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ESMO Update in Gastroesophageal Cancer
Update by Elizabeth Smyth
Gastroesophageal cancer surgery in high volume centres is associated with less postoperative mortality regardless of co-morbidity status
Centralisation of surgery benefits even low risk patients undergoing gastrectomy for stomach cancer, according to a French study presented by Dr Mariette of Lille, France. The effect of surgical volume on postoperative mortality has previously been proven for patients undergoing oesophagectomy, however data on patients undergoing gastrectomy were limited. In this very large study, the outcomes of all patients who underwent oesophagogastric surgery in France over a two year period (2010 -2012) were analysed according to volume of treatment centre. Both 30 and 90 day mortality decreased in a linear manner between low, medium, high and very high volume surgical centres which were classified as operating on <20, 20-39, 40-59≥ 60 cases per year respectively. The potentially confounding effect of comorbidities was evaluated by stratifying outcomes using the formal Charlson comorbidity index; in low vs. very high volume centres the 30 day postoperative mortality was 4.0% vs 1.0% for the fittest patients (Charlson 0) and 14.7% vs. 3.7% for patients with the highest comorbidity score (Charlston 3). The differential in survival outcomes between low and high volume centres was true for patients undergoing gastrectomy and oesophagogastrectomy.
Comment: Significant improvements in surgical outcomes have been achieved in countries such as the UK through centralisation of surgery for oesophagogastric cancer. These data support a similar approach for patients undergoing gastrectomy, regardless of the patients’ comorbidity status.
Negative results for olaparib in gastric cancer: results of the phase III randomised GOLD study
The results of the phase III randomised GOLD study were reported by Dr JY Bang. In this study, Asian patients with advanced, previously treated gastric cancer were treated with either paclitaxel or paclitaxel in combination with the PARP inhibitor olaparib. A previous phase II randomised trial enriched for patients with ATM deficient gastric cancer (who may be more sensitive to PARP inhibition) had reported a statistically significant improvement in overall survival for patients treated with this combination1. In the GOLD study, 18% of 535 patients randomised were ATM deficient. Results of the study in the overall population demonstrated numerically higher overall survival for patients treated with olaparib plus paclitaxel (6.9 vs. 8.8 months, HR 0.79, p =0.0262), however due to a statistical correction made due to inclusion of a co-primary endpoint of the ATM deficient subgroup, this did not reach statistical significance (which would have required a p value of <0.025). In the ATM deficient subgroup, radiological response rates were significantly higher for patients treated with olaparib (37% vs 16%, p=0.03), and a non-statistically significant trend towards improvement in overall survival was also noted (10 vs. 12 months, HR 0.73, p=0.2458). Combination therapy was well tolerated, with no new safety signals demonstrated.
Comment: The results of the GOLD trial are disappointing, especially in view of the previous positive phase II randomised study. However, there are a number of signals that PARP inhibition may yet have promise in gastric or gastroesophageal cancer. A trend towards improved response and overall survival was observed in the entire olaparib treated population, independent of ATM status. This might suggest that there are biomarkers beyond ATM deficiency that predict for PARP efficacy in gastroesophageal cancer. In ovarian cancer, analysis of “BRCAness” or genomic scar using next-generation sequencing technology has identified a subgroup of patients without BRCA mutations who benefit from PARP inhibitor therapy.2 It is possible that a similar approach might be useful in gastroesophageal cancer.3 A more pragmatic clinical approach would be to select patients for PARP inhibitor trials using response to platinum chemotherapy as a surrogate for PARP sensitivity. Thus, although the results of the GOLD study are negative, there is clear evidence of activity of olaparib in this population, and further exploration of PARP inhibitors in gastroesophageal cancer remains justified.
1. Bang YJ, Im SA, Lee KW, et al. Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer. J Clin Oncol. 2015.
2. McNeish IA, Oza AM, Coleman RL, et al. Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. ASCO Meeting Abstracts. 2015;33(15_suppl):5508.
3. Cafferkey C, Smyth E, Loehr A, et al. Genomic loss of heterozygosity (LOH) and survival in patients (pts) treated with epirubicin, oxaliplatin, capecitabine (EOC) ± panitumumab (P) in the REAL3 trial. Annals of Oncology. 2016;27(suppl 6).