What is advanced stomach cancer?
Gastric (stomach) cancer usually begins in the mucous-producing cells lining the stomach. Oesophago-gastric junction (OGJ) cancer starts where the food pipe (oesophagus) joins the stomach. Advanced cancer is cancer that has spread to nearby tissues, or to another part of the body, despite treatment.
Treatments for gastric and OGJ cancer include:
• operation to remove the cancer;
• chemotherapy (medicines that kill cancer cells);
• radiotherapy (radiation to kill cancer cells); and
• biological therapy (medicines made from proteins and other substances that occur naturally in the body).
Biological therapies include immunotherapy (medicines that help the immune system to recognise and kill cancer cells) and therapies that target something in, or surrounding, the cancer, such as the cancer's blood supply. Standard chemotherapy usually combines two medicines containing fluoropyrimidine and platinum.
When standard chemotherapy for advanced cancer has not worked, further treatment aims to slow the growth of the cancer to help people live longer. Further treatments include: other chemotherapy medicines, biological therapies, and best supportive care (care that helps a person cope with life-limiting illness and its treatment).
Why we did this Cochrane Review
Stomach and OGJ cancer are difficult to treat. We wanted to find out which treatments work best to control these cancers and help people live longer, when standard chemotherapy has not worked.
What did we do?
We searched for studies that looked at chemotherapy and/or biological therapies for advanced stomach or OGJ cancer that had not responded to standard chemotherapy. We looked for studies in which the treatment each person received was decided at random. These studies usually give the most reliable evidence about the effects of treatments.
We included evidence published up to October 2020.
What we found
We found 17 studies in 5110 people with advanced stomach or OGJ cancer. Studies compared further chemotherapy and/or biological therapies, given by mouth or through the bloodstream (systemic), with:
• another systemic chemotherapy and/or biological therapy;
• a placebo ('dummy' treatment);
• best supportive care; and
• no treatment.
The studies looked at:
• how long people lived;
• any adverse (unwanted) effects; and
• their quality of life (well-being).
What are the results of our review?
People probably live longer after further chemotherapy (irinotecan or trifluridine plus tipiracil) than with placebo treatment or best supportive care. But chemotherapy probably increases serious unwanted effects, including diarrhoea, fever, and lower numbers of red and white blood cells.
People may live as long after irinotecan chemotherapy as after paclitaxel chemotherapy. Adding another chemotherapy (oxaliplatin or cisplatin) to docetaxel may not affect how long people live.
People live longer after biological therapy (nivolumab, apatinib or regorafenib) than with placebo treatment. We did not find enough evidence about whether biological therapy increases unwanted effects.
People given immunotherapy (pembrolizumab) probably live as long as people given chemotherapy (paclitaxel), but may not have as many unwanted effects as with chemotherapy.
Combining chemotherapy with biological therapy probably does not help people live longer than chemotherapy alone, and we are uncertain whether it increases unwanted effects.
How reliable are these results?
We are moderately confident that chemotherapy probably helps people to live longer than placebo treatment or best supportive care. We are confident that people live longer on biological therapy than placebo treatment. We think more evidence is unlikely to change this result.
We are less confident about the results for unwanted effects. Some studies had missing data or did not report these; and in some studies people and their doctors knew which treatment was given, which could have affected the study results. These results are likely to change when more evidence becomes available.
If advanced stomach or OGJ cancer has not responded to standard chemotherapy, further chemotherapy or biological therapy help people to live longer than placebo treatment, best supportive care, or no treatment. However, chemotherapy is more clearly associated with unwanted effects than biological therapy.
We are unsure if biological therapies work better than chemotherapy, but they may cause fewer unwanted effects. Combining chemotherapy and biological therapies may cause more unwanted effects without giving any extra benefit.
Survival outcome of patients with advanced gastric and OGJ adenocarcinoma whose disease progressed on first-line fluoropyrimidine and platinum-containing chemotherapy can be improved by chemotherapy and biological therapy. Biological therapy, in particular, achieves this without clear increase in SAEs or QoL impairment. Whether biological therapy is preferred over chemotherapy is still unclear and there is no evidence of a difference for OS outcome, although immunotherapy may be associated with less SAEs. Addition of biological therapy to chemotherapy and poly-chemotherapy are associated with frequent treatment-related toxicity without clear survival benefit.
Salvage systemic therapy has become the new standard of care in patients with advanced gastric and oesophago-gastric junction (OGJ) adenocarcinoma, following disease progression on first-line fluoropyrimidine and platinum-containing chemotherapy. Pharmacological agents proven to be effective in this setting include both chemotherapy and biological therapy, however, the consensus on the best salvage systemic therapy has not been reached.
