Biyun Wang

Immunohistochemical expression and clinical significance of P-glycoprotein in previously untreated extranodal NK/T-cell lymphoma, nasal type

Overexpression of P‐glycoprotein (P‐gp) has been identified by a variety of methods in NK cells and NK malignancies. The aim of this study was to determine the clinical significance of P‐gp in previously untreated extranodal NK/T‐cell lymphoma, nasal type. Tumor specimens from 30 patients initially treated with CHOP or CHOP‐based chemotherapy were examined by immunohistochemistry using JSB‐1, a monoclonal antibody recognizing the intracellular epitope of P‐gp molecule. Twenty cases (67%) were positive for P‐gp expression. The complete response rate achieved in P‐gp positive patients was significantly lower than in P‐gp negative ones (20% vs. 60%, P = 0.045). With a median follow‐up of 25 months, the 2‐year progression‐free survival (PFS) and overall survival (OS) rates for all patients were 66 and 69%, respectively. Compared with both PFS and OS rates of P‐gp positive patients, those of P‐gp negative patients showed a trend of benefit that did not reach statistical significance for borderline P values (PFS: 90% vs. 54%, P = 0.1057; OS: 90% vs. 61%, P = 0.2028). Our results suggest that P‐gp expression is related with poor treatment outcomes of extranodal NK/T‐cell lymphoma, nasal type. Am. J. Hematol., 2008.

Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer

Apatinib is an oral, highly potent tyrosine‐kinase inhibitor targeting VEGFR2. Phase I study showed the recommended dose of 750 mg/day with substantial antitumor activity. This phase II study aims to evaluate the optimum dose level for the efficacy and safety of apatinib monotherapy in heavily pretreated patients with metastatic triple negative breast cancer (mTNBC) in China. Phase IIa was first performed among 25 patients previously treated with anthracycline and/or taxane. All patients received apatinib 750 mg/day p.o. in a 4‐week cycle. Subsequently, a phase IIb study of 59 patients was activated, with the endpoint progression‐free survival (PFS). The dosage of drug for the Phase IIb was determined according to safety, tolerability and efficacy from the phase IIa study. As a result of toxicity associated with the 750 mg dose in phase IIa, the recommended initial dose of apatinib in the phase IIb was 500 mg/day. In phase IIb, grade 3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), neutropenia (3.4%) and anemia (1.7%). The most frequent grade 3/4 nonhematologic toxicities were hand–foot syndrome, proteinuria, hypertension, and increased ALT. In the 56 evaluable patients, overall response rate and clinical benefit rate (CBR) were 10.7 and 25.0%, respectively. Median PFS and overall survival were 3.3 (95% CI 1.7–5.0) and 10.6 (95% CI 5.6–15.7) months, respectively. Our results indicate that apatinib dose of 500 mg rather than 750 mg is the recommended starting dose for the heavily pretreated mTNBC patients with measurable rate of partial response and PFS.

Combined chemotherapy and external beam radiation for stage IE and IIE natural killer T-cell lymphoma of nasal cavity.

To evaluate the outcome of CHOP chemotherapy and radiotherapy in Stage IE and IIE nasal natural killer (NK)/T-cell lymphoma, 53 patients with stage IE and IIE nasal NK/T-cell lymphoma were studied. By the Ann Arbor Lymphoma Staging Classification, 41 patients (77%) had Stage IE disease and 12 patients (23%) had Stage IIE disease. All patients were treated curatively using chemotherapy, followed by radiotherapy. Chemotherapy consisted of up to six cycles of the standard CHOP based regimen. The median radiation dose to the tumor bed was 45 Gy for all patients. The median follow-up for all 39 surviving patients was 30.2 months (range, 6 – 104 months). Twenty-six patients had complete response after chemotherapy, and all patients who completed first line chemotherapy achieved complete response after radiotherapy. The 2-year overall survival and progression-free survival rates were 75.6% and 61.8%, respectively. Multivariate analysis revealed that perforation as a presenting symptom, elevated pretreatment serum lactate dehydrogenase level, and ECOG performance status ≥2 were significant independent prognostic factors for this group of patients. Combined chemotherapy followed by involved field radiation produced suboptimal outcome for patients with early stage nasal NK/T-cell lymphoma. Further investigations, preferably prospective clinical trials, for more efficacious treatment strategies are needed to improve the treatment outcome of this malignancy.

