Doublet Group Research Articles

A randomized trial of double vs single-dose etonogestrel implant to overcome the interaction with efavirenz-based antiretroviral therapy

BackgroundConcomitant use of efavirenz-based antiretroviral therapy and a standard-dose etonogestrel contraceptive implant resulted in 82% lower etonogestrel exposure compared to women not receiving antiretroviral therapy. The clinical impact of this reduced exposure is supported by retrospective cohort evaluations which demonstrated higher rates of unintended pregnancies when contraceptive implants were combined with efavirenz. We hypothesized that placement of two etonogestrel implants in those taking efavirenz-based antiretroviral therapy could increase etonogestrel exposure and improve measures of contraceptive efficacy. ObjectivesThis study compared the rate of ovulation and etonogestrel pharmacokinetics in women on efavirenz-based antiretroviral therapy receiving two etonogestrel implants (136mg, DoublET group) versus one etonogestrel implant (68mg, Control group). Study DesignThis randomized, open-label study enrolled Ugandan women with regular menstrual periods who were receiving efavirenz-based antiretroviral therapy for treatment of HIV. Participants were randomized 1:1 to the DoublET or Control group, and the etonogestrel implant(s) were placed in the same arm at enrollment. All participants used a copper intrauterine device to prevent pregnancy. Ovulation was evaluated by weekly serum progesterone concentrations measured over 4 consecutive weeks at months 3 (weeks 9-12), 6 (weeks 21-24), and 12 (weeks 45-48). Progesterone concentrations >3ng/mL were interpreted as ovulation. The ovulation rate in each group was compared using Fisher’s exact test by month and generalized estimating equations over 48 weeks. Plasma was collected at day 3 and weeks 1, 4, 12, 24, 36 and 48 after implant placement, and analyzed by a validated LC-MS/MS method for etonogestrel. Etonogestrel concentrations were summarized as median (interquartile range, IQR) and compared between groups by geometric mean ratio (GMR) with 90% Confidence Interval (CI). ResultsAll participants (n=72) were cisgender Ugandan women, median age 31 (IQR 29, 36), and 36 participants were enrolled in each study group. Two participants in the Control group were discontinued; one at week 1 due to undetected pregnancy at entry and another at week 45 due to clinically significant depression. There were 47 ovulations over 104 person-months (45%) in 25 of 34 participants in the Control Group, and 2 ovulations over 108 person-months (2%) in 2 of 36 participants in the DoublET group [Month 3: 11 (31%) vs 0 (0%); Month 6: 17 (49%) vs 0 (0%); Month 12: 19 (56%) vs 2 (6%), respectively (all p<0.001)]. The odds of ovulation were reduced by 97.7% (95% CI: 90.1- 99.5) in the DoublET group over 48 weeks. At each time point, etonogestrel was more than two-fold higher in the DoublET group compared to controls (GMR 2.30-2.83), with the GMR of 2.83 (1.89, 3.35 90% CI) at week 48. There were no differences in the adverse events between groups and no participant discontinued due to adverse events. ConclusionOver 48 weeks of combined use, placing two etonogestrel implants suppressed ovulation and increased plasma etonogestrel exposure compared to one etonogestrel implant among women on efavirenz-based antiretroviral therapy. Doubling the dose of etonogestrel with efavirenz-based antiretroviral therapy could improve contraceptive effectiveness.

Comparison of Neoadjuvant Systemic Chemotherapy Protocols for the Curative-Intent Management of Peritoneal Metastases from Colorectal Cancer, Regarding Morphological Response, Pathological Response, and Long-Term Outcomes: A Retrospective Study.

Selected patients with colorectal cancer peritoneal metastases (CRPM) could be offered a curative-intent strategy based on complete cytoreductive surgery (CRS), potentially combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and perioperative systemic chemotherapy. The impact of different neoadjuvant systemic chemotherapy (NACT) regimens remains unclear due to a lack of comparative data. Consecutive CRPM patients from a monocentric database who were treated with complete CRS after single-line NACT were included in this study. Chemotherapy regimens were tailored as a doublet drug (FOLFOX/FOLFIRI) with/without targeted therapy (anti-epidermal growth factor receptor/bevacizumab) and triplet-drug combination (FOLFIRINOX). Morphological response (MR) was assessed using the Response Evaluation Criteria in Solid Tumors criteria, and pathological response (PR) was assessed using the Peritoneal Regression Grading Score (PRGS). Long-term oncologic outcomes were compared. The cohort comprised 388 patients, including 127, 202, and 59 patients in the doublet, doublet+targeted, and triplet groups, respectively. MR rates were higher in the triplet (68.0%) and doublet+targeted groups (64.2%) when compared with the doublet group (42.4%, p=0.003). Complete and major PRs were observed in 13.6% and 32.0% of patients, respectively. Higher MR rates were observed after doublet+targeted or triplet regimens, while no difference was observed for PR rates. In multivariate analysis, FOLFIRINOX was independently associated with better overall survival (hazard ratio 0.49, 95% confidence interval 0.25-0.96; p=0.037). FOLFIRINOX also resulted in a higher rate of severe postoperative complications. In this retrospective study, a FOLFIRINOX regimen as NACT seemed to result in better long-term outcomes for CRPM patients after complete CRS/HIPEC, although with higher morbidity. Prospective studies are needed, including groups without NACT and those with FOLFIRINOX+bevacizumab.

