Search

Background: Published data on the effects and toxicities of volumetric modulated arc therapy (VMAT) in the management of inoperable lung cancer are scarce. Materials and methods: The clinical outcomes and pulmonary toxicities of 134 patients with consecutive inoperable lung cancer who underwent VMAT from March 2011 to September 2016 were retrospectively reviewed. The dosimetric and characteristic factors associated with acute radiation pneumonitis (RP) and pulmonary fibrosis were evaluated with univariate and multivariate analysis. Results: The average prescription doses to these 134 patients were 57.07±6.27 Gy (range 52-64 Gy). The overall median follow-up time was 18.6 months (range, 2-45 mo), with a median follow-up time for the surviving patients of 20 months (range, 7-45 mo). The 2-year progression-free survival (PFS) and overall survival (OS) for all patients were 18.2% and 38.4%, with a median PFS and OS of 7.6 months and 18.6 months, respectively. The percent of patients with grade III/higher RP and pulmonary fibrosis were 10.5% and 9.0%, respectively. V13 (p=0.02) and age (p=0.02) were independently associated with acute RP according to multivariate analysis. The constraints for lung dosimetric metrics V10,V13,V20 and V30 were approximately 49%,41%,26% and 17% in VMAT treatment of lung cancer to limit the RP rate < 10%. Conclusion: VMAT can be delivered safely with acceptable acute and late toxicities for lung cancer patients. Lung dosimetric metrics were valuable in predicting acute RP. A lung V13 constraint of 40% was helpful to limit the RP rate < 10% in VMAT treatment of lung cancer patients.

BACKGROUND: Hepatitis E virus (HEV) is a nonenveloped RNA virus causing Hepatitis E worldwide. An increasing transfusion transmission cases of HEV infections from asymptomatic blood donors which causing serious illnesses in immunosuppressed recipients have been reported in the past few years. China is one of the highly prevalent regions of HEV, it is important to evaluate the risk of HEV transmission from blood transfusion. METHODS: A total of 1864 serum samples from blood donors and demographic characteristics were randomly collected from Feb to Mar 2018 in Dali city. Anti-HEV IgG, IgM and IgA antibodies and HEV antigen were examined by enzyme-linked immunosorbent assay (ELISA). HEV RNA was detected by real-time PCR. Multivariable logistic regression modelling was used to examine risk factors associated with HEV prevalence.RESULTS: Overall, the positive rate of anti-HEV IgG, IgM, and IgA antibodies was 13.36% (249/1864), 1.13%(21/1864), and 1.82%(34/1864), respectively. However, none of the 1864 serum samples was detected as HEV antigen-positive nor HEV RNA positive. The positive rate of anti-HEV IgG antibody is high as 28.57% (2/7) in the donors with isolated elevated alanine aminotransferase (ALT). Females (16.69%) had a significantly higher HEV seroprevalence than males (13.04%) (odds ratio [OR]: 1.34 [95% CI, 1.02-1.75]). Other ethnic minority (24.32%) and Bai (18.85%) donors had a significantly higher HEV seroprevalence when compared to Han (12.21%) blood donors (odds ratio [OR], 2.25 [95% CI, 1.04-4.88] for other ethnic minority, 1.65 [95% CI, 1.24-2.19] for Bai). Conclusions: Dali, Yunnan province, China is an endemic region f of hepatitis E virus, and women, Bai and other ethnic minorities may be potential risk factors for hepatitis E virus infection.. The risk of transmission of hepatitis E virus through blood transfusion is relatively low, and the specific risk value needs to be further tested by expanding the sample size. Whether to formulate the strategy for HEV screening in blood center needed further researched.

