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Systemic therapy beyond first-line in advanced gastric cancer: An overview of the main randomized clinical trials
Critical Reviews in Oncology/Hematology, In Press, Corrected Proof, Available online 30 November 2015, Available online 30 November 2015
- Progressive gastric cancer patients may benefit from a second-line therapy.
- Monochemotherapy (both irinotecan and taxanes) is superior to BSC.
- Novel targeted agents such as ramucirumab and apatinib are really promising.
- Ramucirumab is the first targeted drug approved by FDA and EMA in second-line.
- Future investigation should provide stronger predictive markers to targeted therapy.
Following progression on first-line platinum and fluoropyrimidine-based chemotherapy, prognosis for advanced gastric cancer patients is extremely poor. Thus, new and effective treatments are required. Based on positive results of recent randomized controlled trials, second-line monochemotherapies with either irinotecan or taxanes confer a median overall survival of approximately 5 months in gastro-esophageal and gastric adenocarcinoma. Combination of weekly paclitaxel and ramucirumab, a novel anti-angiogenic VEGFR2 antibody, pushes the overall survival up to over 9.5 months, whereas apatinib, a novel oral VEGFR2 tyrosine kinase inhibitor, seems to be promising in heavily pretreated patients. In contrast, the role of EGFR/HER2 and mTOR inhibitors is controversial. Studies are heterogeneous for tumor population, geographical areas, quality of life assessment, type of first-line therapy and response to that, making clinical practice application of the trial results difficult. Furthermore, sustainability is challenging due to high cost of novel biotherapies.
Keywords: Advanced gastric cancer, Second-line chemotherapy, Molecular targeted agents, Randomized controlled trials.
1. Introduction
Despite decreases worldwide since the 1930s in the incidence and death rates of gastric carcinoma (GC), in particular for distal cancers, it remains the third leading cause of cancer mortality worldwide (Anon., 2015a). Nearly 1 million of new stomach cancer cases and >700,000 deaths are estimated to have occurred in 2008, accounting for 8% of the total cases and 10% of total deaths (Jemal et al., 2011). Except for Japan and South Korea (Lee et al., 2006), screening procedures are lacking in most countries, thus GC diagnosis usually occurs very late when curative surgery is not possible. Current evidence shows that palliative first-line chemotherapy improves survival and symptom control in comparison with the best supportive care (BSC) and that polychemotherapy is superior to the single agent 5Fluorouracil (5FU) (Wagner et al., 2006). Although many trials and meta-analyses have been published so far, a well-established standard of care does not exist. At present, fluoropyrimidines and platinum combination with or without epirubicin (E) or docetaxel (D) is regarded as first-line chemotherapy in the treatment of advanced gastric cancer (AGC) (Webb et al, 1997 and Van Cutsem et al, 2006). On the basis of the REAL-2 trial (Cunningham et al., 2010) and other studies (Al-Batran et al, 2008 and Kang et al, 2009), cisplatin (CDDP) may be replaced by oxaliplatin and 5FU by capecitabine. S-1, a novel oral fluoropyrimidine, in combination with CDDP is now accepted as standard first-line chemotherapy in both Asian (Koizumi et al., 2008) and Caucasian subjects (Ajani et al., 2010). Irinotecan (CPT11) plus 5FU/LV (leucovorin) as FOLFIRI regimen may represent an alternative combination to CDDP/5FU when cisplatin may not be integrated (Dank et al., 2008). Among patients with positive HER2 (human epidermal growth factor receptor 2) gastric cancer, trastuzumab (T) plus chemotherapy represent a new standard of care (Bang et al., 2010). Therefore, with the TOGA trial, an era of target therapies in AGC has begun. In contrast, other studies that have tested different biological agents from trastuzumab (such as cetuximab, panitumumab, bevacizumab and lapatinib) have not been able to replicate the same results (Lordick et al, 2013, Waddell et al, 2013, Ohtsu et al, 2011, Shen et al, 2015, and Hecht et al, 2013). Despite these efforts which have led to a considerable improvement in overall survival (OS) and progression free survival (PFS) in first-line therapy, the prognosis of AGC remains poor. On the other hand, the percentage of patients who may benefit from a further treatment is increasing. Rechallenge of the same or an analogous drug after a drug holiday, following disease relapse or progression, could be an option, while for those patients refractory or resistant to the front-line treatment a "pure" second-line chemotherapy with no cross-resistant drugs should be proposed. Over the last few years, several randomized phase II and III trials have been conducted, exploring the role of chemotherapy and targeting drugs, combined or alone, in the second- and third-line settings. Our purpose, unlike previous publications on the same topic based on retrospective reports or single-arm phase II trials, is to provide an overview of the main randomized clinical trials (RCTs), particularly addressing the following settings: (1) chemotherapy vs BSC, (2) comparison of monochemotherapies; (3) polychemotherapy vs monochemotherapy; (4) comparison of polychemotherapy sequences and (5) molecular targeted agents (MTAs).
2. Chemotherapy vs best supportive care
Comparison between chemotherapy (either irinotecan or docetaxel) and BSC as second-line treatment in patients with AGC was the aim of three randomized phase III studies (Table 1).
|Phase and design
|Primary endpoint
|Result (observations)
|AIO group 2011 Thuss-Patience et al. (2011)
2nd line
|CPT-11 vs BSC
|OS months (4.0 vs 2.4)
|p = 0.0012
|Kang et al. (2012)
2nd and 3rd line
|CPT-11 or D vs BSC
|OS months (5.3 vs 3.8)
|p = 0.007
|Positive (no difference between CPT-11 and D)
|COUGAR-2 2014 Ford et al. (2014)
2nd line
|D vs ASC
|OS months (5.2 vs 3.6)
|p = 0.01
|WJOG 4007 2013 Hironaka et al. (2013)
2nd line
|CPT-11 vs wPXT
|OS months (8.4 vs 9.5)
|p = 0.38
|Roy et al. (2013)
2nd line
|UK, Spain, Taiwan, Croatia, Korea and Bosnia
|PEP02 vs CPT-11 vs D
|ORR% (13.6 vs 6.8 vs 15.9)
|Negative (no difference among three arms)
UK: United Kingdom; CPT-11: irinotecan; D: docetaxel; wPXT: weekly paclitaxel; PEP02: liposomal nanocarrier formulation of irinotecan; BSC: best supportive care; ASC: active symptom control; no.: number of patients; R: randomization; HR: hazard ratio; OS: overall survival; ORR: objective response rate; NR: not reported.
The first trial came from the Arbeitsgemeinschaft Internistische Onkologie (AIO) group in 2011; chemotherapy consisted of CPT-11 250 mg/m2 repeated every 3 weeks for patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) from 0 to 2 (Thuss-Patience et al., 2011). Although prematurely stopped after the enrollment of only 40 patients due to poor recruitment, 21 patients treated with CPT-11 had an mOS of 4.0 vs 2.4 months of 19 patients treated with BSC [hazard ratio (HR) 0.48; p = 0.0012]. The main reason for the low recruitment was patient refusal of randomization. Despite the limit of a small sample size, second-line chemotherapy with CPT-11, according to the magnitude of the HR, showed a marked reduction in the risk of death and the achievement of symptom relief in about half of patients (44%).
Similarly, in a Korean trial by Kang et al., (2012) 202 patients (ECOG 0-1) previously treated with chemotherapy containing fluoropyrimidines and platinum, either delivered in sequence or concurrently, were randomized in a 2:1 ratio to salvage chemotherapy (either CPT-11 150 mg/m2 every 2 weeks or D 60 mg/m2 every 3 weeks per investigator's choice) plus BSC or BSC alone. Chemotherapy showed benefit in mOS (5.3 vs 3.8 months, HR 0.66; p = 0.007), reducing the risk of death by 34%. No statistically significant differences were found between CPT-11 and D (6.5 vs 5.2 months).
In the British COUGAR-2 trial, 168 patients with ECOG PS 0-2 progressed on or within 6 months of treatment with a platinum and fluoropyrimidine combination, were allocated to D 75 mg/m2 every 3 weeks plus active symptom control (ASC) or ASC alone (Ford et al., 2014). There was an improved mOS in D arm compared with ASC (5.2 vs 3.6 months, HR 0.67; p = 0.01). Despite toxicity rates being higher in group D, particularly neutropenia, infections and febrile neutropenia, the quality of life (QoL) was markedly improved by chemotherapy in terms of pain, fatigue and dysphagia.
In 2013, Kim and colleagues published a meta-analysis (Kim et al., 2013) of these trials to answer the question as to whether second-line chemotherapy was more effective than BSC (at the time of meta-analysis the COUGAR-2 study had been presented as abstract at the 2013 ASCO annual meeting). A total of 410 patients were eligible for analysis, of whom 150 received D and 81 received CPT-11 chemotherapy. Based on this meta-analysis, the survival benefit was remarkable with a 36% reduction in the risk of death (HR 0.64; p < 0.0001), regardless of the type of drug (CPT-11 or D) and administration schedule, and without substantial differences between Europeans and Asians. Considering the results of univariate analysis for survival in 2 trials (Thuss-Patience et al, 2011 and Kang et al, 2012), good performance status (ECOG 0-1) and long chemotherapy-free interval (≥3 months) could be important positive prognostic indicators that could guide physician's decision-making (Kim et al., 2013).
3. Comparison of monochemotherapies
More recent trials reported that both irinotecan and taxanes can have similar influence in terms of survival (Table 1).
In the WJOG 4007 trial comparing second-line chemotherapy (Hironaka et al., 2013), 219 patients without severe peritoneal metastasis received either weekly paclitaxel (wPTX) (80 mg mg/m2 on days 1, 8, and 15 every 4 weeks) or CPT-11 (150 mg/m2 every 2 weeks). Patients with severe peritoneal carcinomatosis, defined by authors as "ileus or subileus on barium enema examination and moderate to severe ascites exceeding pelvic cavity", were excluded because CPT-11 could be more toxic in this subgroup. CPT-11 was not superior to wPTX (8.4 vs 9.5 months, HR 1.13; p = 0.38), suggesting that also wPTX could be used as control arm of second-line chemotherapy in AGC. Longer mOS achieved in this study than previous phase III trials is likely to depend on the exclusion of patients with severe peritoneal carcinomatosis, recognized as a poor prognostic factor (Chau et al., 2004).