Efficacy and safety of treatments in newly diagnosed adult primary immune thrombocytopenia: a systematic review and network meta-analysis

Immune thrombocytopenia is an autoimmune disease characterised by decreased platelet count. In recent years, novel therapeutic regimens have been investigated in randomised controlled trials (RCTs). We aimed to compare the efficacy and safety of different treatments in newly diagnosed adult primary immune thrombocytopenia. We did a systematic review and network meta-analysis of RCTs involving treatments for newly diagnosed primary immune thrombocytopenia. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched up to April 31, 2022. The primary outcomes were 6-month sustained response and early response. Secondary outcome was grade 3 or higher adverse events. This study is registered with PROSPERO (CRD42022296179). Eighteen RCTs (n=1944) were included in this study. Pairwise meta-analysis showed that the percentage of patients achieving early response was higher in the dexamethasone-containing doublet group than in the dexamethasone group (79.7% vs 68.7%, odds ratio [OR] 1.82, 95% CI 1.10-3.02). The difference was more profound for sustained response (60.5% vs 37.4%, OR 2.57, 95% CI 1.95-3.40). Network meta-analysis showed that dexamethasone plus recombinant human thrombopoietin ranked first for early response, followed by dexamethasone plus oseltamivir or tacrolimus. Rituximab plus prednisolone achieved highest sustained response, followed by dexamethasone plus all-trans retinoic acid or rituximab. Rituximab plus dexamethasone showed 15.3% of grade 3 or higher adverse events, followed by prednis(ol)one (4.8%) and all-trans retinoic acid plus dexamethasone (4.7%). Our findings suggested that compared with monotherapy dexamethasone or prednis(ol)one, the combined regimens had better early and sustained responses. rhTPO plus dexamethasone ranked top in early response, while rituximab plus corticosteroids obtained the best sustained response, but with more adverse events. Adding oseltamivir, all-trans retinoic acid or tacrolimus to dexamethasone reached equally encouraging sustained response, without compromising safety profile. Although this network meta-analysis compared all the therapeutic regimens up to date, more head-to-head RCTs with larger sample size are warranted to make direct comparison among these strategies. National Natural Science Foundation of China, Major Research Plan of National Natural Science Foundation of China, Shandong Provincial Natural Science Foundation and Young Taishan Scholar Foundation of Shandong Province.

WJOG13219G: The Efficacy and Safety of FOLFOXIRI or Doublet plus Anti-VEGF Therapy in Previously Untreated BRAFV600E Mutant Metastatic Colorectal Cancer: A Multi-Institutional Registry-Based Study (BRACELET Study)

BackgroundThe real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAFV600E mutant metastatic colorectal cancer (mCRC). Patients and MethodsWJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAFV600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background. ResultsThe analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60–1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62–1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69–1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73–1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former. ConclusionTriplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAFV600E mutant mCRC.

P-107 Efficacy of 2nd-line ramucirumab (RAM) plus FOLFIRI for RAS wild-type metastatic colorectal cancer (mCRC) by prior regimen: Subgroup analysis of the JACCRO CC-16

There have been few studies which prospectively evaluated the efficacy and safety of RAM plus FOLFIRI after 1st-line anti-EGFR antibody-containing therapy in RAS wild-type mCRC. We therefore conducted a multicenter phase 2 trial, JACCRO CC-16, and reported 6month-PFS rate of 58.2 % and median PFS of 7.0 months. The JACCRO CC-16 was a single arm, phase 2 trial to evaluate the efficacy and safety of RAM (8 mg/kg) plus FOLFIRI (irinotecan 150 mg/m2, bolus 5-FU 400 mg/m2, infusional 5-FU 2400 mg/m2) in mCRC patients with RAS wild-type tumors and ECOG PS 0 or 1, after 1st-line oxaliplatin-based doublet (Ox-doublet) or triplet plus anti-EGFR antibody. Primary endpoint was 6month-PFS rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), early tumor shrinkage (ETS), and overall survival. The subgroup post-hoc analysis was performed to investigate the differences in clinical outcomes of RAM plus FOLFIRI according to previous 1st-line regimen, doublet or triplet. A total of 92 patients were enrolled between October 2018 and 2020 December. Ninety-one patients were analyzed as the full analysis set. In prior 1st-line treatment, 19 (21%) patients were treated with modified-FOLFOXIRI plus cetuximab, and 72 (79%) patients were treated with doublet plus anti-EGFR antibody. The doublet group included 3 patients who failed to achieve an ETS during 1st-line treatment. The 6months-PFS rate (95% CI) was 57.9 % (33.2 to 76.3) in the triplet group and 58.3 % (46.1 to 68.7) in the doublet group. The PFS was significantly longer in the doublet group (median PFS, 7.4 months, 95% CI 5.7 to 9.0) compared to the triplet group (median PFS, 6.4 months, 95% CI 3.8 to 7.35) (p = 0.036, log-rank test). The ORR and DCR were 5.6 % and 94.4 % in the triplet group and 12.1 % and 84.8 % in the doublet group, with no significant difference between 2 groups (p = 0.42 and p = 0.28, respectively). This study demonstrated a favorable efficacy of FOLFIRI plus RAM treatment in RAS wild-type mCRC patients treated with 1st-line anti-EGFR antibody-containing therapy. It may also achieve a certain effect in cases previously treated with triplet-based regimen.