Background: Although superior clinical benefits of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of advanced non-small-cell lung cancer (NSCLC) had been reported with different sensitivity, the sensitivity of second-line TKIs in NSCLC patients with different EFGR mutations was unknown. The purpose of this study is to investigate the clinical outcome of second-line EGFR-TKIs in the treatment of NSCLC patients according to different EGFR genotypes. Methods: The treatment outcomes of 166 NSCLC patients with different EGFR mutations treated by second-line TKIs were retrospectively reviewed. The efficacy was evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. Results: The disease control rate (DCR) and objective response rate (ORR) of enrolled NSCLC patients were 77.7% and 11.4%, respectively. The exon 19 deletion group had a significantly longer median progression-free survival (PFS) (6.7 vs. 4.5 months, P=0.002) and overall survival (OS) (13.7 vs. 11.7 months, P=0.02) compared with the exon 19 L858R mutation group for NSCLC patients, as well for patients with brain metastasis [PFS: (6.7 vs. 3.9 months, p

Background: The rates of locoregional and distant recurrence for esophageal squamous cell carcinoma (ESCC) patients underwent radical esophagectomy remain high. The purpose of this study is to explore an optimal postoperative therapeutic modality by investigating the efficacy of various adjuvant therapies in the treatment of ESCC. Methods: We retrospectively reviewed 408 ESCC patients underwent thoracic esophagectomy and 3-field lymph node dissection from 2010 to 2015. Patients were classified into surgery alone (Group S), adjuvant chemotherapy (Group CT) and postoperative chemotherapy plus radiotherapy (Group CRT), respectively. Univariate and multivariate Cox regression analyses were used to analyze prognostic factors and survival. Results: The overall survival (OS) and disease-free survival (DFS) were similar among groups. Postoperative CT and CRT both were beneficial for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment compared with surgery alone. The 3-year OS and DFS for patients with 3 or more lymph nodes involvement were 30.8%, 53.7%, 50.5% and 19.9%, 41.6%, 34.0% for Group S, CT, and CRT, respectively (p=0.04; p=0.004, respectively). There was no notable difference in OS and DFS between the adjuvant Group CT and CRT (p=0.42; p=0.49, respectively). Postoperative CRT significantly reduced the rates of distant metastasis and overall recurrence for patients with positive lymph nodes (p=0.042; p=0.01, respectively). Number of metastatic lymph nodes, extent of resection, and AJCC stage were independent predictors of survival. Grade 1-2 myelosuppression was experienced significantly more frequently by patients in Group CRT than those in Group CT (P=0.03). Late toxicities were rare and manageable overall. Conclusions: Postoperative CT and CRT both were associated with better survival for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment. Postoperative CRT was significantly more effective at reducing the rates of distant metastasis and overall recurrence for patients with positive lymph nodes.

// Hongqin Zhao 1, * , Lili Li 2, * Huafang Su 2 , Baochai Lin 2 , Xuebang Zhang 2 , Shengliu Xue 2 , Zhenghua Fei 2 , Lihao Zhao 2 , Qintuo Pan 3 , Xiance Jin 2 , Congying Xie 2 1 Departments of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China, 325000 2 Departments of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China, 325000 3 Departments of Eye Fundus Surgery, Eye Hospital of Wenzhou Medical University, Wenzhou, China, 325002 * These authors contributed equally to this work Correspondence to: Xiance Jin, email: jinxc1979@hotmail.com Congying Xie, email: wzxiecongying@163.com Keywords: cervical cancer, chemoradiotherapy, consolidation chemotherapy, cisplatin, paclitaxel Received: March 23, 2016 Accepted: June 30, 2016 Published: July 06, 2016 ABSTRACT A phase III randomized study on the efficacy and safety of consolidation chemotherapy with paclitaxel plus cisplatin following radical hysterectomy and adjuvant chemoradiotherapy (CRT) in the treatment of high risk early-stage cervical cancer were reported. 146 eligible patients were randomized to arm A receiving concurrent CRT or arm B receiving CRT plus consolidation chemotherapy, respectively. An interim analysis showed a trend of improvement on disease-free survival (DFS) and overall survival (OS) in arm B with hazard ratios (HR) of 1.25 (95% CI = 0.60–2.60, p = 0.55) and 1.43 (95% CI = 0.64–3.20, p = 0.38) for DFS and OS, respectively. The 3-year DFS and OS were 82.0% vs.74.3%, and 86.6% vs. 78.3% for patients receiving CRT plus consolidation chemotherapy and CRT alone, respectively. There was significant difference between the two arms in distant alone recurrence ( p = 0.048). Multivariate analysis indicated that pathologic type was a significant prognostic factor for OS ( p = 0.045), positive pelvic nodes were significantly associated with both OS ( p =0.02) and DFS ( P =0.03). Grade 2 to 4 gastrointestinal disorder ( p = 0.95), radiation enteritis ( P =0.48), radiation cystitis ( p = 0.27) and radioepidermitis ( p = 0.46) were similar in the two arms. Overall rates of grade 0–2/3–4 myelosuppression were 87.7%/12.3% for arm A and 74.6%/25.4% for arm B, respectively, but this difference was not statistically significant ( p = 0.05). In conclusion, concurrent CRT plus consolidation chemotherapy may play a potential role in further improving survival outcomes for high-risk early stage cervical cancer patients compared CRT alone.

