Yihebali Chi

S-1 and Cisplatin With or Without Nimotuzumab for Patients With Untreated Unresectable or Metastatic Gastric Cancer: A Randomized, Open-Label Phase 2 Trial

Abstract This open-label, randomized phase II trial was performed to compare the efficacy and safety of nimotuzumab plus S-1 and cisplatin (NCS) versus S-1 and cisplatin (CS) alone in patients with untreated unresectable or metastatic gastric cancer in the first-line setting. Eligible participants were randomly assigned (1:1) to receive either NCS or CS. The treatment consisted of 3-week cycles of twice-daily S-1 40 mg/m2 (on days 1–14) and intravenous cisplatin 30 mg/m2 (on days 1, 2), with or without weekly nimotuzumab (200 mg/m2). The primary endpoint was objective response rate (ORR). The second endpoint included progression-free survival (PFS), overall survival (OS), safety and association between efficacy and tumor epidermal growth factor receptor (EGFR) expression. Between October, 2009, and February, 2012, we enrolled 62 patients in Cancer Hospital Chinese Academy of Medical Sciences (CAMS). The ORR for 31 patients allocated NCS was 54.8% compared with 58.1% for 31 patients who were allocated to receive CS alone (P = 0.798). Median PFS for patients in CS arm was significantly improved than that in NCS arm [7.2 months vs. 4.8 months HR = 2.136 (95% CI 1.193–3.826), P = 0.011]. There was also a trend toward better overall survival for patients in CS arm compared with NCS arm [14.3 months vs. 10.2 months; HR = 1.776 (95% CI 0.972–3.246), P = 0.062]. In the EGFR 2+/3+ subgroup, adding nimotuzumab also failed to show additional benefit than chemotherapy alone. Both groups were well tolerated. Less than 10% of patients in both arms developed grade 3/4 toxicity. Combination of nimotuzumab and S-1-cisplatin provided no additional benefit than chemotherapy alone in the first-line treatment of unresectable or metastatic gastric cancer.

Characteristics and long-term prognosis of patients with rectal neuroendocrine tumors

AIM To analyze the clinicopathologic characteristics and prognostic factors of rectal neuroendocrine tumors. METHODS The records of 48 patients with rectal neuroendocrine tumors who were treated at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, from March 2004 to September 2009 were retrospectively reviewed. The clinicopathological data were extracted and analyzed, and patients were followed-up by telephone or follow-up letter to determine their survival status. Follow-up data were available for all 48 patients. Uni- and multivariate Cox regression analyses were performed to determine the prognostic factors significantly associated with overall survival. RESULTS The tumors occurred mostly in the middle and lower rectum, and the most prominent symptoms experienced by patients were hematochezia and diarrhea. The median distance between the tumors and the anal edges was 5.0 ± 2.257 cm, and the median diameter of the tumors was 0.8 ± 1.413 cm. The major pathological type was a typical carcinoid tumor, which accounted for 93.8% (45/48) of patients. Tumor-node-metastasis (TNM) stages I, II, III and IV tumors accounted for 78.8%, 3.9%, 9.6% and 7.7% of patients, respectively. The main treatment method, in 72.9% (35/48) of patients, was transanal extended excision. The 1-, 3- and 5-year survival rates of the whole group of patients were 100%, 93.7%, and 91.3%, respectively. Univariate analysis showed that age (P = 0.032), tumor diameter (P < 0.001), histological type (P < 0.001), TNM stage (P < 0.001), and surgical approach (P = 0.002) were all prognostic factors. On multivariate analysis, only the pathological type was shown to be an independent prognostic factor (HR = 2.797, 95%CI: 1.676-4.668, P = 0.004). CONCLUSION In patients with rectal neuroendocrine tumors, TNM stage I is the most common stage found, and lymph node or distant metastases are rarely seen. The pathological type of the tumor is an independent prognostic factor.

Randomized, single-centered, phase II clinical trial of nimotuzumab plus cisplatin and S-1 as first-line therapy in patients with advanced gastric cancer.