WJOG13219G: Triplet versus doublet in patients with previously untreated BRAFV600E-mutant metastatic colorectal cancer: A multi-institutional real-world data analysis (BRACELET study).

37 Background: The survival benefit of FOLFOXIRI plus bevacizumab (Triplet) over Doublet in patients (pts) with BRAFV600E-mutant metastatic colorectal cancer (mCRC) remains controversial. We compared Triplet therapy with Doublet and explored the pts subgroups that could benefit from intensive chemotherapy (chemo) using real-world data. Methods: WJOG13219G was a multicenter, retrospective registry-based study of pts with BRAFV600E-mutant mCRC who received first-line doublet or triplet chemo with/out molecular targeted agents in January 2014–December 2019. Primary analysis focused on pts who received VEGF inhibitor-containing chemo. To adjust pts background, the inverse probability of treatment weighting (IPTW) method based on propensity scores calculated by age, ECOG PS, and disease status (recurrent/metastatic) was used. Results: A total of 232 pts from 33 hospitals were registered. After excluding 18 pts treated with anti-EGFR antibody-containing regimen and 44 without any targeted agents, 79 pts with Triplet and 91 with Doublet were analyzed. Baseline pts disposition was as follows: median age, 61 y; male proportion, 51%; PS 0/1/≥2, 63%/32%/5%; recurrent/metastatic, 26%/74%; and right/left primary, 68%/32%. Significant differences were noted in age and PS between the two groups. At median follow-up of 24.0 months, no statistical difference was noted in progression-free survival (PFS) (median 9.7 months of Triplet vs. 7.8 months of Doublet, HR = 0.89, P = 0.49) and overall survival (OS) (median 18.7 vs. 18.3 months, HR = 0.87, P = 0.52). The objective response rate was 53% in the Triplet group and 41% in Doublet (P = 0.10). Curative surgery after chemo was more frequent in the Triplet group than in Doublet (13% vs. 3%, P = 0.02). Two pts (3%) in the Triplet group and 6 (7%) in Doublet received immunotherapy as subsequent chemo; 13 (16%) and 6 (7%) also received BRAF inhibitor-containing therapy. IPTW analysis showed no difference between the two groups in PFS (HR = 0.82, P = 0.07) and OS (HR = 0.92, P = 0.57). In the subgroup analysis, pts with right-sided primary tumor in the Triplet group showed favorable trends of PFS (HR, 0.87; 95% CI, 0.65–1.16) and OS (HR, 0.71; 95%CI, 0.50–1.01), whereas pts with left-sided tumor in the Triplet group showed the reverse trends of PFS (HR, 1.17; 95% CI, 0.77–1.78) and OS (HR, 1.68; 95% CI, 0.97–2.91). Conclusions: Some baseline characteristics were significantly different between real-world pts in the Triplet and Doublet groups. Although the Triplet group did not show any survival benefit compared with Doublet in the original and IPTW cohorts, pts with right-sided BRAFV600E-mutant mCRC could benefit from Triplet therapy.

A Retrospective Study of Neoadjuvant Chemotherapy for Locally Advanced Gastric Cancer.