Roy et al. (2013) designed a randomized three-arm phase II trial to compare the efficacy of single agent PEP02, a novel highly stable liposomal nanocarrier formulation of CPT-11, with CPT-11 or D in the second-line treatment; objective response rate (ORR) was the primary endpoint. With a 1:1:1 randomization, a mixed population of 132 patients was assigned to receive PEP02 120 mg/m2, CPT-11 300 mg/m2 or D 75 mg/m2 every 3 weeks. In the ITT population, no differences were reported in ORR (13.6% vs 6.8% vs 15.9%, respectively) and also PFS and OS were similar among the 3 trial arms. Median OS was 7.3 vs 7.8 vs 7.7 months in the PEP02, CPT-11 and D arm, respectively, while mPFS was 2.7 vs 2.6 vs 2.7 months with PEP02, CPT-11 and D, respectively. With regard to toxicity, the most common grade 3–4 adverse event (AE) in the PEP02 arm was diarrhea, much higher than in CPT-11 and D arms (27.3% vs 18.2% vs 2.3%, respectively).
4. Polychemotherapy vs monochemotherapy
So far, two randomized studies, conducted in Asian countries, have assessed the role of second-line polychemotherapy vs monochemotherapy in AGC (Table 2).
|Phase and design
|Primary endpoint
|Result (observations)
|Sym et al. (2013)
2nd line or more
|FOLFIRI vs CPT-11
(20 vs 17.2)
|p = 0.525
|TCOG GI-0801/BIRIP 2014 Higuchi et al. (2014)
2nd line
|BIRIP vs CPT-11
|PFS months
(3.8 vs 2.8)
|p = 0.03
|Positive (60% of patients platinum-free first-line therapy)
FOLFIRI: irinotecan and fluorouracil/leucovorin; CPT-11: irinotecan; BIRIP: biweekly irinotecan and cisplatin; no.: number of patients; R: randomization; HR: hazard ratio; ORR: overall response rate; PFS: progression free survival.
A modified (m)FOLFIRI regimen [CPT-11 150 mg/m2 plus leucovorin (LV) 20 mg/m2 intravenously (IV) on day 1 followed by 5-FU 2000 mg/m2 over 48 h] was compared with CPT-11 150 mg/m2 alone, every two weeks, in a small Korean randomized phase II study (Sym et al., 2013). Both primary endpoint ORR and secondary endpoints mOS and mPFS were unmet. Fifty-two out of the 59 patients enrolled were assessable for response. Objective response rates were 17.2% and 20.0% in patients treated with CPT-11 and mFOLFIRI, respectively. Median PFS and mOS were 2.2 and 5.8 months in the CPT-11 arm, and 3.0 and 6.7 months in the mFOLFIRI arm, respectively. In conclusion, although well tolerated, mFOLFIRI did not improve the results of CPT-11 monotherapy in patients progressing on or after either platinum-, taxane- or fluopyrimidine-based first-line therapy.
In the recent Japanese phase III TCOG GI-0801, comparing biweekly CPT-11 60 mg/m2 plus cisplatin 30 mg/m2 (BIRIP combination) vs biweekly CPT-11 150 mg/m2 alone, mPFS for BIRIP arm was significantly better than CPT-11 in 130 patients refractory to S1-based first-line chemotherapy (3.8 vs 2.8 months, HR 0.68; p = 0.03) (Higuchi et al., 2014). In an exploratory subgroup analysis, in patients who were previously treated without platinum agents, mPFS was much longer with BIRIP arm (6.4 vs 4.2 months, HR 0.60; p = 0.0786). Otherwise, neither OS (10.7 vs 10.1 months) nor RR (22 and 16%) improved with the combination therapy as compared to CPT-11 group. Moreover, this study only included Japanese patients, more than 40% of whom had received no platinum therapy before study entry. Thus, such data may not be considered reliable for Western patients, who are usually treated with a platinum-based regimen as first-line chemotherapy. Any grade elevation of serum creatinine was more common in the BIRIP group, whereas diarrhea was more common in the CPT-11 group. Overall, toxicity profile of BIRIP arm was better than CPT-11 arm, probably related to lower doses of CPT-11 used in the combination therapy.
5. Comparison of polychemotherapy sequences
In the FFCD-GERCOR-FNCLCC 03-07 phase III trial, which enrolled 416 patients, the sequence FOLFIRI as first-line therapy followed by ECX as second-line was superior in time to failure (TTF) (22.1 vs 18.5 weeks, HR: 0.77; p = 0.008) but with a similar OS (9.5 vs 9.7 months) vs the opposite sequence (ECX → FOLFIRI). The authors concluded that the FOLFIRI → ECX sequence should be preferred in view of longer TTF and greater tolerance (Guimbaud et al., 2014) (Table 3).
|Primary endpoint
|Result (observations)
|Guimbaud et al. (2014)
|FOLFIRI → ECX vs ECX → FOLFIRI
|TTF weeks
(22.1 vs 18.5)
|p = 0.008
|Positive (similar OS between two arms)
|Kim et al. (2011)
|D/CDDP → FOLFIRI vs FOLFIRI → D/CDDP
|2nd PFS months
(8.1 vs 6.7)
|p = 0.865
FOLFIRI: irinotecan and fluorouracil/leucovorin; ECX: epirubicin, cisplatin and xeloda® (capecitabine); D: docetaxel; CDDP: cisplatin; no.: number of patients; R: randomization; TTF: time to treatment failure; OS: overall survival; 2nd PFS: second progression free survival; HR: hazard ratio; NR: not reported.
In a phase III Korean trial by Kim and colleagues, prematurely closed due to poor accrual, 58 patients were randomized to receive a first-line therapy D/CDDP every 3 weeks until progression followed by FOLFIRI (Arm A) or the reverse sequence (Arm B). There was no difference in ORR, tumor control rate (TCR), first PFS, second PFS (primary endpoint), and OS between two arms. More specifically, the second PFS was 8.1 and 6.7 months (HR not reported; p = 0.865) for arm A and B, respectively (Kim et al., 2011) (Table 3).
6. Molecular targeted agents
Over the last few years, different classes of targeted agents, such as angiogenesis inhibitors, mTOR inhibitors, epidermal growth factor receptor (EGFR) inhibitors and tyrosine kinase inhibitors (TKIs), have been studied in clinical trials.
To date, 9 randomized trials (5 phase III and 4 phase II) have been published and others were presented during the latest international oncological meetings (Table 4).
|Phase and design
|Primary end-point
|Result (observations)
|Yi et al. (2012)
2nd line
|Sunitinib/Docetaxel vs Docetaxel
|TTP months
(3.9 vs 2.6)
|p = 0.2
|Negative (high activity)
|Moehler et al. (2013)
2nd and 3rd line
|Sunitinib/FOLFIRI vs placebo/FOLFIRI
|PFS months
(3.6 vs 3.3)
|p = 0.66
|Li et al. (2013)
3rd line or more
|Apatinib 850 mg/daily vs Apatinib 425 mg/bid vs placebo
|PFS months
(3.67 and 3.20 vs 1.40)
|0.18 and 0.21
|p < 0.001 and p < 0.001
|Positive (apatinib better than placebo regardless dosing)
|Qin (2014)
3rd line or more
|Apatinib 850 mg/daily vs placebo
|OS days
(195 vs 140)
|p < 0.016
|Granite-1 2013 Ohtsu et al. (2013)
2nd or 3rd line
|Everolimus/BSC vs placebo/BSC
|OS months
(5.39 vs 4.34)
|p = 0.124
|REGARD 2014 Fuchs et al. (2014)
2nd line
|Ramucirumab/BSC vs placebo/BSC
|OS months
(5.2 vs 3.8)
|p = 0.047
|RAINBOW 2014 Wilke et al. (2014)
2nd line
|Ramucirumab/wPTX vs placebo/wPTX
|OS months
(9.63 vs 7.36)
|p = 0.0169
|Satoh T 2014 Satoh et al. (2014a)
2nd line
|Nimotuzumab/CPT11 vs CPT11
|PFS days
(73 vs 85)
|p = 0.5668
|TyTAN 2014 Satoh et al. (2014b)
2nd line
|Lapatinib/wPTX vs wPTX
|OS months
(11 vs 8.9)
|p = 0.104
|Negative (better efficacy in IHC3+ patients)
TKIs: tyrosine kinase inhibitors; MoAB: monoclonal antibody; FOLFIRI: irinotecan and fluorouracil/leucovorin; BSC: best supportive care; wPXT: weekly paclitaxel; CPT-11: irinotecan; no.: number of patients; R: randomization; TTP: time to progression; PFS: progression free survival; OS: overall survival; ORR: objective response rate; HR: hazard ratio.
6.1. Angiogenesis inhibition
Angiogenesis is the process by which new blood vessels are formed and it is essential for normal reproduction, development and tissue repair. In contrast to normal tissues, angiogenesis in tumors is dysregulated and leads to the formation of a blood supply that is tortuous and hyperpermeable. High levels of VEGF (vascular endothelial growth factor) and VEGFR (vascular endothelial growth factor receptor) correlate with increased tumor growth rate and tumor metastatic potential, and worse patient prognosis.
6.1.1. Ramucirumab
The aim of the international randomized, placebo-controlled, phase III REGARD trial was to assess the role of ramucirumab (RAM), a fully human IgG1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 (VEGFR2) (Fuchs et al., 2014). A total of 350 patients with advanced adenocarcinoma of gastro-esophageal junction (GEJ) and stomach progressive on a first-line platinum- or fluoropirimidine-containing chemotherapy, were assigned in a 2:1 ratio to receive either BSC plus RAM 8 mg/kg or placebo, intravenously every 2 weeks. Despite the absence of a difference in ORR between treatment arms, both mOS (5.2 vs 3.8 months, HR: 0.77; p = 0.047) and mPFS (2.1 vs 1.3 months, HR: 0.48; p < 0.0001) were significantly longer for ramucirumab group. So, for the first time a biological drug has shown a benefit in the second-line setting and the survival results of ramucirumab are very similar to those of other chemotherapeutic agents such as irinotecan and taxanes when used alone (Thuss-Patience et al, 2011, Kang et al, 2012, Ford et al, 2014, and Fuchs et al, 2014). Final results on the combination of RAM and wPTX from the RAINBOW trial, the largest phase III trial of second-line therapy for AGC, indicated a survival of nearly 10 months in favor of the combination treatment (Wilke et al., 2014). This randomized placebo-controlled trial, which included 665 patients with disease progression on first-line platinum/fluoropyrimidine-based combination therapy, showed that the addition of RAM to wPTX significantly prolonged the primary endpoint of OS from a median of 7.4–9.6 months (HR 0.81; p = 0.017), with an absolute gain of 2.2 months. The OS curves split early, within 2 months of treatment, and remained separated beyond 1 year. Consistent benefit from the addition of RAM to wPTX was evident across all efficacy endpoints, doubling the ORR compared with wPTX alone (28% vs 16%; p = 0.0001). Globally, ramucirumab is relatively well tolerated with a toxicity rate not dissimilar to that expected in patients exposed to antiangiogenic drugs (Fuchs et al, 2014 and Wilke et al, 2014).