e21021 Background: Nimotuzumab, a humanized IgG1 anti-EGFR monoclonal antibody, has demonstrated efficacy associated with an absence of severe skin toxicity in many phase I/II cancer trials. METHODS This is a single-center, randomized, parallel assignment and open-label study of nimotuzumab (N: 200 mg iv on day 1, 8 and 15, repeat every 3 weeks) + cisplatin (C: 30mg/m2/day, on day 1 and day 2, repeat every 3 weeks) + S-1 (S: 80mg/m2/day, twice daily on day 1-14, followed 7 days off), vs cisplatin (C: 30mg/m2/day, on day 1 and day 2, repeat every 3 weeks) + S-1 (S: 80mg/m2/day, twice daily on day 1-14, followed 7 days off) as first line in patients with advanced or metastatic gastric cancer. If tumor control was achieved, NCS and CS were continued until unacceptable toxicity or disease progression. The primary endpoint was ORR and the secondary endpoints included TTP, PFS, 1-year survival rates and safety. RESULTS 40 patients, 27 men and 13 women, median age 54 years (21-74 years) ECOG PS 0-2 were treated with NCS (n = 20) or CS (n = 20). Up to 2011-01-14, 36 patients (NCS 19 cases compared with CS 17) have undergone efficacy assessment. The objective response rate (ORR) was 63.2% (12/19) in NCS group compared with 64.7% (11/17) in CS group. Until the same day, 18 patients have achieved progression in both groups (NCS 10 vs. FCS 8), median TTP was 5.5 months in NCS group compared with 3 months in CS group, and average TTP was 5.3 months in NCS group compared with 3.1 months in CS group. The incidence of adverse events was similar between both groups. No adverse events of grade 3 skin rash or grade 3 infusion-related reactions were observed. CONCLUSIONS Initial results have demonstrated benefit in TTP improvement and showed a potential improvement of OS. This study supports that nimotuzumab combine with cisplatin and S-1 has better outcomes compare to cisplatin and S-1. The further study is ongoing.

A study on the association between hyperlipidemia and hypothyroidism and the response to TKIs in metastatic renal cell carcinoma

Vascular endothelial growth facto receptor–tyrosine kinase inhibitors (VEGFR–TKIs) are widely used for metastatic renal cell carcinoma (mRCC). The aim of this study was to investigate the association between the response to VEGFR–TKIs and hyperlipidemia and hypothyroidism.

The Safety and Efficacy of the S1/Temozolomide Regimen in Patients with Metastatic Neuroendocrine Tumors

Purpose: Both capecitabine alone and capecitabine in combination with temozolomide have activities against neuroendocrine tumors (NETs). However, the role of S-1 in NETs is still unknown. We performed a study to evaluate the safety and efficacy of the S-1/temozolomide (STEM) regimen in patients with locally advanced or metastatic NETs. Methods: A retrospective review was conducted in 20 patients with locally advanced or metastatic NETs treated with the STEM regimen. Of the patients, 15 (75.00%) had failed 1 or more lines of treatment with somatostatin analogues, sunitinib, everolimus, anlotinib, or other chemotherapy regimens. The patients received S-1 at 40 mg/m2 orally twice daily on days 1-14 and temozolomide 200 mg orally once daily on days 10-14 of a 21-day cycle. The patients were followed up for evidence of object response, toxicity, and progression-free survival. Results: Response to treatment was assessed using RECIST 1.1. Eight patients (40.00%) achieved a partial response (PR), and another 8 (40.00%) had stable disease (SD). The clinical benefit rate (PR and SD) was 80.00%. The median progression-free survival was not achieved. Only 1 patient (5.00%) had grade 3 adverse events. Among the patients with NETs of different origins, 4 (40.00%) and 5 (50.00%) with pancreatic NETs attained PR and SD, respectively. Four (40.00%) and 3 patients (30.00%) with nonpancreatic NETs attained PR and SD, respectively. Conclusions: The STEM regimen is exceptionally highly active and well tolerated in patients with locally advanced or metastatic NETs. Even in patients who showed disease progression with previous therapies, it is still highly active. In this 20-patient study, the regimen appeared to be similarly active in pancreatic endocrine tumors and nonpancreatic NETs.

Impact of Cytoreductive Nephrectomy on Survival in Patients with Metastatic Renal Cell Carcinoma Treated by Targeted Therapy.