ObjectiveTo explore the efficacy and safety of neoadjuvant chemotherapy in the doublet and triplet regimens of locally advanced gastric cancer.Patients and MethodsA retrospective analysis was conducted on 162 patients with gastric cancer who received neoadjuvant chemotherapy, including 74 patients receiving doublet regimen (fluorouracil/platinum) and 88 patients receiving triplet regimen (fluorouracil/platinum/Taxol). Patients in both groups received neoadjuvant chemotherapy for two cycles, and underwent surgical resection 4 weeks after the end of chemotherapy.ResultsThe total clinical remission rate was 68.6% (105/153), the phase-down rate was 46.4% (71/153), and the pathological response rate was 59.9% (97/162). In the doublet and triplet regimen, the clinical remission rate was 65.7% (44/67) and 70.9% (61/86) (P = 0.708), the descending period rate was 41.8% (28/67) and 50.0% (43/86) (P = 0.485), and the pathological response rate was 51.4% (38/74) and 67.0% (59/88) (P = 0.190). The median disease-free survival (DFS) and overall survival (OS) of 162 patients were 36.0 and 58.5 months. In the doublet and triplet regimen, the median DFS was 38.0 and 34.0 months (P = 0.377), and the median OS was 59.0 and 56.5 months (P = 0.256). The side effects of the doublet group were significantly lower than those of the triplet group, with leucopenia rate of 45.9% (34/74) and 62.5% (55/88) (P = 0.035); thrombocytopenia rate of 18.9% (14/74) and 35.2% (31/88) (P = 0.021); nausea rate of 45.9% (34/74) and 64.8% (57/88) (P = 0.016), and diarrhea rate of 1.4% (1/74) and 9.1% (8/88) (P = 0.032).ConclusionNeoadjuvant chemotherapy is safe and effective for locally advanced gastric cancer. The clinical efficacy of neoadjuvant chemotherapy in the doublet group and the triplet group is equivalent, and the doublet group has better safety and tolerance.

Maintenance chemotherapy is effective in patients with metastatic triple negative breast cancer after first-line platinum-based chemotherapy

Platinum-based chemotherapy (PBCT) has gained an important position as a first-line treatment for metastatic triple-negative breast cancer (mTNBC). We assessed whether maintenance chemotherapy maintenance was superior to observation after first-line PBCT in patients with mTNBC. A total of 265 patients with mTNBC who had exhibited non-PD after 4-6 cycles of firstline PBCT at the Fudan University Shanghai Cancer Center from January 2008 to April 2019 were retrospectively analyzed. 107 patients who did not receive additional treatment were defined as the control observation group, and the remaining 158 patients who continued to receive maintenance therapy were defined as the maintenance treatment group. The median progression-free survival (PFS) time in the maintenance group was 9.63 months, which was significantly longer than the PFS time of 7.47 months in the observation group (HR 0.49, 95% CI: 0.37-0.67, P<0.0001). The median overall survival (OS) of the observation group and the maintenance group was 25.37 months and 31.27 months, respectively (HR 0.65, 95% CI: 0.44-0.95, P=0.019). The survival benefit was still present after adjusting baseline characteristics. Moreover, multivariate analyses suggested that maintenance chemotherapy is an independent predictive factor for both PFS and OS. Interaction and stratified analyses showed no difference in the PFS with between the single-drug maintenance strategy, single agent or doublet group and the doublet-drug maintenance group. The most common adverse event in this study was hematologic toxicity. Except for hand-foot syndrome (0 vs. 7.6%, P=0.004), the incidence of other adverse events was not significantly different between the observation and maintenance groups. After achieving non-PD with the first-line PBCT in mTNBC patients, chemotherapy maintenance may provide OS benefit prior to the era of biologicals.

Comparison of doublet chemotherapy with monotherapy for vulnerable advanced colorectal cancer patients.

143 Background: The efficacy of doublet chemotherapy (fluoropyrimidine + oxaliplatin/irinotecan) for vulnerable colorectal cancer patients is controversial. Some prospective trials have not shown the benefit of doublet chemotherapy for vulnerable patients compared to fluoropyrimidine monotherapy. On the other hand, one trial did show an advantage for doublet chemotherapy in PFS. Moreover, although these trials are designed for vulnerable patients, inclusion was limited by trial criteria, and patient conditions might have been better than those of vulnerable patients in clinical practice. Therefore, the advantage of doublet chemotherapy over monotherapy for vulnerable patients in clinical practice remains unclear. Chemotherapy toxicity and frailty are increased in high modified Glasgow score (mGPS = 2) patients. Therefore, we examined the efficacy of doublet chemotherapy for vulnerable patients, using mGPS. Methods: We retrospectively examined vulnerable advanced colorectal cancer patients who received monotherapy (n = 52) or doublet chemotherapy (n = 195) as 1st line treatment between 2005 and 2016. We defined vulnerable as fulfilling one of the following conditions; age ≥75, ECOG PS = 2, or mGPS = 2. Results: Patient characteristics in the monotherapy group vs the doublet group were as follows; median age (range), 80 (63-88) vs 66 (29-87); gender male/female, 28/24 vs 111/84; ECOG PS 0/1/2, 15/25/12 vs 76/79/40; mGPS = 2, 13 (25%) vs 134 (68%); median metastatic sites (range), 1 (1-3) vs 2 (1-5); presence of ascites, 9 (17%) vs 59 (30%), primary tumor location left, 35 (67%) vs 125 (64%); KRAS mutation 18 (35%) vs 52 (27%); bevacizumab/anti-EGFR antibody, 30/0 vs 79/19. The median PFS was 6.9 months in the monotherapy group and 7.7 months in the doublet group (HR = 1.129, p = 0.480). The median OS was 13.3 months in the monotherapy group and 14.8 months in the doublet group (HR = 0.999, p = 0.994). Multivariate analysis did not show the benefit of doublet chemotherapy in PFS (HR = 0.908, p = 0.615) or OS (HR = 0.764, p = 0.176). Conclusions: This study suggests that doublet chemotherapy may not be beneficial for vulnerable advanced colorectal cancer patients in clinical practice.