6.1.2. Sunitinib
Sunitinib is an oral inhibitor of multiple receptor tyrosine kinases that are involved in tumor proliferation and angiogenesis, such as platelet-derived growth factor receptor (PDGFR) and VEGFR. On the basis of preclinical evidence, suggesting a synergistic antitumor effect of docetaxel and sunitinib (DS), a Korean phase II randomized trial was designed to evaluate the efficacy and safety of this combination in patients progressed on and after fluoropyrimidines and platinum therapy (Yi et al., 2012). DS combination showed non-superiority over D monotherapy for the primary endpoint (time to progression: TTP). However, the ORR was significantly higher in the DS arm (DS vs D only arm: 41.1% vs 14.3%, p = 0.002), with one complete remission maintained over 2 years. Despite the fact that the primary endpoint was not reached, the authors concluded that DS combination according to its high response rate might be considered in the neoadjuvant setting, particularly in potentially resectable locally AGC.
Adding sunitinib 25 mg vs placebo daily for 4 consecutive weeks followed by a 2-week rest to FOLFIRI in second- or third-line, as shown from a Dutch placebo-controlled phase II trial of 91 patients, increases hematotoxicity with no improvement in primary endpoint PFS (3.6 vs. 3.3 months) (Moehler et al., 2013).
6.1.3. Apatinib
Angiogenesis inhibition seems to play an important role also in patients progressing on second-line therapy.
The first clinical evidence of efficacy of apatinib, a novel oral small molecular VEGFR2 TKI, was demonstrated by a randomized, placebo-controlled and parallel-arm phase II trial, published from Li and colleagues in 2013 (Li et al., 2013). One hundred and forty-four Chinese patients, who experienced treatment failure with two or more lines of chemotherapy, were randomized to receive placebo, apatinib 850 mg once daily or apatinib 425 mg twice daily. Primary endpoint PFS was significantly longer in patients treated with either schedule of apatinib (3.67 and 3.20 months, respectively, vs 1.40 months for placebo; HR 0.18 and 0.21, respectively; p < 0.001).
Because patients given apatinib as a 850 mg once-daily experienced fewer grade ≥3 adverse events (AEs), this dosing regimen was chosen for a subsequent randomized phase III trial, presented at the 2014 ASCO annual meeting (Qin, 2014). Two hundred and seventy patients, progressing after second-line chemotherapy, were randomized in a 2:1 ratio to apatinib or placebo. The primary endpoint mOS was met (195 vs 140 days, HR 0.71; p < 0.016). Also mPFS was prolonged (78 vs 53 days, HR 0.44; p < 0.0001) while ORR was similar between two groups (2.84% and 0.00% for apatinib and placebo, respectively). With regard to safety, apatinib was generally well tolerated showing a toxicity profile consistent with other antiangiogenic drugs (Li et al, 2013 and Qin, 2014). Apatinib is the first biological treatment given as single drug that produced survival benefit in heavily pre-treated AGC patients.
6.2. mTOR pathway
Everolimus, an oral derivative of rapamycin, targets the mammalian target of rapamycin (mTOR), a key serine/threonine kinase implicated in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which is known to be disregulated in numerous human cancers.
6.2.1. Everolimus
The aim of the "First Gastric Antitumor Trial With Everolimus", the phase III GRANITE-1 trial, was to demonstrate a benefit of everolimus 10 mg daily plus BSC over placebo plus BSC in previously treated AGC with one or two lines (Ohtsu et al., 2013). This study was designed based on encouraging findings of a phase II trial showing disease control rate (DCR) of 54.7%, PFS of 2.7 months and OS of 10.1 months (Doi et al., 2010). Unfortunately, the primary endpoint mOS was not reached (5.4 vs 4.3 months, HR 0.90; p = 0.124) in a molecularly unselected population. However, the authors highlight that, in a cross-study comparison, the mOS for everolimus arm was not dissimilar to that reported in other trials of second-line monochemotherapy (Table 1). As for PFS, even if it was significantly longer in the everolimus arm (1.7 vs 1.4 months, HR 0.66; p < 0.001), a gain of only 8 days should not be interpreted as clinically relevant. In a pre-planned stratification by number of prior chemotherapies and region of enrollment [Asia vs rest of world (ROW)], a trend toward reduced risk of death in favor of everolimus was seen in patients enrolled in ROW and, more strongly, in those who had undergone two previous chemotherapies. Biomarker analyses from GRANITE-1 trial are currently being awaited.
6.3. EGFR blockade
Human epidermal growth factor receptor (EGFR or HER1), which belongs to HER family and could play a critical role in the development of gastric cancer, has been investigated as possible molecular target in second-line therapy as well as in first-line.
6.3.1. Nimotuzumab
Nimotuzumab is a recombinant humanized monoclonal IgG1 antibody against EGFR. In a phase II trial, 82 patients from Japan and Korea refractory to 5FU-based first-line therapy were randomized to receive nimotuzumab 400 mg weekly plus irinotecan 150 mg/m2 biweekly or irinotecan alone. Primary endpoint PFS was not reached (73 vs 85 days), regardless of EGFR protein expression which was assessed in approximately half of the sample (Satoh et al., 2014a).
6.4. HER2 blockade
Up to 20% of GC patients have tumors that overexpress HER2, another member of the EGFR family, playing a key role in the oncogenesis of gastric epithelium (Hofmann et al., 2008). Most importantly, HER2 has become a predictive factor in GC to trastuzumab, a monoclonal antibody that acts by the inhibition of HER2-mediated signaling as well as by the induction of antibody-dependent cellular cytotoxicity (Hudis, 2007). Based on the ToGA trial results, trastuzumab plus chemotherapy (cisplatin and fluoropyrimidines) has been approved in the first-line setting for AGC (Bang et al., 2010). In this trial, mOS was 13.8 months for trastuzumab arm vs 11.1 months for control arm, corresponding to a 26% reduction in the death rate. More importantly, mOS was even higher for the subgroup of patients with samples that have been scored either immunochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH)+ in the trastuzumab plus chemotherapy arm (16 vs 11.8 months). However, also in HER2 gastric cancers new treatment strategies are required to overcome primary (de novo) or secondary (acquired) resistance to trastuzumab, through a better understanding of the molecular, structural and biological properties of the HER2 and/or other HER family members.
6.4.1. Trastuzumab emtansine (T-DM1)
Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate of trastuzumab and the highly potent microtubule inhibitory drug mertansine (a maytansine derivative, known also as DM1). T-DM1 monotherapy has proven to overcome resistance to trastuzumab in patients with HER2 metastatic breast cancer previously treated with trastuzumab and a taxane (Verma et al., 2012), and in a phase II trial has shown to prolong PFS by 5 months as upfront therapy versus trastuzumab and docetaxel (Hurvitz et al., 2013). A multicenter, randomized, adaptive phase II/III trial is ongoing to evaluate the efficacy and safety of T-DM1 compared to standard taxane treatment (docetaxel or paclitaxel per investigator's choice) in patients with previously-treated HER2-positive AGC (Anon., 2015b). During the first stage, the dose and schedule of T-DM1 (3.6 mg/kg every 3 weeks vs 2.4 mg/kg every week) will be selected for use in the second stage of the study. This trial is currently recruiting subjects.
6.4.2. Lapatinib
Lapatinib is a dually-potent TKI of HER2 and EGFR, blocking the EGFR/HER2-associated downstream signaling cascades. To note, a subgroup of HER2 positive tumors express p95HER2, an amino terminally truncated receptor that has kinase activity. In aberrant HER2 breast cancer cells, lapatinib was also found to be effective in overcoming the resistance to trastuzumab (Scaltriti et al., 2007). The Asian TyTAN phase III trial investigated the efficacy of second-line therapy with lapatinib in HER2 positive AGC patients (Satoh et al., 2014b); 261 patients meeting eligibility criteria were randomly assigned to receive wPTX alone (80 mg/m2 on days 1, 8, and 15 every 4 weeks) or wPTX plus lapatinib 1500 mg daily per os. In ITT population, the primary endpoint OS was not met, although a gain in median survival of more 2 months was registered (8.9 vs 11 months, HR 0.84; p = 0.1044). In a pre-specified subanalysis, the risk of death was significantly lower with lapatinib and wPTX (HR 0.59; p = 0.176) in the subgroup of patients with HER2/ICH 3+, reporting a remarkable 6.4-month advantage in mOS. Notably, few patients in each arm (∼5%) were previously treated with trastuzumab and mOS in paclitaxel monotherapy arm than in previous reports was surprisingly longer (8.9 months).
7. Discussion
After publication of the first randomized trial of second-line chemotherapy in advanced gastric cancer in 2011, we have witnessed an outburst of publications in this setting. Reasons for a such growing interest may be various: (1) a strong unmet medical need for patients with AGC after failure of a first-line chemotherapy, (2) increasing number of fit patients who may benefit from a subsequent therapy and (3) availability of new biological agents.
