesions observed on the lips or floor of the mouth. CONCLUSIONS: Our findings did not support a prophylactic effect of steroid-containing mouthwash on everolimus-associated stomatitis. Given the needs of prevention of everolimus-associated stomatitis in various tumor types, further studies in a larger population using a randomized controlled trial design are, therefore, required to confirm the efficacy of steroid-containing mouthwash.

A short interval between bevacizumab and anti-epithelial growth factor receptor therapy interferes with efficacy of subsequent anti-EGFR therapy for refractory colorectal cancer.

BACKGROUND: Both bevacizumab and anti-epithelial growth factor receptor (EGFR) agents (e.g. cetuximab and panitumumab) are sequentially used for metastatic colorectal cancer (mCRC). Their co-administration as a first-line treatment does not improve outcome, indicating that there are negative interactions between these agents. A long-term pharmacokinetics study demonstrated serum persistence of bevacizumab following termination of bevacizumab 6 months after the last administration. This prompted us to investigate the impact of short intervals between bevacizumab and anti-EGFR antibody on the efficacy of subsequent anti-EGFR therapy. METHODS: We retrospectively reviewed consecutive patients with KRAS exon 2 wild-type mCRC who underwent anti-EGFR therapy after the failure of fluoropyrimidines, oxaliplatin and irinotecan. We divided patients into two groups (Group A: the interval between bevacizumab and anti-EGFR agent< 6 months; Group B: the interval >6 months). RESULTS: Of the 114 included patients (median age, 63 years), 78 (68%) were male. Most patients (88%) were treated with cetuximab plus irinotecan. Groups A and B consisted of 74 and 40 patients, respectively. There were no significant differences in patient characteristics. Group B patients had significantly longer progression-free survival (4.2 vs. 6.6 months; HR, 0.65; 95% CI, 0.43-0.98; P = 0.038) and longer overall survival (11.6 vs. 14.3 months; HR, 0.63; 95% CI, 0.41-0.98, P = 0.039). The response rate was 24.3% in Group A and 47.5% in Group B (P = 0.012). CONCLUSION: A short interval between bevacizumab and anti-EGFR antibody treatment may interfere with the efficacy of subsequent anti-EGFR therapy.

Comparison between surgery and definitive chemoradiotherapy for patients with resectable esophageal squamous cell carcinoma: a propensity score analysis.

PURPOSE: Our intent was to compare survival following neoadjuvant chemotherapy followed by surgery versus chemoradiotherapy (CRT) among patients with potentially resectable esophageal squamous cell carcinoma. METHODS: Information about 406 consecutive esophageal cancer patients with resectable disease who underwent surgery with neoadjuvant chemotherapy consisting of cisplatin plus 5-fluorouracil or who underwent definitive CRT was reviewed. The survival outcomes were analyzed using the Kaplan-Meier method and propensity score-adjusted Cox proportional hazards models. Relevant variables were included in the propensity score model. RESULTS: Overall, 206 patients planned to undergo surgery (S group) and 200 patients planned to undergo CRT (CRT group). In the unadjusted situation, progression-free survival and overall survival did not differ statistically between the groups. After matching, both survival outcomes were better in the S group compared to the CRT group. Subanalysis showed both survival outcomes were better in the S group for patients with only stage III disease. However, survival outcomes for stages I, II, and IV were not significantly different between treatment groups. CONCLUSIONS: Among patients with resectable disease, survival outcomes in the S group were favored over those of the CRT group. These results indicate that different therapeutic strategies should be used for stage III esophageal cancer than for other stages.

A single-arm phase II trial of combined chemotherapy with S-1, oral leucovorin, and bevacizumab in heavily pre-treated patients with metastatic colorectal cancer.

BACKGROUND: The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy. METHODS: Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0-2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80-120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR). RESULTS: A total of 31 patients were enrolled. DCR was 65% [95% confidence interval (CI), 48-100%] and the response rate was 7% (95% CI, 0.7-22%). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95% CI, 2.1-9.3] and 9.9 [95% CI, 7.4-NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26%) and diarrhea (11%), which were manageable by dose reduction/interruption. CONCLUSIONS: SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC. TRIAL REGISTRATION: This study has been registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( ID UMIN000009083 ) on 11 October 2012.

Differences in attitude toward adjuvant chemotherapy between colorectal cancer survivors and the medical staff of Japanese hospitals.