Irinotecan-containing doublet treatment versus irinotecan monotherapy as second-line choice for advanced gastric cancer

BackgroundFor patients with advanced gastric cancer (AGC), second-line chemotherapy regimen remains controversial. The efficacy and safety of irinotecan-containing doublet treatment and irinotecan monotherapy were compared in this systematic analysis.MethodsA search was conducted on EMBASE and Medline databases. All articles compared irinotecan-containing doublet to irinotecan as second-line chemotherapy for AGC. STATA statistical software (Version 12.0) was used to analyze the data.ResultsSeven studies, including 905 cases, were included in the analysis. Irinotecan-containing doublet treatment significantly prolonged progression-free survival compared to irinotecan monotherapy (HR = 0.82, 95% CI: 0.70–0.95). However, doublet treatment neither significantly prolong overall survival compared to monotherapy (HR = 0.94, 95% CI: 0.81–1.10), nor did it significantly increase the overall response rates and disease control rates, when compared to monotherapy. In addition, the irinotecan-containing doublet group had an increase in incidences of ≥ Grade 3 neutropenia (RR = 1.23, 95% CI: 1.01–1.51) and anemia (RR = 2.00, 95% CI: 1.37–2.92).ConclusionsWhen compared to irinotecan monotherapy, irinotecan-containing doublet treatment increased progression free survival and was tolerable as a second- line chemotherapy for AGC.

Efficacy and safety of adding an agent to bevacizumab/taxane regimens for the first-line treatment of Her2-negative patients with locally recurrent or metastatic breast cancer: results from seven randomized controlled trials.

BackgroundThe combined therapy of bevacizumab (BEV) with taxane (paclitaxel or docetaxel) has shown an improvement on progression-free survival (PFS) and objective remission in Her2-negative patients with locally recurrent or metastatic breast cancer (LR/MBC). However, there was no benefit in overall survival (OS). The aim of this study was to evaluate the efficacy and safety of adding an agent to the BEV/taxane regimens for the treatment of Her2-negative patients with LR/MBC in a first-line setting.Materials and methodsWe searched PubMed, Web of Science, EMBASE, EBSCO, and the Cochrane Library databases for eligible trials. A meta-analysis was performed using Review Manager 5.0 freeware package. We calculated the hazard ratio (HR) for PFS and OS. The odds ratio (OR) was used to calculate objective response rate (ORR) and grade 3/4 drug-related adverse events. The heterogeneity of study outcomes was calculated by the χ2 test or I2 statistics.ResultsA total of 1,124 patients from seven randomized controlled trials were analyzed. Our meta-analysis showed that the ORR was significantly improved in the BEV/taxane-based triplet group when compared with the BEV/taxane-based doublet group (OR =1.31, 95% confidence interval [CI]: 1.03–1.67, P=0.03). A subset analysis showed that a similar result was achieved in the triplet group in which a cytotoxic agent was added (OR =1.46, 95% CI: 1.09–1.95, P=0.01). However, the PFS and OS had no statistically significant differences between the two groups (HR =0.87, 95% CI: 0.68–1.13, P=0.31; HR =0.98, 95% CI: 0.82–1.16, P=0.78, respectively). Regarding safety, thromboembolic events, fatigue, and diarrhea (all $grade 3) were more frequently observed in the BEV/taxane-based triplet group (OR =3.8, 95% CI: 1.86–7.79, P=0.0003; OR =1.55, 95% CI: 1.05–2.27, P=0.03; OR =2.1, 95% CI: 1.29–3.41, P=0.003, respectively). Other toxic effects had no statistically significant differences between the two groups.ConclusionOur results showed that adding an agent to BEV/taxane treatment regimens did not significantly improve PFS and prolong OS, except for conferring a significant advantage toward improved ORR in the first-line therapy for Her2-negative patients with LR/MBC. However, its side effects are predictable and manageable.

