An expert commentary from Alessandro Parisi, M.D., from the Medical Oncology Unit of St. Salvatore Hospital in L’Aquila, Italy .
Gastric cancers are the second most common cause of cancer-related deaths worldwide.1 HER2-negative metastatic gastroesophageal adenocarcinomas (GEA) represent about 80% of the cases and in these patients, the question of whether a three-drug regimen is more effective than a potentially less toxic doublet is an element of debate.
A recent systematic literature review and meta-analysis showed a significant improvement in overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) with triplet over doublet regimens. Regimens containing fluoropyrimidines, cisplatin and taxanes were especially effective, yet came with a meaningful incidence of grade 3-4 thrombocytopenia, infections, and mucositis.2
A real-world data analysis and a network meta-analysis recently found that anthracycline-based triplets do not improve the efficacy of platinum-fluoropyrimidine doublets in terms of ORR, OS, and PFS in GEA first-line treatment, and come with greater toxicity and a major impact on quality of life (QoL).3,4
The V325 trial randomised GEA patients to receive cisplatin and fluorouracil (5FU) with (DCF) or without (CF) docetaxel. At a median follow-up of 13.6 months, time to progression (5.6 months vs 3.7 months), median OS (9.2 months vs 8.6 months) and ORR (37% vs 25%) were significantly higher with DCF.
The modified DCF regimen has recently been shown to have at least equal efficacy and lower toxicity compared to standard DCF chemotherapy in a phase 2 trial.5
The GATE trial randomised GEA patients to receive docetaxel plus oxaliplatin (TE) with or without 5FU (TEF) or capecitabine (TEX). TEF had a better safety profile and was also associated with higher ORR and longer median PFS and median OS (47%, 7.7 and 14.6 months) compared to TEX (26%, 5.6 and 11.3 months). Grade 3 or 4 adverse events were lower among patients treated with TEF (25%) compared to those treated with TE (37%) or TEX (38%). Febrile neutropenia was reported in only 2% of patients treated with TEF (compared to 14% and 9% for TE and TEX), which is also lower than the 16.4% reported with DCF in the V325 trial.6
The GASTFOX trial is comparing 5FU and oxaliplatin with or without docetaxel in first-line GEA patients.7
A triplet with docetaxel also demonstrated efficacy in the neoadjuvant setting in locally advanced disease, increasing significantly the proportion of patients achieving pathological complete regression compared with ECF/ECX in the phase 2/3 trial FLOT4-AIO.8
And for previously treated GEA, the placebo-controlled REGARD and RAINBOW trials examined ramucirumab monotherapy or with paclitaxel and demonstrated significant OS increases.9,10
A major problem with triplet chemotherapy is achieving good clinical outcomes, ensuring an appropriate dose intensity of each drug and acceptable limiting toxicities. Moreover, a triplet cannot always be used and it is crucial to select patients eligible for an intensive regimen. The features of patients (age, comorbidities, expected QoL, prolonged survival) and those of neoplasia (tumour burden, symptoms) play a central role in the decision-making process and the use of validated prognostic factors such as the Royal Marsden Hospital Prognostic Index or similar could aid clinicians.11,12
With this in mind, a taxane could be used in association with platinum compounds and fluoropyrimidines in 'high risk' first-line patients, who probably will not reach a second line (ie patients with PS-ECOG 2, liver metastasis, peritoneal metastasis, increase of alkaline phosphatase), when a rapid relief of symptoms due to high tumour burden is required. Otherwise a taxane should be used in second line, associated with ramucirumab, in 'low risk' patients (ie patients with none of the risk factors mentioned above), with better prognosis, after progression on a first-line treatment based on platinum and fluoropyrimidines, modulating the treatment in view of this potential second line. Both choices could be correct in 'intermediate risk' patients (ie patients with 1-2 of these risk factors).