To assess the effects of systemic chemotherapy and biological therapy, either alone or in combination, on overall survival (OS) and progression-free survival (PFS) in patients with advanced gastric and OGJ adenocarcinoma, whose disease has progressed on, or relapsed after first-line fluoropyrimidine and platinum-containing chemotherapy. Adverse events (AEs), tumour response rate (TRR) and quality of life (QoL) associated with systemic chemotherapy and/or biological therapy were additionally assessed.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, trial registries and proceedings of the major oncology conferences up to October 2020. We additionally handsearched the reference lists of studies. No language restriction was applied.
We included randomised controlled trials (RCTs) comparing salvage systemic therapy (chemotherapy and/or biological therapy) and either another type of salvage systemic therapy, placebo, best supportive care (BSC) or no treatment in patients with gastric and OGJ adenocarcinoma refractory to first-line fluoropyrimidine and platinum-containing chemotherapy.
Two review authors independently performed selection of eligible studies and the primary author extracted study characteristics and outcome data from included studies. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We expressed pooled estimates of effect using hazard ratio (HR) calculated using an inverse variance random-effects model for time-to-event data, and risk ratio (RR) calculated using Mantel-Haenszel random-effects model for binary data. The certainty of evidence was graded using GRADEpro.
We identified 17 RCTs with 5110 participants for inclusion in this review. Tweenty-nine studies are ongoing and twenty studies are awaiting classification. No studies examined the following comparisons: chemotherapy combined with biological therapy versus placebo, BSC or no treatment, chemotherapy combined with biological therapy versus biological therapy, biological therapy versus biological therapy and chemotherapy combined with biological therapy versus chemotherapy combined with biological therapy.
Chemotherapy versus placebo, best supportive care or no treatment
Chemotherapy probably improves OS (HR = 0.66, 95% CI 0.52 to 0.83, moderate-certainty evidence) based on two studies involving 547 participants and improves PFS (HR = 0.57, 95% CI 0.47 to 0.69, high-certainty evidence) based on one study involving 507 participants over placebo and BSC. Chemotherapy probably increases serious AEs (SAEs) (RR = 1.38, 95% CI 1.20 to 1.59, moderate-certainty evidence) based on one study involving 503 participants.
Biological therapy versus placebo, best supportive care or no treatment
Biological therapy improves OS (HR = 0.55, 95% CI 0.41 to 0.73, high-certainty evidence) and probably improves PFS (HR = 0.33, 95% CI 0.19 to 0.57, moderate-certainty evidence) over placebo based on three studies involving 781 participants. There is currently insufficient evidence for increased SAEs from biological therapy (RR = 1.14, 95% CI 0.95 to 1.37, low-certainty evidence) based on two studies involving 638 participants.
Chemotherapy versus biological therapy
This comparison only considered immunotherapy. There is probably no evidence of a difference for OS (HR = 0.82, 95% CI 0.66 to 1.02, moderate-certainty evidence) between chemotherapy and immunotherapy, and immunotherapy probably reduces PFS (HR = 1.27, 95% CI 1.03 to 1.57, moderate-certainty evidence) based on one study involving 395 participants. SAEs may be less frequent with immunotherapy compared to chemotherapy (RR = 0.41, 95% CI 0.30 to 0.57, low-certainty evidence).
Chemotherapy combined with biological therapy versus chemotherapy
Addition of biological therapy to chemotherapy probably does not improve OS (HR = 0.93, 95% CI 0.83 to 1.04, moderate-certainty evidence) and we are uncertain whether it improves PFS (HR = 0.87, 95% CI 0.74 to 1.02, very low-certainty evidence) based on seven studies involving 2743 participants. We are similarly uncertain whether combined chemotherapy and biological therapy increases SAEs (RR = 1.17, 95% CI 0.95 to 1.44, very low-certainty evidence) based on four studies involving 1618 participants.
Chemotherapy versus chemotherapy
There is no evidence of a difference for OS and PFS between irinotecan and paclitaxel (HR = 1.13, 95% CI 0.86 to 1.48, low-certainty evidence for OS; HR = 1.14, 95% CI 0.88 to 1.48, low-certainty evidence for PFS) based on one study involving 219 participants. Similarly, there is no evidence to indicate improved OS and PFS from addition of another chemotherapy to docetaxel (HR = 1.05, 95% CI 0.72 to 1.54, low-certainty evidence for OS; HR = 0.75, 95% CI 0.52 to 1.09, low-certainty evidence for PFS) based on two studies involving 121 participants. Grade ≥ 3 neutropenia occurred commonly with both mono- and poly-chemotherapy except for docetaxel-S1 and EOX chemotherapy.