NF-κB Activation Through the Alternative Pathway Correlates with Chemoresistance and Poor Survival in Extranodal NK/T-cell Lymphoma, Nasal Type

OBJECTIVE Nuclear factor-kappaB (NF-kappaB) activation has been identified in a variety of solid tumors and lymphoid malignancies. The aim of our study was to determine the expression status and clinical significance of NF-kappaB in extranodal natural killer (NK)/T-cell lymphoma, nasal type. METHODS Tumor specimens from 23 patients with previously untreated NK/T-cell lymphoma initially treated with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) or CHOP-based chemotherapy were examined by immunohistochemistry for three NF-kappaB subunits (p65, p50 and p52), which are involved in either the canonical or alternative pathway. RESULTS None of the cases could be detected with p65 or p50 nuclear staining. On the other hand, 15 (65.2%) cases had p52 nuclear staining, suggesting NF-kappaB activation through the alternative pathway. All major clinical characteristics were balanced between NF-kappaB p52-positive and -negative patients. The objective response rate achieved in NF-kappaB-positive patients was significantly lower than that in negative patients (33.3% vs. 87.5%, P = 0.027). At a median follow-up of 25 months, 8 (53.3%) of 15 NF-kappaB-positive patients had died compared with none of 8 NF-kappaB-negative patients (P = 0.041). In a multivariate analysis, NF-kappaB status and stage were identified to be independent prognostic factors. CONCLUSIONS Our results suggest that NF-kappaB activation through the alternative pathway is frequently observed in NK/T-cell lymphoma and associated with chemoresistance and poor survival.

Cisplatin and gemcitabine as the first line therapy in metastatic triple negative breast cancer

No standard first‐line treatment exists for patients with metastatic triple‐negative breast cancer (mTNBC). In this single‐arm, phase II study (NCT00601159), we evaluated the efficacy and tolerability of cisplatin and gemcitabine (GP) as the first‐line therapy in mTNBC. Eligible women were those who had measurable disease with no prior chemotherapy for mTNBC. All patients received 21‐day‐cycle of cisplatin 25 mg/m2 on days 1–3 and gemcitabine 1,000 mg/m2 on days 1 and 8. Treatment was continued until disease progression, unacceptable toxicity or up to 8 cycles. BRCA1/2 mutation status and immunohistochemical basal markers were included in the correlative studies. Sixty‐four patients with the median age of 49 years were enrolled. Thirty patients (46.9%) had ≤1 year from diagnosis to recurrence. The median progression free survival (PFS) was 7.2 months (95%CI, 5.6–8.9 months) and overall survival (OS) was 19.1 months (95%CI, 12.4–25.8 months) with median follow‐up 42 months. Patients received treatment for a median of six cycles. The overall response rate was 62.5%. The most common grades 3/4 toxicities were neutropenia (42.2%), thrombocytopenia (29.7%), anemia (18.8%) and nausea/vomiting (15.6%).No specific BRCA1/2 mutation carriers were identified. The efficacy of responses and basal‐like subtype were independent favorable factors for PFS and OS, respectively. We conclude that the combination of GP has significant activity and a favorable safety profile as the first‐line chemotherapy in mTNBC patients, in particular patients with basal‐like subtype. The promising role of this combination as the front‐line treatment for mTNBC continued to be evaluated in our ongoing phase III trial (CBCSG006).

A randomized phase II study of CEOP with or without semustine as induction chemotherapy in patients with stage IE/IIE extranodal NK/T-cell lymphoma, nasal type in the upper aerodigestive tract.

PURPOSE In this randomized phase II study, we evaluated the efficacy of semustine added to CEOP regimen as induction chemotherapy in patients with stage I(E)/II(E) extranodal NK/T-cell lymphoma, nasal type in the upper aerodigestive tract. PATIENTS AND METHODS Seventy-five eligible patients were randomized to receive either CEOP or CEOP plus semustine followed by involved-field radiotherapy. RESULTS The overall response rate of induction chemotherapy was 57.9% in CEOP arm compared with 62.2% in CEOP plus semustine arm (P=0.71). With a median follow-up of 30.1 months, 2-year overall survival was 73.3% and 62.2%, respectively (P=0.37). Toxicities in both arms were comparable and manageable. Through univariate and multivariate analysis, PS of 2, Stage II(E) and elevated LDH level were identified to be adverse prognostic factors. A new prognostic index categorized three groups of patients (low risk, no adverse factors; intermediate risk, one factor; and high risk, 2 or 3 factors) with highly significant difference of prognosis. Two-year overall survival was 87.5%, 60.6% and 30%, respectively (P=0.0002). CONCLUSIONS The addition of semustine to CEOP regimen was not associated with improved efficacy. More effective treatment needs to be explored in patients with intermediate or high risk.