Irinotecan-Based Regimen as Second-Line Chemotherapy for Extensive- Stage Small Cell Lung Cancer

Purpose: This study evaluates the clinical outcomes of extensive-stage small-cell lung cancer (SCLC) patients who received Irinotecan-based second-line chemotherapy after platinum-based first-line therapy, especially focused on efficacy and toxicity between single-agent and doublet chemotherapy. Patients and methods: We retrospectively reviewed 83 patients who given irinotecan-based second-line chemotherapy for extensive-stage SCLC. Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis. Results: Fifty-nine patients received doublet chemotherapy and 24 with single-agent treatment. The objective response rate (ORR) was 23.7% in the doublet group and 25% in the single-agent group (P=0.90). The disease control rate (DCR) was 65.7% and 58.3%, respectively, (P=0.71). The Progression-free survival (PFS) was 3.10 months in the doublet group and 2.10 months in the single-agent group (P=0.35). In the sensitive recurrence group, 27 patients were with doublet chemotherapy and 10 with single-agent treatment. The Median PFS was 4.73 months (95% CI: 4.37-5.09) and 3.83months (95% CI: 2.65-5.02), respectively (P=0.543). In the refractory recurrence group, there were 32 patients with doublet chemotherapy and 14 with single-agent treatment. The median PFS was 2.57 months (95% CI: 2.19-2.93) and 1.40 months (95% CI: 1.13-1.64), respectively (P=0.048). The grade III/IV toxicity in single-agent group is lower than doublet group (45.8% vs.71.2%, P=0.029). No difference was found in cancerrelated symptoms improvement between the doublet and single group (P=0.36). Conclusion: Patients with extensive-stage SCLC could benefit from irinotecan-based second-line treatments. The refractory recurrence patients with doublet treatment obtain a moderate PFS advantage than single-agent chemotherapy.

ISOLATION AND CHARACTERIZATION POLYHYDROBUTYRATE (PHB) PRODUCING BACTERIA FROM WASTE COOKING OIL USING POMEGRANATE MOLASSES AS CARBON SOURCE

In this study, a polyhydroxybutyrate (PHB) producing bacterium was isolated from waste cooking oil and characterized for its morphological and biochemical properties. Staining methods utilizing Sudan Black B and Nile Blue A were used on isolated bacterium to demonstrate good capability for synthesizing PHB. It was shown that the isolated bacterium species was related to Bacillus thuringiensis LMA by using 16S rRNA gene sequences analysis. During the stationary phase, the Bacillus strain was subjected to 10 % (w/v) of pomegranate molasses as a carbon source and 5 g/L of peptone as a nitrogen source. 2 ml of batch fermentation was collected. Samples were collected twice during the incubation period for detection of PHB using Sudan Black B. The PHB production accounted for up to 57.45% of the cell dry weight. The PHB produced was characterized using Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance Spectroscopy (NMR). The drastic absorption band at approximately 1717 cm-1 indicated the stretching vibration of C=O group in PHB polyester, while the functional groups of PHB were identified methyl (-CH3) at 1.28 ppm, methylene (-CH2) 2.0 and 2.5 ppm, and methylene doublet group (CH3) at 5.3 ppm.

The efficacy and safety of pemetrexed-based doublet therapy compared to pemetrexed alone for the second-line treatment of advanced non-small-cell lung cancer: an updated meta-analysis

BackgroundPemetrexed is currently recommended as the second-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether pemetrexed-based doublet therapy improves treatment efficacy and safety. Thus, this meta-analysis was performed to resolve this controversial question.MethodsElectronic databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant articles before April 2015. Hazard ratios (HRs) were used to estimate overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) were used to analyze the overall response rate (ORR) and grade ≥3 toxicities. Subgroup analysis, sensitivity analysis, and publication bias were also evaluated.ResultsA total of 2,519 patients from ten randomized controlled trials were included. Compared to pemetrexed alone, PFS and ORR significantly improved in the pemetrexed-based doublet group (HR, 0.86; 95% CI [confidence interval], 0.75–0.99; P=0.038; and OR, 1.98; 95% CI, 1.25–3.12; P=0.003, respectively). However, no statistically significant differences in OS were observed between groups (HR, 0.92; 95% CI, 0.83–1.02; P=0.132). In addition, subgroup analyses indicated that improved OS was only observed in nonsquamous NSCLC patients who received the combination of pemetrexed and erlotinib. An increasing incidence of grade ≥3 neutropenia and thrombocytopenia was observed in the pemetrexed-based doublet group.ConclusionAmong patients with advanced NSCLC, pemetrexed-based doublet treatment tended to be associated with improved PFS, ORR, and increased toxicity, but not OS.

Comparing single-agent with doublet chemotherapy in first-line treatment of advanced non-small cell lung cancer with performance status 2: a meta-analysis.