Background In the era of intensity-modulated radiotherapy (IMRT), the role of additional concurrent chemotherapy (CC) to radiotherapy (RT) after induction chemotherapy (IC) compared to IC followed by RT alone remains unclear for stage II-IVB nasopharyngeal carcinoma (NPC) patients. The aim of this study was to evaluate the efficacy and toxicities of IC/RT and IC/CCRT in the treatment of NPC with volumetric modulated arc therapy (VMAT). Methods From January 2012 to March 2016, a total of 217 NPC patients were retrospectively assessed. Of the 217 patients, 139 patients received IC followed by VMAT alone and 78 patients received IC plus CCRT. Overall survival (OS), progression-free survival (PFS) and toxicities were assessed. Results The 5-year OS, PFS rates were 57.5%, 41.8% and 47.8%, 38.4% for the IC/RT and IC/CCRT arms, respectively, without significant difference in survival between the two groups (both p > 0.05). Multivariate analysis indicated that treatment modality (IC/RT vs. IC/CCRT) was not an independent prognostic factor for OS or PFS. Grade 3–4 leukopenia/neutropenia (3.60% vs. 20.51%, p

Recent studies demonstrated a significantly increased frequency of epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC) patients with malignant pleural effusions (MPEs). The purpose of this study is to investigate the effect of first-line and second-line EGFR-tyrosine kinase inhibitors (TKIs) in the treatment of NSCLC with MPEs harboring exon 19 deletion and L858R mutation. From 2010 to 2015, 203 NSCLC patients with MPEs harboring EGFR mutation treated with EGFR-TKIs were reviewed. The efficacy were evaluated with Pearson chi-square or Fisher’s exact tests, Log-rank test and Cox proportional hazards model. The objective response rate (ORR) and disease control rate (DCR) for patients treated with first-line and second-line EGFR-TKIs were 21.9%, 91.4% and 14.7%, 85.3%, respectively. The overall median PFS and OS of enrolled NSCLC patients with MPE were 9.3 months (95% CI, 8.4–10.2 months), 20.9 months (95% CI, 18.9–22.9 months) after first-line TKIs, and 7.6 months (95% CI, 6.6–8.6 months), 15.3 months (95% CI, 13.6–15.9 months) after second-line TKIs. The exon 19 deletion arm had a longer median PFS (9.4 vs 7.1 months, p=0.003) and OS (16.8 vs 13.8 months, p=0.003) compared with the L858R mutation arm after second-line TKIs. In a conclusion, EGFR genotype was an independent predictor of PFS and OS. No significant side effects differences between the two mutation groups was observed for first or second-line EGFR-TKIs. This study demonstrated that EGFR mutations are significant predictors for advanced NSCLC patients with MPE receiving second-line EGFR-TKIs treatment.