Patients with AGC are difficult to treat, since they are commonly symptomatic for weight loss, abdominal pain, loss of appetite, nausea and malnutrition. First-line chemotherapy has been reported to prolong survival and to improve symptom control; combinations are more active than monotherapy but complete responses to chemotherapy are rare; responses are mostly of short duration and survival is <1 year in more than half of patients (Wagner et al., 2006). There is general consensus that the benefit achieved from platinum-based first-line chemotherapy in an unselected population has reached a plateau with a response rate of about 35%, a median survival time of 10 months and a 1-year survival rate of about 40%. Given the limitations of chemotherapy and its activity plateau, we can suppose that further progress may not be reached by conventional chemotherapy alone. Actually, several attempts have been undertaken to improve outcome of standard first-line platinum-based therapy by adding new biological agents to various chemotherapy doublets and triplets. Unfortunately, with the exception of ToGA trial (Bang et al., 2010), most studies with molecular targeted agents (MTAs) have failed to improve survival (Lordick et al, 2013, Waddell et al, 2013, Ohtsu et al, 2011, Shen et al, 2015, and Hecht et al, 2013). Although some progress has been made over the last decade in systemic treatment of AGC, the majority of patients will experience disease progression during or shortly after completion of first-line therapy. On the other hand, at the time of progression, an increasing number of patients still maintain a good performance status, and therefore remain good candidates for a second-line therapy.
To our knowledge, at the time of this writing, 18 randomized controlled trials (RTCs) focusing on the role of additional treatment beyond first-line chemotherapy have been published or presented at major scientific conferences. Randomized controlled trials of salvage therapy in AGC are heterogeneous showing significant differences in design, phase (II and III), sample size, primary and secondary endpoints, patients' ethnicity and region of provenience.
Despite that, the results of these trials indicate that BSC may no longer be justified as control arm in future investigations or in clinical practice (Thuss-Patience et al, 2011, Kang et al, 2012, Ford et al, 2014, Fuchs et al, 2014, Li et al, 2013, and Qin, 2014) (Table 1 and Table 4). Second-line chemotherapy using either irinotecan or taxanes (docexatel and paclitaxel) may be recognized as standard of care for patients with AGC in both Asian and Western population, as demonstrated by single RTCs (Thuss-Patience et al, 2011, Kang et al, 2012, Ford et al, 2014, Hironaka et al, 2013, and Roy et al, 2013), Kim's meta-analysis (Kim et al., 2013) and Iacovelli's meta-analysis (Iacovelli et al., 2014). The mOS with monochemotherapy ranges from 4.0 to 10.1 months and ORRs from 0 to 40%. Monochemotherapy is able to reduce the risk of death from 27% to 36%, in Iacovelli's and Kim's meta-analysis, respectively (Iacovelli et al, 2014 and Kim et al, 2013), with a mOS ∼5 months (Tables 1, 2 and 4). By contrast, conventional polychemotherapy such as mFOLFIRI and BIRIP regimen, although well tolerated, do not improve outcomes in second-line setting, at least in Asian subjects (Sym et al, 2013 and Higuchi et al, 2014) (Table 2), whereas no data are available in Western population. Moreover, several RTCs investigating additional benefits of MTAs in second-line chemotherapy are planned or being conducted using either irinotecan or taxanes as either a platform or reference regimen (Table 4 and Table 5).
|ClinicalTrials.gov identifier
|Brief title
|Estimated primary completion date
|A study of trastuzumab emtansine versus taxane in patients with advanced gastric cancer
|Trastuzumab emtansine 3.6 mg/kg every 3 weeks vs Trastuzumab emtansine 2.4 mg/kg every week vs docetaxel or paclitaxel
|December 2016
|Paclitaxel plus raltitrexed plus compare with taxol second-line treatment for advanced gastric cancer
|Paclitaxel/Raltitrexed vs Paclitaxel
|March 2016
|Phase 3 study of nimotuzumab and irinotecan as second line with advanced or recurrent gastric and gastroesophageal junction cancer
|Irinotecan/nimotuzumab vs irinotecan
|December 2014
|Phase II trial of AUY922 vs comparators in advanced gastric cancer
|AUY922 70 mg/m2 vs docetaxel or irinotecan
|May 2012
|A phase 3 Study to Compare Efficacy and Safety of DHP107 vs Taxol® in patients with metastatic or recurrent gastric cancer after failure of first-line chemotherapy (DREAM)
|DHP107 (oral paclitaxel) vs paclitaxel
|April 2015
|A study of raltitrexed plus docetaxel versus docetaxel as second-line chemotherapy in subjects with gastric cancer
|Raltitrexed/docetaxel vs docetaxel
|Ongoing, Not Recruiting
|December 2016
|Trial of lapatinib vs lapatinib with capecitabine in Her2+ metastatic gastro-esophageal cancer (GastroLap)
|Lapatinib vs lapatinib/capecitabine
|February 2013
|A study of BBI608 plus weekly paclitaxel to treat gastric and gastro-esophageal junction cancer (BRIGHTER)
|BBI608/Paclitaxel vs paclitaxel
|August 2017
|Sorafenib trial in advanced and/or recurrent gastric adenocarcinoma: treatment evaluation (STARGATE)
|Capecitabine/cisplatin vs capecitabine/cisplatin + sorafenib
|November 2013
|A randomized, double-blind study of capecitabine plus tesetaxel vs capecitabine plus placebo as second-line therapy in subjects with gastric cancer
|Tesetaxel/capecitabine vs placebo/capecitabine
|July 2014
ORR: objective response rate; PFS: progression free survival; OS: overall survival.
Considering the relatively poor survival of these patients and the palliative intent of a second-line therapy, the choice of the best therapeutic agent is crucial. In the first-line setting, on the basis of a pooled analysis of 1080 individual patients data and of REAL2 trial, three main poor prognostic factors have been identified: PS ECOG ≥ 2, liver metastases and peritoneal carcinomatosis (Chau et al, 2004 and Cunningham et al, 2010). On the other hand, HER2 status has been recognized as a predictive response factor to first-line trastuzumab-based therapy (Bang et al., 2010). Concerning the second-line setting, differences in performance status (ECOG 0-1 vs 2), progression-free interval to the first-line chemotherapy (<3 vs ≥3 months), number and type of prior chemotherapies (platinum-based or not), ethnicity and region, drug toxicity profile and treatment schedule, and tumor biology should be taken into account in choosing the most appropriate treatment.
Univariate analyses of single RTCs show that a good PS (ECOG 0-1), a chemotherapy-free interval longer than 3 months from the first-line therapy and a lower number of prior chemotherapies may be important positive indicators for survival (Thuss-Patience et al, 2011, Kang et al, 2012, and Kim et al, 2013).
Patients that had undergone free-platinum first-line chemotherapy, if maintaining good conditions and with no comorbidities conditioning platinum delivery, could benefit from second-line platinum-based therapy as shown by comparison of polychemotherapy sequences (Guimbaud et al, 2014 and Kim et al, 2011) and the BIRIP trial (Higuchi et al., 2014).
Regional differences in prescribing post-discontinuation therapy after disease progression have been advocated to explain survival diversities, as revealed by subset analyses of the larger recent RCTs. Overall, salvage chemotherapy is more frequently prescribed for Asian people than non-Asians, even in second-line setting. In the international RAINBOW trial (Wilke et al., 2014), the lack of benefit in OS for Japanese patients seems to be related to the higher use of post-discontinuation treatment in this group than Western patients (75% vs 38%), which indeed might have diluted the potential advantage of the combination arm (Hironaka et al., 2015). Moreover, some differences seem to exist among Asian countries. In the TyTAN trial, a clinically relevant OS benefit was observed with the addition of lapatinib to paclitaxel only in HER2 positive Chinese patients, but not in the Japanese subgroup in which, paradoxically, survival was much longer with paclitaxel alone compared to the combination (Satoh et al., 2014b). Because medical insurance in China does not cover second- and third-line drugs, Chinese patients are more comparable to population of the rest of world rather than to Japanese subjects (Satoh et al., 2014b).
Indeed, we are not completely sure that differences in clinical practices and reimbursement systems among countries can encompass every explanation of this phenomenon. So, we argue that other factors, such as differences in screening strategies, ethnicity and/or tumor biology, should be taken in consideration. Thus, in the near future, both regional differences in prescribing further chemotherapy and the choice of best primary end-point (OS vs PFS) should be carefully debated in an attempt to minimize and/or avoid inconsistent results in scientific research (Takiuchi, 2011).
Gastric cancer is a heterogeneous disease which may divided into different subgroups on histological, anatomical and molecular/genetic classifications. Historically, based on histopathological Lauren classification, gastric cancer is divided in intestinal and diffuse (Lauren, 1965), while, more recently, according to distinct patterns of gene expression two major intrinsic genomic subtypes have been identified: Genomic Intestinal (G-INT) and Genomic Diffuse (G-DIF) (Tan et al., 2011). Moreover, on the basis of histological-anatomical and genetic differences three distinct subtypes have been recognized: proximal non-diffuse (type 1), diffuse (type 2) and distal non-diffuse (type 3) (Shah et al., 2011). Interestingly, in the REGARD trial, as shown from a forest plot analysis, ramucirumab markedly improved OS in patients with diffuse GC type (Fuchs et al., 2014), although this finding was not confirmed in the RAINBOW trial (Wilke et al., 2014).
So, it could be assumed that specific genetic aberrations and molecular alterations may be involved in each subtype and that novel molecular subtypes would be considered (Tay et al, 2003 and Cancer Genome Atlas Research Network, 2014). Potentially, such anomalies could provide predictive biomarkers of response to targeted therapy in experimental studies and clinical practice (Wong and Yau, 2013).
Except for HER2 overexpression/amplification, however, a few predictive biomarkers are pending validation in GC: plasma VEGF-A levels and tissue neurolipin-1 expression (Van Cutsem et al., 2012), VEGFR2 overexpression (Fuchs et al, 2014, Wilke et al, 2014, Li et al, 2013, and Qin, 2014), HGF/MET (hepatocyte growth factor/mesenchymal-epithelial transition) pathway (Iveson et al, 2014, Salgia et al, 2014, and Lennerz et al, 2011), components of PI3K-AKT-mTOR pathway (Ohtsu et al., 2013) and FGFR2 (fibroblast growth factor receptor 2) amplification (Deng et al., 2012) (Fig. 1).
To date, the most promising molecular targets for salvage treatment appear to be angiogenesis signaling and HER2 overexpression. Two novel antiangiogenic agents, ramucirumab and apatinib, have shown to significantly prolong survival in second- and third-line therapy, respectively, highlighting the role of the VEGFR2 as biomarker to targeted treatment (Fuchs et al, 2014, Wilke et al, 2014, Li et al, 2013, and Qin, 2014). Instead, lapatinib could be delivered at least to HER2 positive Chinese subjects (Satoh et al., 2014b), whereas results from T-DM1 are being anxiously awaited (Hurvitz et al., 2013) (Table 4). For other targeted agents, such as sunitinib and everolimus (Yi et al, 2012 and Moehler et al, 2013), stronger predictive biomarkers are required, whereas anti-EGFR drugs should be abandoned (Satoh et al., 2014a) (Table 4).