BACKGROUND: Adding oxaliplatin to fluorouracil-based chemotherapy can improve the survival of patients with stage III colorectal cancer by approximately 20 %. Reportedly, cancer patients are much more likely to prefer chemotherapy than medical professionals, although there is only a very small chance of achieving benefits from treatment. However, chronic neurotoxicity may be long lasting after the administration of oxaliplatin-based chemotherapy. This study aimed to evaluate potential side effects and differences in attitude between colorectal cancer patients and medical staff regarding the risk-benefit trade-offs of chemotherapy. METHODS: Relapse-free colorectal cancer patients who received adjuvant chemotherapy, doctors, and nurses were surveyed using a questionnaire regarding the side effects of chemotherapy and hypothetical clinical scenarios to quantify gains in the risk of relapse that were deemed necessary to make chemotherapy worthwhile. RESULTS: Responses were obtained from 147 patients, 54 doctors, and 84 nurses. Of these, 39 % of patients and 85 % of doctors replied that moderate side effects of adjuvant chemotherapy were worthwhile to achieve an absolute gain in the risk of relapse of 10 % from a baseline of 40 %. More severe side effects, as reported by colorectal cancer patients, were not associated with the larger gains necessary to make treatment worthwhile. Seven percent of patients treated with oxaliplatin, 40 % of doctors, and 43 % of nurses replied that side effects associated with oxaliplatin-based chemotherapy were severe. CONCLUSIONS: Doctors should consider potential heterogeneity in side effects and attitudes regarding the risk-benefit balance of adjuvant chemotherapy, and that patient perspectives should enhance shared decision-making.

[A questionnaire survey on QOL and toxicity in colorectal cancer survivors who received adjuvant chemotherapy].

The relative risk of cancer recurrence with postoperative adjuvant FOLFOX/CapeOX therapy(Ox)for stage III colorectal cancer is reduced by approximately 20%when compared to that with fluorouracil plus Leucovorin. We performed a questionnaire survey to evaluate the quality of life(QOL)and extent of side effects in patients who received adjuvant chemotherapy. In order to evaluate the risks and benefits of oxaliplatin administration, we also examined the differences in awareness of oxaliplatin side effects between patients and medical staff. Responses were obtained from 147 patients, 54 doctors, and 84 nurses. Analysis of the patient responses showed higher current QOL scores regardless of the chemotherapy regimen, although patients in the Ox group had a high rate of residual sensory peripheral neuropathy. In the Ox group, 81% of patients responded that the side effects were moderate. In contrast, 40% of medical staff identified the side effects of oxaliplatin as severe, which differed from that reported by the patients. Considering that Ox adjuvant chemotherapy may reduce the risk of recurrence by approximately 20%, the risk/benefit balance is acceptable.

Anastrozole versus tamoxifen as adjuvant therapy for Japanese postmenopausal patients with hormone-responsive breast cancer: efficacy results of long-term follow-up data from the N-SAS BC 03 trial.

Aromatase inhibitors are superior to tamoxifen as adjuvant therapy in postmenopausal patients with hormone-responsive breast cancer. We report the follow-up efficacy results from the N-SAS BC 03 trial (UMIN CTRID: C000000056) where anastrozole was compared with tamoxifen as adjuvant therapy in postmenopausal Japanese patients with hormone-responsive early breast cancer. The full analysis set contained 696 patients (anastrozole arm, n = 345; tamoxifen arm, n = 351). The log-rank test was used to compare the two groups in terms of disease-free survival (DFS) and relapse-free survival (RFS); Kaplan-Meier estimates were calculated. The treatment effects were estimated by Cox's proportional hazards model. To examine time-varying effect of hazard ratios, we estimated time-varying hazard ratios at time t [HR(t)] using data from time t up to 12 months. After a median follow-up of 98.5 months, hazard ratios (95% CIs) were 0.90 (0.65-1.24; log-rank p = 0.526) for DFS and 0.83 (0.56-1.23; log-rank p = 0.344) for RFS. Hazard ratios (95% CIs) for DFS and RFS up to 36 months were 0.69 (0.40-1.17) and 0.54 (0.27-1.06) and those after 36 months were 1.06 (0.70-1.59) and 1.05 (0.64-1.73), respectively. Time-varying hazard ratios for both DFS and RFS showed that hazard ratios were initially in favor of anastrozole and approached 1.0 at around 36 months. Superior efficacy of anastrozole to tamoxifen suggested by the initial analysis was not confirmed in the present analysis after a long-term follow-up period. Advantage of anastrozole was the greatest immediately after switching from tamoxifen and then decreased thereafter.

[The revision of Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan].