Objective To assess the frequency of brain metastasis in patients with primary esophageal cancer and to describe the clinical characteristics, diagnosis, and prognosis. Methods Of 1612 patients with primary esophageal carcinoma treated at a single institution from 2000–2010, a retrospective analysis of the medical files of 26 consecutive patients with central nervous system involvement was carried out. The clinical history, imaging, and pathologic findings were analyzed. Results Of the 26 patients, 12 initially presented with a single cerebral metastatic lesion, and 14 had multiple brain lesions. There were 4 patients with adenocarcinoma and 22 with squamous cell carcinoma. Treatments were as follows: 5 patients underwent surgery followed by whole-brain radiation, 5 underwent stereotactic radiosurgery, 13 received whole-brain radiation, and 3 received chemotherapy. The median survival was 4.2 months; 1-year survival rate was 5.8%. Conclusions In this retrospective study of 1612 patients with esophageal carcinoma at a single medical center, 1.61% (26 of 1612) of the patients had a diagnosis of brain metastasis. The prognosis is poor for patients with brain metastasis from esophageal carcinoma. A solitary brain lesion, surgical treatment, and a good Karnofsky Performance Status may indicate a good prognosis.

Preoperative elevation of serum C-reactive protein (CRP) is reportedly associated with poor prognosis in several types of cancer. This study investigated the role of serum CRP as a prognostic factor in early-stage esophageal squamous cell carcinoma (ESCC). The preoperative serum CRP levels were measured in 156 newly diagnosed pT1–2N0M0 patients using an enzyme-linked immunosorbent assay. Correlations between serum CRP levels and other clinical parameters were analyzed. Multivariate analyses were performed to find prognostic markers using Cox's proportional hazards model. CRP concentrations were within the normal range in 117 (75%) individuals, but were elevated in 39 (25%) patients. Serum CRP levels were significantly correlated with the tumor length ( p = 0.032), depth (T classification, p = 0.0157), or histologic grade ( p = 0.034). The overall 5-year survival rates were 76.3% and 50.2% in the low- and high-CRP groups, respectively ( p = 0.005). By multivariate analyses, the elevated serum CRP level was found to be an independent prognostic factor for poor survival (hazard ratio = 2.131; p = 0.007), regardless of tumor classification or other prognostic factors. In conclusion, preoperative, high serum CRP is an independent determinant of poor prognosis in early-stage ESCC.

To evaluate the prognostic value of the absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) at diagnosis in diffuse large B-cell lymphoma (DLBCL), we performed a meta-analysis of published studies that provided survival information with reference to the ALC/AMC ratio at diagnosis. Nine studies covering a total of 4198 subjects were included in this analysis. The summary hazard ratios of low ALC/AMC ratio for overall survival were 2.00 (p = 0.000) in the population that received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 1.12 (p = 0.479) in the population that received CHOP. The corresponding ratios for event-free survival and progression-free survival were 1.93 (p = 0.000) and 2.31 (p = 0.000) in the population that received R-CHOP. These results may justify risk-adapted therapeutic strategies for patients with DLBCL treated with R-CHOP to account for the ALC/AMC ratio at diagnosis.

e20046 Background: Volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time and less MU compared to conventional intensity-modulated fixed-field treatment (IMRT) in the treatment of inoperable non–small-cell lung cancer (NSCLC). However, published data on clinical outcome and lung toxicities of VMAT in the treatment of NSCLC are scarce. Methods: The clinical outcome, acute and late pulmonary toxicities of 134 consecutive inoperable NSCLC patients treated by VMAT with or without concurrent chemotherapy were retrospectively reviewed. Univariate and multivariate analysis on the dosimetric and characteristic factors associated with acute radiation pnuemonitis (RP) and pulmonary fibrosis were evaluated. Results: The average prescriptions dose to these patients were 5736.38±649.11 cGy (range from 5200 to 6400 cGy) with a median follow-up of 18.6 months (range, 2–45 months) for the enrolled 134 patients. The two-year progression-free survival (PFS) and overall survival (OS) for all patients was 18.2% and 38.4% with a median PFS and OS of 7.6 months and 18.6 months, respectively. There were 14 and 12 out of 134 patients experienced grade III/higher RP (10.45%) and pulmonary fibrosis (8.95%), respectively. Age, chemotherapy exposure, dose prescription, V10, V13, V20 and V30 were significantly associated with acute RP. Dose prescription was related to pulmonary fibrosis. Only V13 (p = 0.02) and age (p = 0.02) were independently associated with acute RP according to multivariate analysis. Based on regression analysis, the threshold for lung dosimetric metrics V10,V13,V20 andV30 were 50%,40%,28% and 18% in VMAT treatment of NSCLC to limit the RP rate < 10%. Conclusions: VMAT can be delivered safely with acceptable acute and late toxicities for NSCLC. Lung dosimetric metrics were valuable in predicting acute RP. A threshold of 40% of Lung V13 in VMAT treatment of NSCLC was helpful to limit the RP rate < 10%.