Background: The metastatic renal cell carcinoma (mRCC) patients treated with upfront cytoreductive nephrectomy combined with &agr;-interferon yields additional overall survival (OS) benefits. It is unclear whether mRCC patients treated with vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) will benefit from such cytoreductive nephrectomy either. The aim of the study was to identify variables for selection of patients who would benefit from upfront cytoreductive nephrectomy for mRCC treated with VEGFR-TKI. Methods: Clinical data on 74 patients enrolled in 5 clinical trials conducted in Cancer Hospital (Institute), Chinese Academy of Medical Sciences from January 2006 to January 2014 were reviewed retrospectively. The survival analysis was performed by the Kaplan–Meier method. Comparisons between patient groups were performed by Chi-square test. A Cox regression model was adopted for analysis of multiple factors affecting survival, with a significance level of &agr; = 0.05. Results: Fifty-one patients underwent cytoreductive nephrectomy followed by targeted therapy (cytoreductive nephrectomy group) and 23 patients were treated with targeted therapy alone (noncytoreductive nephrectomy group). The median OS was 32.2 months and 23.0 months in cytoreductive nephrectomy and noncytoreductive nephrectomy groups, respectively (P = 0.041). Age ⩽45 years (P = 0.002), a low or high body mass index (BMI <19 or >30 kg/m2) (P = 0.008), a serum lactate dehydrogenase (LDH) concentration >1.5 × upper limit of normal (P = 0.025), a serum calcium concentration >10 mg/ml (P = 0.034), and 3 or more metastatic sites (P = 0.023) were independent preoperative risk factors for survival. The patients only with 0–2 risk factors benefited from upfront cytoreductive nephrectomy in terms of OS when compared with the patients treated with targeted therapy alone (40.0 months vs. 23.2 months, P = 0.042), while those with more than 2 risk factors did not. Conclusions: Five risk factors (age, BMI, LDH, serum calcium, and number of metastatic sites) seemed to be helpful for selecting patients who would benefit from undergoing upfront cytoreductive nephrectomy.

Clinicopathological Characteristics and Prognosis of Colorectal Cancer in Chinese Adolescent Patients

Background:Colorectal adenocarcinoma rarely occurred in adolescent. Clinical feature and prognosis of this population are not clear until now. In addition, DNA mismatch repair (MMR) status may relate to the early disease occurrence. The present study aimed to perform a retrospective analysis of adolescent patients with colorectal cancer, including clinicopathological characteristics and prognosis. Methods:The medical records of 11,503 patients diagnosed as colorectal cancer in Cancer Hospital, Chinese Academy of Medical Sciences from January 1999 to December 2009 were retrospectively reviewed. Finally, 19 patients who were between 10 and 20 years old were selected as the study group. We summarized the clinicopathological characteristics, analyzed the association with prognosis and assessed the expression of MMR protein by immunohistochemical method. Results:The most common primary site was the right colon in 7 patients. Ten patients had Stage III colorectal cancer, 5 patients had Stage IV disease. Signet ring cell carcinoma was the most frequent pathological type (7/19). Deficient MMR was identified in 2 patients. The 5-year survival rate and median survival time were 23.2% and 26 months. Distant metastasis was identified as an independent prognostic factor (P = 0.02). Conclusions:Colorectal cancer in Chinese adolescents was very rare. The chinese adolecents with colorectal cancer were frequently diagnosed in the right colon, as Stage III/IV disease with signet ring cell carcinoma. The prognosis was relatively poor.

Anlotinib for the Treatment of Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer

BACKGROUND The prognosis of advanced or metastatic medullary thyroid carcinoma (MTC) is poor, and there are few therapeutic options. Anlotinib has previously shown promising antitumor activity on MTC in preclinical models and a Phase I study. This Phase II clinical trial was devised to confirm the antitumor activity of anlotinib in patients with advanced or metastatic MTC. METHODS Patients with unresectable locally advanced or metastatic MTC received once daily oral anlotinib 12 mg, two weeks on/one week off, until disease progression, death, unacceptable toxicity, or withdrawal of consent for any reason. The dose was adjusted on the basis of observed toxicity. The primary endpoint was progression-free survival (PFS). RESULTS Fifty-eight patients received anlotinib treatment. The primary endpoint PFS has not yet been reached at the time of analysis. On the basis of investigator assessments, 56.9% of patients experienced a partial response. PFS rate at 48 weeks was 85.5%. Forty-five patients had a ≥50% decrease in serum calcitonin concentration from baseline. The most common adverse events were hand-foot syndrome, hypertriglyceridemia, cholesterol elevation, fatigue, and proteinuria. CONCLUSIONS Anlotinib demonstrated a durable antitumor activity with a manageable adverse event profile in locally advanced or metastatic MTC.

Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients With Refractory Metastatic Soft Tissue Sarcoma.

Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies. Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks). Results: A total of 166 patients were included in the final analysis. Overall, the PFR12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%–18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months for UPS (n = 19); 63%, 5.6 and 13 months for LPS (n = 13); 75%, 11 and 15 months for LMS (n = 26); 75%, 7.7 and 12 months for SS (n = 47); 81%, 5.6 and 12 months for FS (n = 18); 77%, 21 and not reached for ASPS (n = 13); 54%, 11 and 16 months for CCS (n = 7); and 44%, 2.8 and 8.8 months for other sarcoma (n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred. Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233–8. ©2018 AACR.