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This meta-analysis provides high quality evidence that second-line chemotherapy with supportive care can boost survival by about two months. In the three trials included, two types of chemotherapy were investigated for people with recurrent gastric cancers and compared to supportive care alone.
Not all patients benefited from chemotherapy – over a third did not live longer or suffered side effects. A number of predictive factors were assessed that could be used for deciding which patients are most likely to benefit from second-line chemotherapy. These included the time it took for the disease to progress or relapse after first-line chemotherapy and the stage of disease at diagnosis. Health related quality of life was assessed in one of the included trials and could be measured in future trials to ensure that any increased survival is not at the expense of reduced quality of life. NICE do not currently recommend any second-line chemotherapy in this situation but are due to update their gastric cancer guidance in 2018.
Why was this study needed?
Stomach and oesophageal cancers are some of the common cancers worldwide, ranking as fourth and seventh respectively. In 2011, about 8300 people were diagnosed with oesophageal cancer and 7100 people diagnosed with the gastric cancer in the UK. Over the last couple of decades, there has been an annual increase in the number of people with these cancers in the UK. This is possibly related to the effect of chronic gastro-oesophageal reflux disease and the increase in obesity, both known to be linked to these cancers.
After first-line combination treatment including surgery and chemotherapy, the cancer returns in most patients and disease progression can be rapid. The proportion of people surviving ten years after diagnosis of a gastric cancer in the UK is 15%, and currently only about 30% of people who could receive second line therapy do receive it.
This systematic review and meta-analysis aimed to find out whether second-line chemotherapy for people with recurrent cancer in addition to supportive care prolongs survival.
What did this study do?
This systematic review included all three completed trials that investigated the effect of second-line chemotherapy and supportive care compared with supportive care alone on overall survival in people with stomach, gastroesophageal and oesophageal cancers. Supportive care was specialised nurse-led advanced care. The cancers were all of a type known as adenocarcinoma, one that is known to respond to chemotherapy.
One of the trials was conducted in the UK, the other two in Germany and South Korea. A total of 410 patients participated in these trials and just over half of them, 238, received one of two chemotherapy drugs, docetaxel or irinotecan, both widely used in the UK, in addition to supportive care. The other 172 people received supportive care alone.
A meta-analysis of patient-level data was performed, where data from all trials were pooled. The lead researchers of the three included trials were co-authors of this review and they could provide comprehensive data from the original trials. The review excluded studies with high risk of bias, such as non-randomised trials, retrospective analysis, case series and case reports, so the results of the meta-analysis are likely to be more reliable.
What did it find?
- The increased average survival was about two months (range 1.6 to 2.6 months) with chemotherapy and supportive care compared with supportive care alone.
- Chemotherapy and supportive care significantly reduced the risk of death in people with recurrent gastric cancers compared with supportive care alone (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.51 to 0.77).
- This effect was confirmed for chemotherapy with docetaxel in 154 patients (HR 0.71, 95% CI 0.56 to 0.89) as well as for chemotherapy with irinotecan in 84 patients (HR 0.49, 95% CI 0.36 to 0.67).
- People who survived between three to six months after their first chemotherapy without getting worse tended to have more benefit from second-line treatment (HR for overall survival 0.39, 95% CI 0.26 to 0.59) compared with people whose cancer progressed earlier.
- Not all patients benefited from chemotherapy, for example 24% received further chemotherapy and 10% suffered side effects, which led to them stopping therapy.
What does current guidance say on this issue?
The NICE guideline on stomach and oesophageal cancer is currently in development and will be published in 2018.
The 2011 British Society of Gastroenterology guidelines for the management of oesophageal and gastric cancer state that second-line chemotherapy with irinotecan resulted in small survival benefit over best supportive care for gastric adenocarcinoma.
The 2013 European Society for Medical Oncology, the European Society of Surgical Oncology and the European Society of Radiotherapy and Oncology guidelines on gastric cancer discuss the evidence about second-line therapy and recommend considering patients for clinical trials.
What are the implications?
This meta-analysis supports second-line chemotherapy for advanced gastric cancers. However the disease control rate is just above 40%, and 10% of those enrolled stopped treatment because of side effects.
This means that almost half of patients do not benefit from second-line chemotherapy or suffer from a chemotherapy toxic effect. This is the reason that the authors looked at a number of prognostic factors including time to progression after first-line chemotherapy and disease stage to help decide which patients are most likely to benefit from second-line chemotherapy.
The finding that the longer the time without progression was the better a response is likely to be helpful for those deciding whether to accept more chemotherapy.
Quality of life is an important consideration for people taking chemotherapy at this stage of their disease and was only assessed in one of the trials. As this is a major factor in deciding whether or not to consider a treatment, this limits the implications for clinical practice and the ability to translate the findings into information supporting choice for patients with this disease. These kinds of factors will be taken into account by NICE, together with any newer evidence which might be available in the next few years as it develops clinical guidelines.
Citation and Funding
Janowitz T, Thuss-Patience P, Marshall A, et al. Chemotherapy vs supportive care alone for relapsed gastric, gastroesophageal junction, and oesophageal adenocarcinoma: a meta-analysis of patient-level data. Br J Cancer. 2016;114(4):381-7.
Authors Tobias Janowitz (RJAG/076) and Claire Connell were supported by the Wellcome Trust Translational Medicine and Therapeutics programme and the National Institute for Health Research.
Bibliography
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Ford H, Gounaris I. Docetaxel and its potential in the treatment of refractory esophagogastric adenocarcinoma. Therap Adv Gastroenterol. 2015;8(4):189-205.
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NICE. Oesophago-gastric cancer. NICE guidance in development. [GID-CGWAVE0801]. London: National Institute for Health and Care Excellence; 2016.
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