In clinical practice, we think that the choice of a second-line chemotherapy should be based on drug toxicity profile and patients' characteristics. Diarrhea is a common adverse reaction to CPT-11 and occurs less frequently in Asian patients than in Western patients also in second-line setting, likely because of ethnic diversity in metabolism of CPT-11 and higher doses commonly used in Western countries (Roy et al., 2013). By contrast, taxanes are more often affected by alopecia and neurotoxicity (Hironaka et al, 2013 and Roy et al, 2013). Among new active biological agents, the most common grade AE reported with either ramucirumab or apatinib was hypertension which occurred at similar rates (∼8%) to those previously described with bevacizumab in AVAGAST trial (Fuchs et al, 2014, Li et al, 2013, and Ohtsu et al, 2011). In the RAINBOW trial, grade 3 toxicity, including myelotoxicity, fatigue and hypertension, was more frequent with RAM/wPTX combination than with wPTX monotherapy, with no difference in febrile neutropenia (Wilke et al., 2014). However, higher toxicity rates of second-line treatment were counterbalanced by consistent clinical benefit in QoL (Ford et al, 2014 and Fuchs et al, 2014).
In conclusion, patients who are not refractory to a first-line chemotherapy, who have still a good PS (ECOG 0-1) and with a free-interval ≥3 months seem to be the best candidates for a further treatment. In solid tumors, the likelihood of responding to a subsequent treatment is strongly conditioned by the best response to the first-line chemotherapy and by the time interval between completion of the first-line and the beginning of a further treatment. Reintroduction of the same therapy and specifically of a platinum-based chemotherapy is more often used in clinical practice, even in AGC. It is possible to recognize three main categories of platinum-sensitive patients: "refractory" when PD occurs on treatment, "resistant" when progression-free interval is lesser than 3 months and "sensitive" when PD occurs after a long-lasting response (>3 months). Thus, for "sensitive patients", in particular those with >6 months response, the reintroduction of the same regimen could be evaluated (NCCN, 2015). Interestingly, disease progression occurred during or within 4 months after the last dose of first-line therapy for the metastatic disease was one of the key inclusion criteria in both REGARD and RAINBOW trials (Fuchs et al, 2014 and Wilke et al, 2014). The choice of a platinum derivative, at the time of rechallenge, should be based on the different toxicity profile of the platins and on their cumulative toxicity. With regard to AGC, cisplatin is more emetic, oto- and nephro-toxic, while oxaliplatin is mainly characterized by cumulative neurotoxicity (Cunningham et al., 2010). By contrast, when an intrinsic or acquired resistance to platins occurs, other potentially active agents should be considered. However, BSC cannot be accepted as gold standard anymore, except for patients with poor performance status (ECOG ≥ 3), while the effectiveness of second-line therapy for patients with ECOG PS 2 has not been sufficiently demonstrated so far. Ethnicity and region of provenience, type of previous first-line chemotherapy, possible residual neurotoxicity and drug toxicity profile, patients' desire (i.e., alopecia) and local regulatory issues (i.e., ramucirumab, apatinib) (Fig. 2), should guide us in the choice of the best drug. As for future research in this field, heterogeneity of the literature so far has not indicated a specific direction; it is not clear whether biological pathways, single biomarkers or specific clinical settings should represent the bases of the future design of second-line trials in AGC. However, we assume that the topics issued in this review could be particularly helpful in customizing medical therapy of AGC in routine daily practice in the era of tailored medicine. Finally, we are confident that simultaneous care and multidisciplinary approach are essential in management of this challenging disease and that a well-defined BSC should always be combined with anti-tumor therapy to make it more feasible.
Conflict of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
We would like to express our gratitude to IEO-CCM Foundation for supporting Dr Salvatore Galdy's research fellowship through a donation in memory of Massimo Bottini. We also thank Kimberley Davies for English editing, Russell Edu Samuel William for his help with literature research and Daniele Maffeis for scientific figures designing.
- Ajani et al., 2010 J.A. Ajani, W. Rodriguez, G. Bodoky, V. Moiseyenko, M. Lichinitser, V. Gorbunova, et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J. Clin. Oncol.. 2010;28:1547-1553 Crossref
- Al-Batran et al., 2008 S.E. Al-Batran, J.T. Hartmann, S. Probst, H. Schmalenberg, S. Hollerbach, R. Hofheinz, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J. Clin. Oncol.. 2008;26:1435-1442 Crossref
- Anon., 2015a Anon., 2015a http://www.cancerresearchuk.org/cancer-info/cancerstats/world/mortality/ last visit on 22 March 2015.
- Anon., 2015b Anon., 2015b https://clinicaltrials.gov/ct2/results?term=NCT01641939 last visit on 22 March 2015.
- Bang et al., 2010 Y.J. Bang, C. Van, E. utsem, A. Feyereislova, H.C. Chung, L. Shen, A. Sawaki, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697 Crossref
- Cancer Genome Atlas Research Network, 2014 Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202-209
- Chau et al., 2004 I. Chau, A.R. Norman, D. Cunningham, J.S. Waters, J. Oates, P.J. Ross. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer-pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J. Clin. Oncol.. 2004;22:2395-2403 Crossref
- Cunningham et al., 2010 D. Cunningham, A.F. Okines, S. Ashley. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N. Engl. J. Med.. 2010;362:858-859 Crossref
- Dank et al., 2008 M. Dank, J. Zaluski, C. Barone, V. Valvere, S. Yalcin, C. Peschel, et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann. Oncol.. 2008;19:1450-1457 Crossref
- Deng et al., 2012 N. Deng, L.K. Goh, H. Wang, K. Das, J. Tao, I.B. Tan, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 2012;61:673-684 Crossref
- Doi et al., 2010 T. Doi, K. Muro, N. Boku, Y. Yamada, T. Nishina, H. Takiuchi, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J. Clin. Oncol.. 2010;28:1904-1910 Crossref
- Ford et al., 2014 H.E. Ford, A. Marshall, J.A. Bridgewater, T. Janowitz, F.Y. Coxon, J. Wadsley, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol.. 2014;15:78-86 Crossref
- Fuchs et al., 2014 C.S. Fuchs, J. Tomasek, C.J. Yong, F. Dumitru, R. Passalacqua, C. Goswami, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31-39 Crossref
- Guimbaud et al., 2014 R. Guimbaud, C. Louvet, P. Ries, M. Ychou, E. Maillard, T. Andre, et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Federation Francophone de Cancerologie Digestive, Federation Nationale des Centres de Lutte Contre le Cancer, and Groupe Cooperateur Multidisciplinaire en Oncologie) study. J. Clin. Oncol.. 2014;32:3520-3526 Crossref
- Hecht et al., 2013 J.R. Hecht, Y. Bang, Qin Shukui, H. Chung, J. Xu, J. Park, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): the TRIO-013/LOGiC trial. J. Clin. Oncol.. 2013;31(Suppl) (abstr LBA4001)
- Higuchi et al., 2014 K. Higuchi, S. Tanabe, K. Shimada, H. Hosaka, E. Sasaki, N. Nakayama, et al. Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial). Eur. J. Cancer. 2014;50:1437-1445 Crossref
- Hironaka et al., 2013 S. Hironaka, S. Ueda, H. Yasui, T. Nishina, M. Tsuda, T. Tsumura, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J. Clin. Oncol.. 2013;31:4438-4444 Crossref
- Hironaka et al., 2015 S. Hironaka, Y. Shimada, N. Sugimoto, Y. Komatsu, T. Nishina, K. Yamaguchi, et al. RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab (RAM) plus paclitaxel (PTX) versus placebo (PL) plus PTX in the treatment of metastatic gastroesophageal junction and gastric adenocarcinoma (mGC) following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy—efficacy analysis in Japanese and Western patients. J. Clin. Oncol.. 2015;32(5s) (abstr 4005)
- Hofmann et al., 2008 M. Hofmann, O. Stoss, D. Shi, R. Buttner, van, V. de, M. ijver, W. Kim, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797-805 Crossref
- Hudis, 2007 C.A. Hudis. Trastuzumab–mechanism of action and use in clinical practice. N. Engl. J. Med.. 2007;357:39-51 Crossref
- Hurvitz et al., 2013 S.A. Hurvitz, L. Dirix, J. Kocsis, G.V. Bianchi, J. Lu, J. Vinholes, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J. Clin. Oncol.. 2013;31:1157-1163 Crossref
- Iacovelli et al., 2014 R. Iacovelli, F. Pietrantonio, A. Farcomeni, C. Maggi, A. Palazzo, F. Ricchini, et al. Chemotherapy or targeted therapy as second-line treatment of advanced gastric cancer. A systematic review and meta-analysis of published studies. PLoS One. 2014;9:e108940 Crossref
- Iveson et al., 2014 T. Iveson, R.C. Donehower, I. Davidenko, S. Tjulandin, A. Deptala, M. Harrison, et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol.. 2014;15:1007-1018 Crossref
- Jemal et al., 2011 A. Jemal, F. Bray, M.M. Center, J. Ferlay, E. Ward, D. Forman. Global cancer statistics. CA Cancer J. Clin.. 2011;61:69-90 Crossref
- Kang et al., 2009 Y.K. Kang, W.K. Kang, D.B. Shin, J. Chen, J. Xiong, J. Wang, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann. Oncol.. 2009;20:666-673 Crossref
- Kang et al., 2012 J.H. Kang, S.I. Lee, Lim, H. do, K.W. Park, S.Y. Oh, H.C. Kwon, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J. Clin. Oncol.. 2012;30:1513-1518 Crossref
- Kim et al., 2011 J.A. Kim, J. Lee, B. Han, S.H. Park, J.O. Park, Y.S. Park, et al. Docetaxel/cisplatin followed by FOLFIRI versus the reverse sequence in metastatic gastric cancer. Cancer Chemother. Pharmacol.. 2011;68:177-184 Crossref
- Kim et al., 2013 H.S. Kim, H.J. Kim, S.Y. Kim, T.Y. Kim, K.W. Lee, S.K. Baek, et al. Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis. Ann. Oncol.. 2013;24:2850-2854 Crossref