It has been ten years since the Ministry of Health and Welfare in Japan issued Guidelines for Clinical Evaluation Methods of anti-cancer Drugs in February, 1991. The circumstance surrounding anti-cancer drugs have now changed dramatically with the development of molecular-targeting drugs, introduction of clinical data in overseas countries for approval of new drugs in Japan, etc. Based on these changes, this guideline was revised in November 2005.

Impact of docetaxel in addition to cisplatin and fluorouracil as neoadjuvant treatment for resectable stage III or T3 esophageal cancer: a propensity score-matched analysis.

PURPOSE: To investigate the influence of addition of docetaxel to neoadjuvant chemotherapy (NAC) with cisplatin plus 5-fluorouracil (CF) in patients with clinical stage III or T3 esophageal squamous cell carcinoma. METHODS: Information about 209 esophageal cancer patients with stage III or T3 disease, who underwent NAC consisting of CF with or without docetaxel, was reviewed. The survival outcomes were analyzed using the Kaplan-Meier method and propensity score-adjusted Cox proportional hazards models. The relevant variables were included in the propensity score model. RESULTS: NAC was administered to 149 patients in the CF group and 60 patients in the docetaxel plus CF (DCF) group. Overall, 129 patients treated with CF and 58 patients treated with DCF underwent surgery after NAC. The overall response rate was significantly higher in the DCF group compared with the CF group (61.0 vs. 43.2 %, p = 0.021). After matching, recurrence-free survival did not differ statistically between the CF and DCF groups [hazard ratio (HR) 0.83, 95 % confidence interval (CI) 0.50-1.37, p = 0.46]. After matching, the improvement in overall survival in the DCF group reached statistical significance (HR 0.49, 95 % CI 0.24-0.999, p = 0.050). No significant differences in rate of locoregional or distant recurrences were observed between the CF and DCF groups (53.0 vs. 48.3 %, p = 0.54). CONCLUSIONS: NAC with DCF is superior to CF in patients with clinical stage III or T3 esophageal squamous cell carcinoma.

CA19-9 level as a prognostic and predictive factor of bevacizumab efficacy in metastatic colorectal cancer patients undergoing oxaliplatin-based chemotherapy.

PURPOSE: The prognostic and predictive values of carbohydrate antigen 19-9 (CA19-9) levels in metastatic colorectal cancer (mCRC) remain unclear. We reviewed all mCRC patients at a single institution to evaluate the relationship between CA19-9 levels and survival. METHODS: Two hundred and fifty-two patients underwent first-line chemotherapy using oxaliplatin-based regimens between April 2005 and December 2009. The relationship between baseline CA19-9 levels and survival was analyzed. Moreover, we evaluated the relationship between baseline CA19-9 levels and clinicopathological factors. RESULTS: One hundred and fifty patients had elevated baseline CA19-9 levels (elevated group), and 79 patients had normal baseline CA19-9 (normal group) levels. Both KRAS and BRAF mutation rates were higher in the elevated group than in the normal group. Elevated CA19-9 level was a poor prognostic factor compared with normal CA19-9 levels (P = 0.0021). In the elevated group, the median survival time with bevacizumab was significantly longer with bevacizumab than without it (median OS, 27.8 vs. 15.3 months, P = 0.0019). However, the median survival time was not different with or without bevacizumab in the normal group (median OS, 36.5 vs. 38.0 months, P = 0.9515). CONCLUSION: Our results suggest that baseline CA19-9 level is an independent prognostic factor in mCRC patients, and it correlated with the KRAS/BRAF mutation status. Bevacizumab exhibits clinical activity only for high CA19-9 levels in mCRC.

Atypical tumor-stromal fibroblasts in invasive ductal carcinomas of the breast treated with neoadjuvant therapy.

Tumor-stromal fibroblasts have recently been reported to play important roles in the tumor progression of cancer in various organs. The purpose of the present study was to investigate whether any characteristic histologic features of tumor-stromal fibroblasts could accurately predict the outcome of 318 patients with invasive ductal carcinoma of the breast who had received neoadjuvant therapy. We observed a small number of tumor-stromal fibroblasts with characteristic nuclear features existing in the tumor stroma and named these cells "atypical tumor-stromal fibroblasts." We then assessed the absence or presence of atypical tumor-stromal fibroblasts in biopsy (taken before neoadjuvant therapy) and surgical (taken after neoadjuvant therapy) materials and analyzed the outcome predictive powers of the presence of atypical tumor-stromal fibroblasts in biopsy and surgical materials using multivariate analyses that included well-known clinicopathological factors. The multivariate analyses demonstrated that the presence of atypical tumor-stromal fibroblasts assessed using biopsy materials had significantly higher hazard ratios for tumor recurrence and tumor-related death in patients with nodal metastasis and also significantly higher hazard ratios for tumor recurrence and tumor-related death independent of the hormone receptor status of the tumors. The results of this study clearly indicated that the presence of atypical tumor-stromal fibroblasts, especially in biopsy materials, is significantly associated with tumor recurrence and the tumor-related death of patients with invasive ductal carcinoma of the breast who have received neoadjuvant therapy.