This systematic review and meta-analysis was performed to assess the efficacy and side effects between single-agent and doublet chemotherapy in first-line treatment of advanced non-small cell lung cancer with performance status 2 (PS2). We searched for randomized controlled trials in online electronic databases and extracted data from eligible studies for meta-analysis. Pooled hazard ratio (HR) for overall survival (OS), pooled risk difference (RD) for 1-year survival, pooled risk ratio (RR) for objective response rate (ORR) and adverse effects were calculated using a fixed-effect model. Six trials with 386 participants in the single-agent group and 389 participants in the doublet group were included in this review. Compared with single-agent chemotherapy, doublet significantly improved OS (HR 0.72; 95% CI 0.61-0.84; P < 0.0001) and significantly increased 1-year survival rate (RD -0.09; 95% CI -0.14 to -0.03; P = 0.004) and ORR (RR 0.4; 95% CI 0.30-0.69; P = 0.0002). Doublet chemotherapy also significantly increased the risk of grade 3/4 neutropenia (RR = 4.97; 95% CI 2.93-8.43; P < 0.00001), thrombocytopenia (RR = 10.29; 95% CI 3.80-27.85; P < 0.00001) and anemia (RR = 2.50; 95% CI 1.27-4.90; P = 0.008). Our study implies that carboplatin-containing doublet chemotherapy improved OS, 1-year survival rate and ORR, but increased the risk of grade 3/4 hematotoxicity. Carboplatin-containing doublet may well be superior to non-carboplatin-containing treatment.

Secondary malignant neoplasms after osteosarcoma: early onset and cumulative alkylating agent dose dependency.

To analyze the impacts of chemotherapeutic agent exposures on the development of secondary malignant neoplasms (SMP) after osteosarcoma. Of 132 patients who had been treated for high-grade extremity osteosarcoma from September 1992 to September 2008, 90 survivors were retrospectively reviewed. Fifty-eight of the survivors received a doublet of doxorubicin (ADR) and cisplatin (DDP), and 32 received a triplet of ADR, DDP, and ifosfamide (Ifos). On the basis of the dose distributions in the study cohort, the association between SMN and the cumulative dose of each agent was evaluated. After a mean of 13.1 years of follow-up, six SMNs were noted, three in each regimen. There were no SMNs among 42 patients who died of osteosarcoma. In Kaplan-Meier estimates, the triplet regimen group showed a higher cumulative incidence and shorter latency for SMNs than the doublet group (log rank P = 0.032). Fifteen years' cumulative incidence of SMNs in the triplet and doublet regimen group was 9.4 and 3.8%, respectively. In the independent t test, the mean latency to SMN in the triplet group (3.7 ± 1.3 years) was shorter than that in the double group (13.1 ± 2.8 years) (P = 0.017). In Cox regression, the alkylating agent score (AAS) [hazard ratio (HR) = 2.459, P = 0.015] and DDP (HR = 1.779, P = 0.046) showed a significant relationship with SMNs, whereas ADR (HR = 0.896, P = 0.664) and Ifos (HR = 3.694, P = 0.119) did not. AAS was also significant after adjusting for ADR and DDP (HR = 3.319, P = 0.020). High cumulative AAS is an independent risk factor for SMN and its early-onset development after osteosarcoma.

Passively athermalized broadband optical design using doublet combinations.

In this paper we propose a method for broadband achromatic and passive athermal optical system design using a combination of three doublets. In the implementation of this method, the first-order color dispersion is corrected by distributing proper power to the elements inside the doublets; the thermal and secondary color dispersion are corrected by distributing proper power to the doublet group units. The theoretical deviation is given and we summarize the power distribution equations. A design of an example system using this method, which covers the 350-1200 nm wavelength band, is given and the image quality evaluation is presented. It is shown that the example system maintains high imaging qualities over the required wavelength and temperature range, which proves the effectiveness of the method.

Comparison of the efficacy and safety of single-agent erlotinib and doublet molecular targeted agents based on erlotinib in advanced non-small cell lung cancer (NSCLC): a systematic review and meta-analysis