To investigate the efficacy of Taxanes- and Oxaliplatin-based chemotherapies (TC and OC) in the treatment of gastric cancer patients after D2 gastrectomy with different Lauren types. In this study, 299 patients of gastric adenocarcinoma with D2 lymph node dissection were reviewed between 2007 and 2014. Chemotherapies were classified as Oxaliplatin-based and Taxanes-based regimen. Treatment outcomes were analyzed according to different Lauren types, such as the intestinal type, diffuse type, and mixed type groups, respectively. The disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The log-rank test was used for univariate analysis, and Cox regression was used for multivariate analysis. In diffuse type gastric cancer, the Oxaliplatin-based arm had a longer median DFS and OS compared with Taxanes-based arm (DFS: 47.0 vs 28.6 months, P = 0.04; OS: 51.9 vs 34.5 months, P = 0.048). The chemotherapy regimen was an independent prognostic factor for DFS and OS of diffuse type gastric cancer patients by multivariate analysis (P = 0.01). In the intestinal type, although the DFS and OS of intestinal type patients in TC group were higher than those in OC group (DFS: 53.4 vs 42.4 months; OS: 69.7 vs 57.8 months), there was no statistical significance observed (both P > 0.05). For the mixed type, the 2 different chemotherapy regimens achieved similar median DFS and OS. In a conclusion, the patients of diffuse type were more sensitive to OC, and the intestinal type patients may be benefit from TC. Therefore, it will be of benefit for gastric patients by introducing Lauren classification clinically and to help the choice of chemotherapy regimen for gastric patients after D2 gastrectomy.

Background Tumor length is an important prognostic factor for many carcinomas, but its role in esophageal cancer remained undetermined. The aim of this study was to investigate the effect of tumor length on survival for patients with confined tumors (grade pT1-2) without lymph-node metastases in esophageal squamous cell carcinoma. Methods We enrolled 201 patients with esophageal squamous cell carcinoma (SCC) who had undergone surgical resection and been confirmed as pT1-2N0M0. The relationship of tumor length with overall survival was assessed and compared with other factors detailed in the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system published in 2009. Results The overall survival (OS) rates at 1, 3, and 5 years were 93.0%, 83.7%, and 69.2%, respectively. The tumor length adversely affected OS, with the 5-year rate being 93.5%, 82.0%, 68.6%, 67.9%, 55.3% and 41.1%, respectively for tumor lengths of less than 10 mm, 10 to 20 mm, 20 to 30 mm, 30 to 40 mm, 40 to 50 mm, and greater than 50 mm (P< 0.001). Multivariate analyses showed that the pathologic T classification and grade of tumor was significantly associated with OS. Tumor length of 30 mm or more remained an independent prognostic factor (P = 0.04), as did the other current TNM factors. Conclusion Tumor length appears to affect the OS of patients with early-stage esophageal squamous cell carcinoma. It may provide additional prognostic information for the current TNM staging system.

Cutaneous metastases in primary advanced non-small cell lung cancer (NSCLC) rarely occur in comparison with other site involvement. The incidence of cutaneous metastases and its prognosis is not well known. Data from a 2,130 patients with advanced NSCLC were analyzed, in order to assess the incidence and survival prognosis of cutaneous metastases in primary advanced NSCLC. The clinical data of 2,130 patients with advanced NSCLC who were admitted to Zhejiang cancer Hospital from January 1998 to December 2007 were retrospectively analyzed. Data pertaining to their presentation, diagnosis treatment, pathology, follow–up, and clinical course were documented. Clinical characteristics were investigated based on the clinical and pathologic records. All of the cutaneous metastases were confirmed by cytology or biopsy. Survival analysis was made by Kaplan–Meier method. The Cox regression model was performed to analyze the relationship between the influential factors and the overall survival. Among the 2,130 advanced NSCLC patients as initial diagnosis, 60 (2.8 %) demonstrated abnormally cutaneous metastases. Fifteen patients with only cutaneous metastases, forty-five subjects combined with other site metastasis. There were 56 patients who received chemotherapy, and the first-line disease control rate was 33.9 %, the median free progression survival time was 1.9 months. There were significant differences in overall survival between cutaneous metastases and non-cutaneous metastases arms (3.9 vs. 10.0 months, P