Cisplatin improves antitumor activity of weekly nab-paclitaxel in patients with metastatic breast cancer

Although nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved to be given every 3 weeks, weekly use of this drug is becoming a new standard of care in patients with metastatic breast cancer (MBC). This prospective Phase II study was conducted to improve the efficacy of weekly nab-paclitaxel with cisplatin in MBC patients. Seventy-three women with recurrent or MBC were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m2 on day 1, day 8, and day 15, followed by cisplatin 75 mg/m2 on day 1, repeated every 28 days with a maximum of 6 cycles. The primary objective was investigator-assessed overall response rate (ORR). A high ORR of 67.1% was obtained, with rates of 80.6% for the first-line patients and 80% for patients not pretreated with taxanes. Among those who had objective responses, a large percentage of patients (83.7%) showed quickly remarkable tumor shrinkage during the first two cycles. The median progression-free and overall survival times were 9.8 and 26.9 months, respectively. For the patients receiving first-, second-, and third-line therapy or beyond, median progression-free survival was 11.7, 7.7, and 7.6 months, respectively (P=0.005). Molecular subtype was not significantly associated with ORR or disease progression. Grade 4 neutropenia occurred in 46 patients (63.0%), with febrile neutropenia found in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%). Efficacy of weekly nab-paclitaxel can be improved by adding cisplatin. The doublet is highly effective, with quick response, manageable toxicity, and possible equivalence across molecular subtypes in MBC patients.

A phase II trial of biweekly vinorelbine and oxaliplatin in second- or third-line metastatic triple-negative breast cancer

Patients with metastatic triple-negative breast cancer (mTNBC) typically have a poor prognosis. The purpose of this study was to prospectively evaluate the efficacy and toxicity of biweekly combination of vinorelbine and oxaliplatin (NVBOX) in second- or third-line setting for mTNBC. Eligible patients were female with 18–70 y old, and had mTNBC that had progressed after 1or 2 prior chemotherapy regimens in the metastatic setting. NVBOX was given biweekly every 4 week for a maximum of 6 cycles. The primary endpoint was progression-free survival (PFS). Forty-4 patients were recruited. All patients had been exposed to anthracyclines and/or taxanes; 56.8% of patients were cis/carbo-platin pretreated. Among the 38 evaluable patients, overall response rate was 31.6% and 7 lasted ≥ 6 months. The median PFS and overall survival (OS) were 4.3 (95% CI, 3.6–5.0) months and 12.6 (95% CI, 8.1–17.0) months, respectively. PFS and OS was significantly shorter in patients with interval from diagnosis to recurrence ≤ 1 y and time to progression (TTP) of 1–2 previous regimens before recruitment ≤ 3 months. For 34 patients who were treated in second line setting, prior platinum was a factor significantly compromising the PFS of NVBOX. Grade 3/4 hematologic toxicities included neutropenia (70.5%), thrombocytopenia (27.3%) and anemia (15.9%). The most frequent grade 3/4 non-hematologic toxicities were constipation/abdominal distension (20.5%) and nausea/vomiting (13.6%). We conclude that biweekly NVBOX regimen is effective with a good safety profile in the second- or third-line mTNBC, which warrants further investigation in a phase III study. This trial was registered with www.clinicaltrials.gov (no. NCT01528826).

