Systemic therapy beyond first-line in advanced gastric cancer: An overview of the main randomized clinical trials

https://doi.org/10.1016/j.critrevonc.2015.09.004Get rights and content

Highlights

  • 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.

Abstract

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.

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, 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, 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, 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).

Section snippets

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).

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

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

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).

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.

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).

In a phase III Korean trial by Kim

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).

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

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.

Acknowledgement

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.

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.

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    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.

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