Systemic therapy beyond first-line in advanced gastric cancer: An overview of the main randomized clinical trials
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.
References (60)
- 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) - 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) - et al.
Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial
Lancet Oncol.
(2014) - 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) - 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) - 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) - 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) - et al.
Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis
Ann. Oncol.
(2013) - 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) - 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)
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.
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
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.
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.
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.
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.
Comprehensive molecular characterization of gastric adenocarcinoma
Nature
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.
Capecitabine and oxaliplatin for advanced esophagogastric cancer
N. Engl. J. Med.
A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets
Gut
Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer
J. Clin. Oncol.
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.
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.
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.
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.
Assessment of a HER2 scoring system for gastric cancer: results from a validation study
Histopathology
Trastuzumab–mechanism of action and use in clinical practice
N. Engl. J. Med.
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.
Cited by (20)
Cancer nanotheranostics: A review of the role of conjugated ligands for overexpressed receptors
2017, European Journal of Pharmaceutical SciencesCitation Excerpt :This was ascribed to the higher cellular internalization of this combination compared to the other two antibodies and their greater EGFR degradation (Fukuoka et al., 2016). Recently it has been found that the most promising molecules for salvage treatment are through angiogenesis signaling (Galdy et al., 2016). It was found that in early embryogenesis, the signal transduction systems responsible for oxygenation and nutrients supply develop via vasculogenesis and angiogenesis (Flamme et al., 1997; Shibuya and Claesson-Welsh, 2006).
Characteristics of the Immune Cell Infiltration Landscape in Gastric Cancer to Assistant Immunotherapy
2022, Frontiers in GeneticsImmunological impact of chemotherapy on the tumor microenvironment in gastric cancer
2021, Journal of Surgical OncologyHypoxia Signaling in Cancer: From Basics to Clinical Practice
2021, Pathology and Oncology ResearchSalvage systemic therapy for advanced gastric and oesophago-gastric junction adenocarcinoma
2020, Cochrane Database of Systematic Reviews
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.