Identification of predictive biomarkers for response to trastuzumab using plasma FUCA activity and N-glycan identified by MALDI-TOF-MS.

The aim of this study was to identify glycobiological biomarkers that indicate sensitivity to trastuzumab, a humanized monoclonal antibody against HER2 in plasma samples from breast cancer patients. Plasma samples were obtained from 24 breast cancer patients treated with trastuzumab monotherapy. The catalytic activities of plasma alpha1-6, fucosyltransferase (FUT8) and alpha-L fucosidase (FUCA) were analyzed using high-performance liquid chromatography (HPLC) and spectrophotometer, respectively. The plasma N-glycan profiles were investigated using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Plasma FUT8 activity was not significantly correlated with either the clinical response or progression-free survival (PFS). On the other hand, plasma FUCA activity was significantly correlated with PFS (p < 0.05). The MALDI-TOF-MS analysis of the plasma N-glycan profile revealed that the expression of 2534 m/z N-glycan was lower in patients with progressive disease (PD) and was correlated with PFS. Low expression of 2534 m/z N-glycan discriminated between PD and non-PD with 75% sensitivity and 82% specificity. We demonstrated that the plasma FUCA activity and 2534 m/z N-glycan may be predictive biomarkers of sensitivity to trastuzumab. Our results suggest that glycosylation analysis may provide useful information for determining clinical cancer therapy and provide novel insight into biomarker studies using glycobiological tools in the field of breast cancer.

The safety and efficacy of the weekly dosing of irinotecan for platinum- and taxanes-resistant epithelial ovarian cancer.

OBJECTIVE: Irinotecan is one of the drugs that might be effective against platinum- and taxanes-resistant epithelial ovarian cancer. We investigated efficacy and safety of the weekly dosing schedule of irinotecan. METHODS: From September 2001 to March 2003, 28 eligible patients who have histologically confirmed epithelial ovarian cancer, which was resistant or refractory to both platinum and taxanes, were consecutively treated at the National Cancer Center Hospital. Irinotecan (100 mg/m(2)) was administered intravenously over 90 min on days 1, 8, and 15. The chemotherapy was repeated every 4 weeks, up to 6 cycles. RESULTS: A total of 107 treatment cycles of irinotecan were administered to 28 patients. The median number of prior chemotherapy regimen was 3. Among 28 patients, 8 (29%) responded to irinotecan (2 complete responses and 6 partial responses). The median time to progression was 17 weeks. Three patients experienced hematological toxicities of Grade 4. Five patients experienced non-hematological toxicities Grade 3 or 4. No treatment-related death occurred. CONCLUSION: The weekly dosing schedule of irinotecan seems to be effective and safe salvage chemotherapy regimen for platinum- and taxanes-resistant or refractory epithelial ovarian cancer. Gastrointestinal toxicities, especially diarrhea, were moderate and manageable in an outpatient setting.

Weekly paclitaxel in patients with CAP-resistant advanced or recurrent endometrial carcinoma: a series of four patients.

We evaluated the feasibility of weekly paclitaxel in patients with recurrent or advanced endometrial carcinoma who had failed treatment with cyclophosphamide, doxorubicin, and cisplatin (CAP). We treated four patients with CAP-resistant recurrent or advanced endometrial carcinoma with paclitaxel. Paclitaxel (80 mg/m(2); infused over 1 h) was administered weekly for a maximum of 18 weeks, unless disease progression or intractable toxicity developed. A complete response was observed in one patient and a partial response in two patients. Disease progression was found in one patient. Two patients developed grade 3 leukopenia or neutropenia. Neurotoxicity for all patients was within grade 1. Outpatient treatment with weekly paclitaxel was well-tolerated and feasible for patients with CAP-resistant recurrent or advanced endometrial carcinoma. Further trials to confirm the efficacy and toxicity of weekly paclitaxel are warranted.