- Koizumi et al., 2008 W. Koizumi, H. Narahara, T. Hara, A. Takagane, T. Akiya, M. Takagi, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol.. 2008;9:215-221 Crossref
- Lauren, 1965 P. Lauren. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand.. 1965;64:31-49
- Lee et al., 2006 K.J. Lee, M. Inoue, T. Otani, M. Iwasaki, S. Sasazuki, S. Tsugane, et al. Gastric cancer screening and subsequent risk of gastric cancer: a large-scale population-based cohort study, with a 13-year follow-up in Japan. Int. J. Cancer. 2006;118:2315-2321 Crossref
- Lennerz et al., 2011 J.K. Lennerz, E.L. Kwak, A. Ackerman, M. Michael, S.B. Fox, K. Bergethon, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J. Clin. Oncol.. 2011;29:4803-4810 Crossref
- Li et al., 2013 J. Li, S. Qin, J. Xu, W. Guo, J. Xiong, Y. Bai, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J. Clin. Oncol.. 2013;31:3219-3225 Crossref
- Lordick et al., 2013 F. Lordick, Y.K. Kang, H.C. Chung, P. Salman, S.C. Oh, G. Bodoky, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol.. 2013;14:490-499 Crossref
- Moehler et al., 2013 M.H. Moehler, P.C. Thuss-Patience, H. Schmoll, S. Hegewisch-Becker, H. Wilke, S. Al-Batran, et al. FOLFIRI plus sunitinib versus FOLFIRI alone in advanced chemorefractory esophagogastric cancer patients: a randomized placebo-controlled multicentric AIO phase II trial. J. Clin. Oncol.. 2013;4086(Suppl) (abstr 4086)
- NCCN, 2015 NCCN, Clinical Practice Guidelines in Oncology (NCCN Guidelines) Small Lung Cell Cancer: version1.2015. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (last visit on 03 August 2015)
- Ohtsu et al., 2011 A. Ohtsu, M.A. Shah, C. Van, E. utsem, S.Y. Rha, A. Sawaki, S.R. Park, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J. Clin. Oncol.. 2011;29:3968-3976 Crossref
- Ohtsu et al., 2013 A. Ohtsu, J.A. Ajani, Y.X. Bai, Y.J. Bang, H.C. Chung, H.M. Pan, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J. Clin. Oncol.. 2013;31:3935-3943 Crossref
- Qin, 2014 S. Qin. Phase III study of apatinib in advanced gastric cancer: a randomized, double-blind, placebo-controlled trial. J. Clin. Oncol.. 2014;32(Suppl):5s (abstr 4003)
- Roy et al., 2013 A.C. Roy, S.R. Park, D. Cunningham, Y.K. Kang, Y. Chao, L.T. Chen, et al. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann. Oncol.. 2013;24:1567-1573 Crossref
- Salgia et al., 2014 R. Salgia, P. Patel, J. Bothos, W. Yu, S. Eppler, P. Hegde, et al. Phase I dose-escalation study of onartuzumab as a single agent and in combination with bevacizumab in patients with advanced solid malignancies. Clin. Cancer Res.. 2014;20:1666-1675 Crossref
- Satoh et al., 2014a T. Satoh, K.H. Lee, S.Y. Rha, Y. Sasaki, S.H. Park, Y. Komatsu, et al. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer. 2014;
- Satoh et al., 2014b T. Satoh, R.H. Xu, H.C. Chung, G.P. Sun, T. Doi, J.M. Xu, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN-a randomized, phase III study. J. Clin. Oncol.. 2014;32:2039-2049 Crossref
- Scaltriti et al., 2007 M. Scaltriti, F. Rojo, A. Ocana, J. Anido, M. Guzman, J. Cortes, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J. Natl. Cancer Inst.. 2007;99:628-638 Crossref
- Shah et al., 2011 M.A. Shah, R. Khanin, L. Tang, Y.Y. Janjigian, D.S. Klimstra, H. Gerdes, et al. Molecular classification of gastric cancer: a new paradigm. Clin. Cancer Res.. 2011;17:2693-2701 Crossref
- Shen et al., 2015 L. Shen, J. Li, J. Xu, H. Pan, G. Dai, S. Qin, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2015;18:168-176 Crossref
- Sym et al., 2013 S.J. Sym, J. Hong, J. Park, E.K. Cho, J.H. Lee, Y.H. Park, et al. A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy. Cancer Chemother. Pharmacol.. 2013;71:481-488 Crossref
- Takiuchi, 2011 H. Takiuchi. Second-line chemotherapy for gastric cancer: a new issue lies ahead in global trials. Gastric Cancer. 2011;14:206-211 Crossref
- Tan et al., 2011 I.B. Tan, T. Ivanova, K.H. Lim, C.W. Ong, N. Deng, J. Lee, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011;141:476-485 e1–11
- Tay et al., 2003 S.T. Tay, S.H. Leong, K. Yu, A. Aggarwal, S.Y. Tan, C.H. Lee, et al. A combined comparative genomic hybridization and expression microarray analysis of gastric cancer reveals novel molecular subtypes. Cancer Res.. 2003;63:3309-3316
- Thuss-Patience et al., 2011 P.C. Thuss-Patience, A. Kretzschmar, D. Bichev, T. Deist, A. Hinke, K. Breithaupt, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer—a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur. J. Cancer. 2011;47:2306-2314 Crossref
- Van Cutsem et al., 2006 E. Van Cutsem, V.M. Moiseyenko, S. Tjulandin, A. Majlis, M. Constenla, C. Boni, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. J. Clin. Oncol.. 2006;24:4991-4997 Crossref
- Van Cutsem et al., 2012 E. Van Cutsem, S. de Haas, Y.K. Kang, A. Ohtsu, N.C. Tebbutt, J. Xu Ming, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J. Clin. Oncol.. 2012;30:2119-2127 Crossref
- Verma et al., 2012 S. Verma, D. Miles, L. Gianni, I.E. Krop, M. Welslau, J. Baselga, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med.. 2012;367:1783-1791 Crossref
- Waddell et al., 2013 T. Waddell, I. Chau, D. Cunningham, D. Gonzalez, A.F. Okines, C. Okines, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol.. 2013;14:481-489 Crossref
- Wagner et al., 2006 A.D. Wagner, W. Grothe, J. Haerting, G. Kleber, A. Grothey, W.E. Fleig. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J. Clin. Oncol.. 2006;24:2903-2909 Crossref
- Webb et al., 1997 A. Webb, D. Cunningham, J.H. Scarffe, P. Harper, A. Norman, J.K. Joffe, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J. Clin. Oncol.. 1997;15:261-267
- Wilke et al., 2014 H. Wilke, K. Muro, C. Van, E. utsem, S.C. Oh, G. Bodoky, Y. Shimada, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol.. 2014;15:1224-1235 Crossref
- Wong and Yau, 2013 H. Wong, T. Yau. Molecular targeted therapies in advanced gastric cancer: does tumor histology matter?. Ther. Adv. Gastroenterol.. 2013;6:15-31 Crossref
- Yi et al., 2012 J.H. Yi, J. Lee, J. Lee, S.H. Park, J.O. Park, D.S. Yim, et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br. J. Cancer. 2012;106:1469-1474 Crossref
SalvatoreGaldy achieved his graduation in Medicine in October 2004 at University of Parma (Italy) and completed its training in Medical Oncology in November 2008. He is working currently as a research fellow at the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of European Institute of Oncology (IEO) in Milan (Italy), where he is involved in clinical research projects mainly in the field of upper gastrointestinal cancer.
ChiaraAlessandraCella graduated from Faculty of Medicine at University of Naples Federico II (Italy) in September 2008 and obtained post-graduate degree in Medical Oncology in November 2014. She is working currently as a research fellow at the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of IEO.
FrancescaSpada graduated in Medicine at University of Cagliari (Italy) in July 2004. She was involved in Regional Emergency Medical Services and completed her training in Medical Oncology at University of Sassari (Italy) in July 2011. Since 2011, she has been dealing with clinical practice and research activity in the field of neuroendocrine and gastrointestinal tumors at the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of IEO, where she is currently working.
SabinaMurgioni is a trainee in Medical Oncology at University of Cagliari (Italy), with graduation in Medicine achieved in December 2007. Since November 2014, she has started a scientific collaboration with Dr Nicola Fazio at the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of IEO, where she is currently attending.
AnnaMariaFrezza graduated in 2009 and is a trainee in Medical Oncology at University Campus Bio-Medico (Rome). During the years, she developed an interest in the field or rare cancers and she is currently attending the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors at IEO as a research fellow.
PaolaSimonaRavenda earned her medical degree in 2005 from University of Medicine in Messina (Italy) and completed her training in Medical Oncology in 2011 at the University of Pavia (Italy). In 2010 she attended Medical Oncology department at the Moffitt Cancer Center in Tampa (FL, USA) and, in 2011, at the Memorial Sloan Kettering Cancer Center in New York City (NY, USA). Since 2012, she has been working as medical oncologist at IEO within the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors.
MariaGiuliaZampino is deputy Director of the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors at IEO. She is actively part of a multidisciplinary team dedicated to gastrointestinal tumors, and focused on the management and research in the topic of lower gastrointestinal tract cancers.
NicolaFazio, consultant in Internal Medicine and Medical Oncology with PhD in Digestive Oncology, has been leading the Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors at IEO since July 2011. With more than 80 scientific publications in peer reviewed journals, he is a member of all the main national and international oncological societies and he is recognized as opinion leader in neuroendocrine tumors management.
Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
⁎ Corresponding author. Fax: +39 0294379273.
Article information
DOI: 10.1016/j.critrevonc.2015.09.004
© 2015 Elsevier Ireland Ltd, All rights reserved.


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Jon Fischer is the new Managing Director of MGNdirect™ announced today by Gill Davis, Founder, and CEO of MGN Online. "With his diversified professional history in the News Business, we are all very excited to have Jon join the Team at MGN." Jon has served in multiple positions over the past 25 years including, News Director, Executive Producer, News Consultant and Educator. Most recently, Jon was owner of his own firm, Fischer Media Consulting, an Internet, Broadcast consulting firm.