In patients with advanced non-small cell lung cancer (NSCLC), the benefit-to-risk ratio of doublet-targeted agents versus single agent is not clear. A systematic review and quantitative meta-analysis were, therefore, undertaken to evaluate the available evidence from randomized trials. This study aims to evaluate the efficacy and safety of erlotinib versus doublets (erlotinib plus another targeted agent) in advanced NSCLC and, if adequate data are available, to investigate whether or not predefined patient groups benefit more or less from doublet-targeted therapy based on erlotinib. Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled clinical trials were conducted in which any erlotinib was compared with doublets based on erlotinib in patients with NSCLC who had failed to respond to any previous chemotherapy regimen. Two review authors independently selected studies for inclusion in the review and extracted data. A systematic review and meta-analysis based on aggregate data extracted from trial publications were carried out to assess the effectiveness of doublets (erlotinib plus another targeted drug) in NSCLC treatment. The efficacy outcomes were objective response rate (ORR), complete response plus partial response; disease control rate (DCR), complete response plus partial response and stable disease; and 1-year overall survival (OS). The adverse effects (AEs) were also considered. This involved identifying eligible randomized controlled trials (RCTs) and extracting aggregate data from the reports of these RCTs. Hazard ratios were calculated from published summary statistics and then combined to give pooled estimates of treatment efficacy. This meta-analysis comprised five studies including 2,100 patients (mean age 63; 1,224 men and 876 women; 118 stage IIIB and 1,180 stage IV; 441 squamous cell cancers, 1,287 adenocarcinomas, and 372 other pathological types). Doublets regimen significantly improved ORR [hazard ratio (HR) 1.49, 1.13-1.98, p < 0.05] and DCR (HR 1.25, 1.12-1.39, p < 0.05) compared with single erlotinib, but 1-year OS was not significantly improved for doublets [HR 1.06; 95% confidence interval (CI), 0.95-1.18]. All-grade rash, anemia, diarrhea, anorexia, and fatigue were not significantly different between doublet and erlotinib groups (HR 1.25, 0.99-1.58; 0.98, 0.78-1.24; 1.43, 0.97-2.11; 1.18, 0.84-1.65; and 1.23, 0.86-1.77, respectively). The total grade of ≥3 AEs was also not significantly different (HR 1.40, 95% CI 0.97-2.01). Compared with single-agent erlotinib, doublets (erlotinib plus another targeted agent) significantly improve ORR and DCR, but not OS, and induce no significance of more frequent and serious AEs. The benefit-to-risk ratio of doublets in advanced NSCLC may be more favorable than that of single-agent. The results of this systematic review suggest that patients with advanced NSCLC might benefit from doublet-targeted therapy based on erlotinib compared to erlotinib alone. However, an individual patient data systematic review and meta-analysis are needed to give us a more reliable assessment of the size of benefits and to explore whether doublet therapy may be more or less effective for particular types of patients.

Analysis of the efficacy and survival of third-line treatment in advanced non-small cell lung cancer

背景与目的随着高效低毒药物的出现，越来越多的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者有机会接受三线治疗，但目前三线的标准治疗除厄洛替尼外尚无其它选择方案。本研究旨在比较单药化疗、靶向药物与双药联合化疗在晚期NSCLC患者三线治疗中的疗效与安全性。方法回顾分析115例Ⅲb期/Ⅳ期接受三线治疗的NSCLC患者的疗效及生存状况。采用Kaplan-Meier曲线、Cox多因素生存分析模型进行单因素和多因素分析。结果单药组、靶向治疗组与双药联合组中位无进展生存时间（progression free survival, PFS）分别为2.30个月、3.17个月和2.37个月（P=0.045），三线治疗后的中位生存时间（overall survival, OS）分别为8.00个月、10.40个月和7.87个月（P=0.110），Ⅲ度-Ⅳ度毒性反应发生率分别为33.3%、18.2%和68.8%（P < 0.001）。多因素分析显示体能状况（performance status, PS）评分（P < 0.001）是PFS的独立预后因素，既往无吸烟史（P=0.011）、PS评分0分-1分（P < 0.001）和一二线治疗疗效获得疾病控制（P=0.044）是三线治疗OS的独立预后因素。结论PS评分较好、既往不吸烟和一二线治疗疗效疾病控制的患者在三线治疗中更能获益，与化疗单药或双药相比靶向药物组PFS显示出优势。

Impact of AJCC staging system (2010 edition) on the choice of postoperative adjuvant chemotherapy after radical resection of gastric cancer

To investigate whether AJCC staging system(2010 edition) for gastric cancer has influence on the adoption of adjuvant chemotherapy. This was a cohort study and the data were collected from patients who underwent radical surgery and received adjuvant chemotherapy from January 2004 to December 2009. There were 48 patients with stage II( disease and 95 patients with stage III( disease according to TNM staging(2010 edition). Doublets were defined as 5-fluorouracil or capecitabine plus cisplatin or oxaliplatin, while triplets had epirubicin added. Ninety-six patients received doublet chemotherapy and 47 received triplet. All the patients were followed-up in the outpatient clinic until death or the censor time of May 2011. The median follow-up time was 48 months in this cohort of 143 patients. The two groups had similar disease-free survival(DFS)(median, 23 months vs. 30 months, P>0.05). The median overall survival was 48 months in both groups. Subgroup analysis by TNM staging(2010 edition) showed that the median DFS of patients with stage III( gastric cancer was 15 months in the doublet group, significantly shorter than that of patients in the triplet group (18 months, P<0.05). However, the difference in overall survival was not statistically significant between the two groups. Patients with stage II( disease had comparable DFS and OS between the two groups(all P>0.05). Triplets regimens (epirubicin, platins and fluorouracil) show benefit on disease-free survival for the stage III( gastric cancer patients staged by TNM staging 2010 edition.