Efficacy and safety of everolimus in Chinese metastatic HR positive, HER2 negative breast cancer patients: a real-world retrospective study

Background Everolimus combined with endocrine therapy has been proved to be effective among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). We aimed to evaluate the efficacy and safety of everolimus plus endocrine therapy in Chinese real-world practice for the first time, and investigate factors associated with efficacy. Methods Seventy-five HR+/HER2- MBC patients were included in this retrospective study who received everolimus plus endocrine therapy after progression on prior endocrine therapy in Fudan University Shanghai Cancer Center (FUSCC) between June 2013 and February 2016. Main outcome measures are progression free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety profile. Results After a median follow up of 10.3 (range: 2.1-32.2) months, median PFS was 5.9 months (95%CI 4.6-7.2), and median OS was not reached. The CBR was 38.8% (95%CI, 26.8-50.8) and ORR was 9.0% (95%CI, 2.0-16.0). Most common all-grade adverse events were stomatitis (57.1%), fatigue (25.7%), infection (24.3%) and hyperglycemia (21.4%). The most common ≥3 grade adverse events were stomatitis (9.3 %) and thrombocytopenia (5.7%). No treatment-related death was documented during and one month after the drug administration. Conclusions The combination of everolimus and endocrine therapy proved to be effective in Chinese population. The safety profiles were similar to previous studies but incidences were lower. In conclusion, everolimus combined with endocrine therapy provides a reasonable option for Chinese HR+/HER2- metastatic breast cancer patients.BACKGROUND Everolimus combined with endocrine therapy has been proved to be effective among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). We aimed to evaluate the efficacy and safety of everolimus plus endocrine therapy in Chinese real-world practice for the first time, and investigate factors associated with efficacy. METHODS Seventy-five HR+/HER2- MBC patients were included in this retrospective study who received everolimus plus endocrine therapy after progression on prior endocrine therapy in Fudan University Shanghai Cancer Center (FUSCC) between June 2013 and February 2016. Main outcome measures are progression free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety profile. RESULTS After a median follow up of 10.3 (range: 2.1-32.2) months, median PFS was 5.9 months (95%CI 4.6-7.2), and median OS was not reached. The CBR was 38.8% (95%CI, 26.8-50.8) and ORR was 9.0% (95%CI, 2.0-16.0). Most common all-grade adverse events were stomatitis (57.1%), fatigue (25.7%), infection (24.3%) and hyperglycemia (21.4%). The most common ≥3 grade adverse events were stomatitis (9.3 %) and thrombocytopenia (5.7%). No treatment-related death was documented during and one month after the drug administration. CONCLUSIONS The combination of everolimus and endocrine therapy proved to be effective in Chinese population. The safety profiles were similar to previous studies but incidences were lower. In conclusion, everolimus combined with endocrine therapy provides a reasonable option for Chinese HR+/HER2- metastatic breast cancer patients.

Apatinib for metastatic breast cancer in non-clinical trial setting: Satisfying efficacy regardless of previous anti-angiogenic treatment

Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2. This study aimed to evaluate the efficacy and safety of apatinib in metastatic breast cancer (MBC) under non-clinical trial setting, and to study the impact of previous antiangiogenic treatment to the efficacy of apatinib. 52 MBC patients treated with apatinib under non-clinical trial setting in Fudan University Shanghai Cancer Center between January 1st 2015 and October 1st 2016 were included. All patients were included in time-to-treatment failure (TTF) analysis, while 45 patients were enrolled for progression-free survival (PFS) and overall survival (OS) analysis because 7 of the patients with treatment discontinuation due to intolerable toxicities had too short time for efficacy assessment. Impact of previous exposure to antiangiogenic treatment and other factors to patients’ survival were analyzed by Log-rank analysis and Cox multivariate analysis. The median PFS, median OS, and median TTF were 4.90 (95% confidence interval [CI] 3.44 – 6.36), 10.3 (unable to calculate 95% CI), and 3.93 (95% CI 1.96 – 5.90) months, respectively. Previous treatment of bevacizumab did not affect the efficacy of apatinib. Previous exposure to anthracycline, age of 60 years or older and palmar-plantar erythrodysesthesia syndrome were independent predictors for prolonged PFS. Discontinuation of treatment was more common in age group of 60 years or older than that in younger group, although the difference was not significant. Although toxicities were generally managable, a previously unrecorded grade 3~4 adverse event of dyspnea has been observed. This study confirmed the encouraging efficacy and manageable safety of apatinib on pretreated MBC patients in non-clinical trial setting. For the first time to our knowledge, this study found that previous treatment of bevacizumab did not affect the efficacy of apatinib, and reported an undocumented severe adverse effect of dyspnea.