"Jon's complete knowledge of the News business, allows him to recognize the importance of Quality Services and Products that are continuing to evolve in today's fast paced technology-centric news operations. I believe that as the Managing Director for MGNdirect, his experience will provide a balanced view and understanding of the importance of aligning our Affiliate News Departments with opportunities to partner with the best and most affordable Companies," said Gill Davis.
Before Fischer Media, Jon brought his skills and expertise to several news departments around the country as News Director for WFTC-TV in Minneapolis, KTVX-TV in Salt Lake City, KMIR-TV in Palm Springs and XETV-TV in San Diego. He was also an Assistant News Director at KTLA successfully positioning the "KTLA Morning News" and "News at Ten" as #1 in Southern California. Jon's employment at KCOP, as Assistant News Director, he was placed in charge of the build out of the station's "new" News department. He has received numerous commendations for coverage of live and breaking news stories, including several Emmys, Golden Mikes, UPI, AP and Los Angeles Press Club Awards. Jon was a Board Member of Radio Television News Association and NATAS-Upper Midwest Chapter.
Jon has taught Journalism at UCLA and been a guest speaker at USC, BYU, and the College of the Desert. As a second-generation broadcaster, Jon's father George Fisher was a broadcast pioneer and has a star on the Hollywood Walk of Fame.
About MGN Online
America's premier resource for still and animated graphics, MGN Online has a wide-ranging client roster of affiliates extending across television, online and print media. MGN Online serves newscasts, webcasts, newspapers, web radio and other news and information services 24/7 through its innovative content creation, storage, and distribution facilities. MGN Online is a division of Multimedia Graphic Network Inc., founded in 1982 and based in Cardiff by the Sea, California.
Original Source: https://www.newswire.com/news/award-winning-jon-fischer-joins-mgn-online-as-managing-director-of-19613815

subset: commoncrawl


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Credit cards served me spending budget, vacation, and rebuild my credit score.
I know that it might appear strange for someone who fought with credit card debt for many years to state that credit cards could be helpful. You may even think that it's mad or unfounded. As I've gotten older (and hopefully wiser), I have learned even more the way we develop and learn.
With several years of shrewd monetary living under my belt, I now see that credit cards can be an extremely handy instrument on your financial arsenal -- should you use them sensibly. In reality, I think credit cards may even be helpful for your financial plan. Consider some of these reasons why.
Charge Cards Permit You to Use Money On Different Matters
Maybe my favourite thing about using credit cards will be the benefits you can make. My spouse and I really like to utilize travel rewards credit cards to finance our journey dependence.
Some others use comparable travel hacks also it lets you allocate the money you would normally spend on traveling expenses to various regions of your financial plan. It is a triumph in my view.
Charge cards as a means to repay debt? It is quite correct. If you use money back credit cards wisely you can find the money back and use the money to any type of debt.
It is not. 1 blogger recently wrote about the way he and his wife used the sign-on incentive of 2 credit cards for $1,100 in money back plus they implemented it directly to their own student loan obligations.
That is money they otherwise wouldn't have experienced. It is money they got in their regular everyday spending to use towards debt. It might sound absurd, but I feel it is a good example of thinking outside the box also can be helping them kill their student loan debt.
Charge Cards Help You Build Your credit score
Nobody will assert that the credit rating system is ideal.
Enhancing your credit rating has numerous advantages that could aid your financial plan. A fantastic credit rating can lead to anything from a much better rate on car insurance without a deposit when registering for new mobile phone service to greater rates when you take out a mortgage or personal loan. All of these will have an immediate, positive effect on your financial plan.
While I think credit cards may be beneficial for your finances, I am the first one to mention they are not for everybody. In case you have consumer debt or even a spending problem, a brand new credit card would be the very last thing you ought to receive.
No free excursion or money back is well worth the capacity of new debt. Furthermore, if you are feeling a charge card would induce you to go down a street you would rather not traveling, then you need to probably look elsewhere. Credit cards can be a essential tool on your fiscal arsenal. When used sensibly they can extend your budget and offer many perks.


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MIMI TRAN Autumn/Winter 2015
Posted on
Feminine shapes and powerful colours and lines defined the Mimi Tran show at Fashion Scout 2015. We loved the hourglass silhouettes and perilously long hemlines, as well as the boldly glamorous colour choices, from vibrant violet to a scandalous red. This was power dressing for the ultra female – no straight cut lines and all-encompassing navy here. Peplums and shoulder pads, sheers, contemporary cut outs and draping all featured in the looks, balancing the modern with the more traditional, and there was intricate beading on just about every outfit that strutted down the catwalk. The show closed with the traditional wedding gown, sheer, crystal embellished and dramatic.


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Jimmy Sheirgill
Jimmy Sheirgill has joined the bandwagon of Bollywood folk venturing into short films. He features in Papa We Love U Too, directed by Kabir Sadanand.
"The film is an ode to the most underrated relationship in a family, that of a father and son," says Sadanand. The film's cast includes veteran director Lekh Tandon and Kabir's son Arya as the child artiste.
Trending Video
Shocking! Ram Gopal Varma shares 'vulgar' photo of Sania Mirza
Download the new mid-day android app to get updates on all the latest and trending stories on the go https://goo.gl/8Xlcvr


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Plenty of Fish also known as POF.com is initially, a free online dating web site that can easily be upgraded to premium services. This company is based in Vancouver BC and is very popular in Canada, but is available in other countries as well to include the United States. The site has been featured on the cover of many popular magazines, news publications and in many celebrity videos. Create an account and begin communicating with other singles on PC or mobile device,who are registered on the web site, free of charge.
How To Login
Step 1 – Go to POF.com or type POF.com into your brower
Step 2 – Once you've reached the homepage, in the top right corner you will find a user sign in box where you will place your username and password then click "check mail" to gain access to the site
Forgot Password – You may go to Retrieve Login Information from this link or if you're on the site and would like to use the link on the site, while you're logged into the homepage, scroll to the bottom of the page and go to the Help Center – scroll down to Security and select the link "retrieve login information" from that location. You will find information to assist in retrieving your password.
Mobile Login
If you would like to login to POF from a mobile device, simply download one of the apps available for your device. You may find these device downloads on the POF Website by going to the Help Center and scrolling down the categories and links on the left of the page to "Mobile"- There you will be able to acquire apps for the POF supported devices.
Mobile Applications
POF.com has mobile apps that support the following mobile devices:
Once you have downloaded the appropriate app for your particular device you may log in with your username and password, click "check mail" and you will be logged into your account from your mobile device
How To Register
Plenty of Fish makes it easy to register and get started with the service.
Step 1 – Simply go to POF.com
Step 2- When you arrive at the homepage, look to the far upper right corner in the black POF bar, click Register
Step 3 – Provide the following information
- Create a Username
- Create a Password
- Confirm Password
- Gender (select one from the drop down box)
- Birthday- Select month/day/year from the drop down boxes for each
- Country (select your country from the drop down box)
- Ethnicity (select from the drop down box
Step 4 – Human Verification and Terms Agreement
- Enter, into the text box only the letters that are under the circles in the picture
- Review the terms and conditions then click the box to agree. You must agree to the terms in order to become a member of Plenty of Fish.
- Click the "continue" button at the bottom of the page
Step 5 – After you click continue, all of your information will be protected and secured. Simply follow all of the prompts by completing information and clicking "continue" until your registration is complete


text: Graduates will acquire basic knowledge of economics and management in a range of subjects included in the degree course according to the curriculum. Their skills will be extended by knowledge in project management, application of quantitative methods for problem solving and practical orientation in terms of organizations. The tuition of foreign languages is also beneficial for the graduates when searching for jobs in the labour market.


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Nokia Networks is buying infrastructure provider SAC Wireless for an undisclosed amount.
SAC, headquartered in Schaumburg, Illinois, provides infrastructure and network deployment services. The company's services include managing site development, architectural, engineering, regulatory and compliance activities for national networks, plus implementing indoor and outdoor small cells and distributed antenna systems.
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- Days: Thu, Fri, Sat
- City: Monterey
- Time: 10:00 PM
- Facility: Monterey Fellowship Hall
- Location: 519 Hartnell (near Monterey post office, rear of bldg, lower level)
This meeting adheres to standard A.A. format (either speaker or topic discussion as voted upon in the beginning of each meeting). Meeting is one hour long, ending at 11 PM, with a 5 minute limit allowed for shares in order to give everyone a chance to speak. The lights are dimmed after reading of A.A. literature to create a comfortable ambiance for sharing.
The Monterey Fellowship Hall faces the parking lot of Trader Joe's and Peet's Coffee. The parking lot can be accessed from either 519 Hartnell Street or 560 Munras Ave. From Hartnell Street look for the "Carl's Alley" street sign and take the alley down to the parking lot. The meeting room is on the ground floor of the two story building, where the alley meets the parking lot.


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its 5am and i've been running on empty fore 8 hours.
been eating chips and feeling gay
its 5am and i've been running on empty fore 8 hours.
been eating chips and feeling gay
Okay kiddies, I'm gonna teach you how to get rid of bedbugs today, bc I feel like I'm qualified to do that.
Step 1) figure out if you have bedbugs. Have you been getting a lot of random bug bites lately? does the side of your bed look like this?
congrats! You have bed bugs!
Step 2) Clean EVERYTHING! Literally everything! Wash ALL OF YOUR CLOTHING AND SHEETS on hot! ALL OF THEM! EVEN IF THEY WERE CLEAN! Empty out your drawers and wash the insides! Wipe off the bottom side of your desk! Bedbugs like wood and they will ruin your wood stuff, so do this really really well!
Step 3) Spray your furniture! You can use bedbug spray or just rubbing alcohol, but do that! I personally use both! Spray your furniture and move it out of your room when it's done drying! Make sure to get the bottom of your box spring and your mattress!
Step 4) vacuum
Step 5) spray your floor and let it dry then vacuum again!
Step 6) wrap your box spring in plastic and tape all the sides shut! This will make sure that any bugs in there can't get out and will die from lack of nutrition and that no bedbugs can get in. Wrap your mattress too, if you can't drop the cash on a bedbug cover atm. If you can, though, do that! Much quieter than plastic.
Step 7) Put everything back and then vacuum one last time!