Background Adenosquamous carcinoma (ASC) of the lung is a rare subtype of nonsmall-cell lung cancer (NSCLC). To date, the efficacious targeted therapy for advanced ASC remains unclear and the epidermal growth factor receptor (EGFR) mutation rate is not well known. Methods We retrospectively reviewed clinical information of patients with ASC who were treated with gefitinib or erlotinib at Zhejiang Cancer Hospital between January 2007 and December 2011. Survival analysis was evaluated by the Kaplan-Meier method. EGFR mutations were assessed in part using direct sequencing methods. Results In total, 49 patients with a median age of 57 years were used in this study. Thirteen patients achieved a partial response and 19 had disease stabilization. The objective response rate was 26.5%, and the disease control rate was 65.3%. The median progression-free survival and overall survival were 4.3 and 17.6 months, respectively. In 21 patients with adequate specimens for molecular analysis, 7 (33.3%) had EGFR mutations (4 with deletions within exon 19 and 3 with L858R messenger mutation in exon 21). EGFR mutations were significantly more frequent in women (4/9, 44.4%) than men (3/12, 25%), never-smokers (6/15, 40%), and smokers (1/6, 16.7%). Conclusion EGFR-tyrosine kinase inhibitor (TKI) is an effective treatment for ASC. The frequency of EGFR mutation and clinical characteristics of the EGFR mutants in ASC are similar to those of Asian patients with adenocarcinoma.

Background Brain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). The efficacy and roles of combining temozolomide (TMZ) with whole brain radiotherapy (WBRT) in protection neurocognitive function (NCF) and improvement quality of life (QOL) were investigated and compared with WBRT alone in the treatment of NSCLC patients with BM. Methods A total of 238 NSCLC patients with BM were reviewed and categorized into WBRT plus TMZ (RCT) arm and WBRT alone (RT), respectively. The efficacy was evaluated with Pearson chi-square or Fisher’s exact tests, Log-rank test and Cox proportional hazards model. NCF was assessed by using revised Hopkins Verbal Learning Test (HVLT-R), Controlled Oral Word Association (COWA) test and Trail-making Test (TMT). QOL was assessed by the Functional Assessment of Cancer Treatment-Lung (FACT-L) Chinese version 4.0 questionnaire. Results The average intracranial objective response (ORR) and disease control rate (DCR) for all the patients were 26.9 and 95.8%, respectively. The intracranial ORR and DCR for RCT and RT arm were 34.9% vs. 20.2% (p = 0.01) and 98.4% vs. 92.7% (p = 0.03), respectively. The median intracranial progression-free survival (PFS) and overall survival (OS) of NSCLC patients with BM were 5.2 and 7.3 months, respectively. The median PFS of RCT arm was significantly longer than that of RT arm (5.9 vs. 4.9 months, p = 0.002). The median OS of the RCT arm was also slightly longer than that of the RT arm (8.5 vs. 5.9 months), but without statistical significance (p = 0.11). Multivariate analysis indicated that TMZ was a significant factor for PFS. Statistically significant differences on NCF and QOL were observed between CRT and RT arms at 5 months. RCT showed a trend of toxicities increase compared with RT, however, the toxicities were tolerable and manageable. Conclusions Adding TMZ to WBRT in the treatment of NSCLC patients with BM could improve the intracranial ORR, DCR, and median PFS compared with WBRT alone. Although no remarkable difference on median OS was found, adding TMZ could prevent NCF and QOL from worsening. The side effects increased by adding TMZ, but the difference was not statistical significance and toxicities were well tolerated.