Final step) Spray behind your furniture and stuff every week, you don't need to move everything out, but spray against the baseboards and floors and vacuum and junk. Spray more than once a week if the idea of bedbugs makes your skin crawl! Do that until you are 100% sure you have no more bedbugs and then add another month bc they're sneaky.
*note*: I am a child and junk and my family has been fighting bedbugs for the past 2 years and it sucks yo! do this as soon as you think you might have them or even if you want to make sure you don't bc they suck so hard.
TPoH music time!
Considering I let slip about RGB actually singing this at some point in the faraway future (hopefully far enough for you to forget before we get there dohoho), I figure it's only reasonable to add this one to the mix.


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Western Carolina University physiology major
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Find info concerning Western Carolina University physiology major, and registering for discussion sections. Which college degrees give you the best chances of finding employment after graduation? You can enter nursing with either an associates degree or BSN. As a licensed vocational nurse (LVN), you may provide patient care under the supervision of a registered nurse (RN). Concentrating on Western Carolina University physiology major, for example, you may gain an advantage in job recruiting on-campus. Check with the human anatomy department for course registration deadlines, and anatomy and physiology program requirements. Please use the form above to request admissions info for Western Carolina University.
Biology is one of the original natural sciences, even reaching back as far as the study of anatomy in ancient Egypt, where evidence has been found of surgery, forensics, and anatomical knowledge of both organ structure and function. Biology in general is the study of life and living organisms, with specific attention to function, growth, evolution, identification and taxonomy. Modern biology is becoming an interdisciplinary field, overlapping with biomedical engineering, molecular chemistry, and genetics. The biological sciences recognize the cell as the basic unit of life, and DNA as the basic unit of heredity. Moreover, all organisms survive by consuming and transforming energy via respiration or photosynthesis, and by regulating their internal environment via homeostasis.
The life sciences are defined by the scale at which organisms are studied, in that biochemistry focuses on chemical processes of life while molecular biology involves molecules and protein synthesis. Cellular biology may be broken down further into a structural analysis of cell organelles and lipid membrane boundries, such as in skin tissue or alveolar sacs in the lungs. In the field of genetic engineering, DNA (deoxyribonucleic acid) may be spliced together from different organisms, in an attempt to transfer hereditary traits that may increase crop yields, create a supply of stem-cells, or even clone sheep. Beyond major requirements within the human anatomy department, you may consider Gordon College nursing informatics as a complementary elective to your primary course of study.
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|image source
When I first started this blog we had just decided to move to Alaska. In fact, I had been toying with the idea of blogging for awhile and had nearly started one titled 'YacoltMama'. Things moved quickly that summer though, and before I knew it I was applying for a leave of absence, packing up a house, and moving my family 2500 miles away. In the midst of all of this I started blogging to share our adventure as we embarked on this journey to a new life in Whittier.
As we settled in here, I became a more regular poster. I worked out the kinks in my formatting, learned how to manipulate templates a bit more, and tried lots of different things. For awhile I posted recipes that I was trying every week. I kept the focus on our life here, our kids, and our adventures. Then I axed the recipes in favor of the {this moment} posts and somewhere in there I began to realize that although I rarely post about myself this blog really chronicles my journey as a parent. We are always evolving and changing--and my outlook on parenting as evolved with me. I blog because I want to remember these moments. I try to live very intentionally--I try to choose my reactions to those moments in motherhood where you can smile or scream--I try to live my days calmly, focusing on the positive and with patience. It doesn't always work out the way I envision it--my kids bicker, make horrific messes, get on my nerves, and drive me completely batty some days. But I try.
I believe this blog is about all of us--it tells the story of how we spend our days, the highlights of our lives. But if you read between the lines it also tells the story of me. How I try to stay on top of things but don't always succeed. How I try to balance being a mama, a wife, a friend, and me. How I spend those precious moments with my kids, and how I spend those moments by myself. How much I love my life, my family, my friends, and our Alaskan experience.
So thank you friends! Thanks for being a part of my journey. I appreciate the fact that you pop by here occasionally to read what I write. I hope you enjoy reading it as much as I enjoy posting it!


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A team of solar physicists from the Bay Area Environmental Research Institute, University of Oslo and Lockheed Martin Solar and Astrophysics Laboratory has built a model that accurately explains the formation of spicules — small jets of plasma lasting a few minutes that form in the solar chromosphere. The research is published in the journal Science.
In the lower solar atmosphere, the chromosphere is permeated by violently driven jets called spicules.
Spicules occur thousands of times per day, erupt as fast as 60 miles per second, and can reach lengths of 6,000 miles before collapsing.
Their origin is poorly understood, although they are expected to play a role in heating the million-degree corona and are associated with so-called Alfvén waves, a strong kind of magnetic wave solar scientists suspect is key to heating the Sun's atmosphere and propelling the solar wind.
To better grasp how spicules form, Dr. Juan Martínez-Sykora, a solar physicist at Lockheed Martin and the Bay Area Environmental Research Institute, and co-authors used state-of-the-art numerical models to develop simulations that spontaneously produced numerous spicules.
"The model began with a basic understanding of how plasma moves in the Sun's atmosphere. Constant convection, or boiling, of material throughout the sun generates islands of tangled magnetic fields," the researchers said.
"When boiling carries them up to the surface and farther into the Sun's lower atmosphere, magnetic field lines rapidly snap back into place to resolve the tension, expelling plasma and energy."
"Out of this violence, a spicule is born. But explaining how these complex magnetic knots rise and snap was the tricky part."
"Usually magnetic fields are tightly coupled to charged particles," Dr. Martínez-Sykora said.
"With only charged particles in the model, the magnetic fields were stuck, and couldn't rise beyond the Sun's surface. When we added neutrals, the magnetic fields could move more freely."
"Neutral particles provide the buoyancy the gnarled knots of magnetic energy need to rise through the Sun's boiling plasma and reach the chromosphere. There, they snap into spicules, releasing both plasma and energy. Friction between ions and neutral particles heats the plasma even more, both in and around the spicules."
The team's model revealed something else about how energy moves in the solar atmosphere: it turns out this whip-like process also naturally generates Alfvén waves.
The scientists found that the properties of their simulations matched observations of real spicules by NASA's Interface Region Imaging Spectrograph (IRIS) and the Swedish 1-m Solar Telescope in La Palma, the Canary Islands.
"Numerical models and observations go hand in hand in our research," said co-author Dr. Bart De Pontieu, a researcher at Lockheed Martin Solar and Astrophysics Laboratory.
The simulations indicate spicules could play a big role in energizing the Sun's atmosphere, by constantly forcing plasma out and generating so many Alfvén waves across the Sun's entire surface.
"This is a major advance in our understanding of what processes can energize the solar atmosphere, and lays the foundation for investigations with even more detail to determine how big of a role spicules play," said IRIS mission scientist Dr. Adrian Daw, from NASA's Goddard Space Flight Center.
"A very nice result on the eve of our launch anniversary."
J. Martínez-Sykora et al. 2017. On the generation of solar spicules and Alfvénic waves. Science 356 (6344): 1269-1272; doi: 10.1126/science.aah5412


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KLA-Tencor Corp. (KLAC) Shares Gap Up to $67.52
Shares of KLA-Tencor Corp. (NASDAQ:KLAC) gapped up prior to trading on Monday . The stock had previously closed at $66.86, but opened at $67.52. KLA-Tencor Corp. shares last traded at $68.85, with a volume of 1,085,067 shares changing hands.
A number of analysts recently issued reports on the company. Cowen and Company raised KLA-Tencor Corp. from a "market perform" rating to an "outperform" rating and lifted their target price for the company from $79.00 to $80.00 in a research report on Monday. They noted that the move was a valuation call. JPMorgan Chase & Co. reissued a "buy" rating on shares of KLA-Tencor Corp. in a research report on Wednesday, August 17th. Susquehanna reissued a "neutral" rating on shares of KLA-Tencor Corp. in a research report on Saturday, August 13th. Zacks Investment Research raised KLA-Tencor Corp. from a "sell" rating to a "hold" rating in a research report on Tuesday, August 9th. Finally, B. Riley reissued a "neutral" rating and set a $78.00 price target on shares of KLA-Tencor Corp. in a research report on Tuesday, August 2nd. Eleven investment analysts have rated the stock with a hold rating and three have given a buy rating to the company's stock. The company presently has a consensus rating of "Hold" and a consensus price target of $73.46.
The stock's 50 day moving average is $73.34 and its 200 day moving average is $71.44. The company has a market capitalization of $10.72 billion and a price-to-earnings ratio of 15.31.
KLA-Tencor Corp. (NASDAQ:KLAC) last posted its quarterly earnings data on Thursday, July 28th. The company reported $1.77 earnings per share for the quarter, topping the Zacks' consensus estimate of $1.42 by $0.35. During the same quarter in the prior year, the company posted $0.99 earnings per share. The company had revenue of $919.17 million for the quarter, compared to analyst estimates of $842.10 million. The business's revenue was up 21.5% on a year-over-year basis. On average, equities analysts predict that KLA-Tencor Corp. will post $4.80 EPS for the current year.
The business also recently disclosed a quarterly dividend, which will be paid on Thursday, September 1st. Shareholders of record on Monday, August 15th will be given a dividend of $0.52 per share. This represents a $2.08 dividend on an annualized basis and a yield of 3.03%. The ex-dividend date is Thursday, August 11th.
In other KLA-Tencor Corp. news, CFO Bren D. Higgins sold 363 shares of the company's stock in a transaction on Tuesday, July 5th. The shares were sold at an average price of $72.23, for a total transaction of $26,219.49. The transaction was disclosed in a legal filing with the Securities & Exchange Commission, which can be accessed through this link.
A hedge fund recently raised its stake in KLA-Tencor Corp. stock. Principal Financial Group Inc. increased its position in KLA-Tencor Corp. (NASDAQ:KLAC) by 1.4% during the fourth quarter, according to its most recent disclosure with the SEC. The fund owned 227,019 shares of the company's stock after buying an additional 3,106 shares during the period. Principal Financial Group Inc. owned approximately 0.15% of KLA-Tencor Corp. worth $15,743,000 as of its most recent SEC filing.
KLA-Tencor Corporation is a supplier of process control and yield management solutions for the semiconductor and related nanoelectronics industries. The Company's products are also used in various other industries, including the light emitting diode (LED) and data storage industries, as well as general materials research.
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