The main finding of the present study is that tight adherence (TI ³ 0.95) to the chemotherapy time schedule was associated with a higher probability of a major histopathologic response (0-10% residual cancer cells) in patients receiving neoadjuvant EOX for resectable gastric or esophageal adenocarcinoma. We also found a significant association between a high cumulative dose (DI ³ 0.95) and a more modest response (0-50% residual cancer cells). Since the aim of neoadjuvant chemotherapy is to reduce the tumor burden before surgery, the goal should be to achieve as good a response as possible. Therefore, an interpretation of our results could be that it is more important to avoid treatment delays than to give full dose in this context. The TI cutoff at 0.95 implies that the total treatment duration should not be delayed by more than a factor 1/0.95 » 1.05, i.e. not more than one day per 21-day cycle.
Previous studies [11–16] in this treatment setting have proposed small tumor size (but not T stage), differentiated tumor and Laurén intestinal subtype as predictors for histopathologic response to chemotherapy, but there are conflicting results regarding Laurén subtype . We found no other factors than TI and DI to be associated with histopathologic response, though we did not have data on tumor size.
In the present study we chose to use histopathologic response, rather than survival, as primary endpoint. The reason for this is that response is usually a direct effect of the given treatment, whereas survival may be influenced by several other factors, such as age, comorbidities, tumor stage, surgical quality and complications. Therefore, the neoadjuvant setting, where chemotherapy is followed by surgical resection with histopathologic response evaluation, is a very good model for studies on chemotherapy dose intensity.
Regarding the clinical significance of histopathologic response, the literature is conflicting, as some studies have found it to be an independent predictor for survival  and others have not . The present study showed significant associations between survival and histopathologic response, especially in patients with 0-10% residual cancer cells who had an excellent survival. It should however be pointed out that these were univariable analyses, not taking other prognostic factors into account.
In the present investigation we applied a similar methodological approach as in a study by Nakayama et al.  on patients with metastatic colorectal cancer, evaluating irinotecan-based (FOLFIRI regimen) and oxaliplatin-based (FOLFOX regimen) chemotherapy, wherein it was demonstrated that dose reductions of irinotecan and treatment delays of oxaliplatin, respectively, were independent negative prognostic factors for progression-free survival. Another study, on platinum-based chemotherapy in patients with ovarian cancer , showed that treatment delays, but not dose reductions, were independently associated with worse survival. Furthermore, a randomized phase II trial  in metastatic gastric and gastroesophageal junction adenocarcinoma, with standard DCF (docetaxel, cisplatin and fluorouracil) given every three weeks compared to reduced dose DCF given every two weeks, demonstrated a six months longer OS in favor of the latter regimen, further emphasizing the importance of having short intervals between treatments. Even though these studies were made on different chemotherapy regimens and in different malignancies, a possible interpretation could be that delayed dosing of platinum-based chemotherapy has a negative impact on outcome, which is also in accordance with our results. However, additional studies are needed to confirm this hypothesis.
The previous literature on RDI in gastric cancer is very sparse. In the metastatic setting Kitagawa et al.  found no differences in survival whether RDI of cisplatin and the fluoropyrimidine analogue S-1 was above or below 80%. Another study  showed that low RDI (89.5% or less) of adjuvant S-1 was an independent predictor of poor disease-free survival. To the best of our knowledge, the present study is the first to examine RDI, as well as DI and TI, of neoadjuvant chemotherapy in gastric and esophageal adenocarcinoma.
A major limitation of this exploratory, retrospective study is the relatively small sample size with few events, precluding multivariable analyses. Thus, our results should be interpreted with caution and considered mainly as hypothesis generating with a need for validation in additional studies. Moreover, we did not assess the impact of DI and TI for the individual drugs (although TI is usually the same) and it is possible that larger studies could identify cutoffs for the separate chemotherapy components. Based on a preliminary report in 2017 on the now published FLOT4-AIO trial , EOX has been gradually replaced by FLOT (fluorouracil, oxaliplatin and docetaxel) as the new standard perioperative regimen, and it would be of interest to assess DI and TI in patients receiving FLOT, which shares the common backbone of oxaliplatin and a fluoropyrimidine with the EOX regimen.
Given that side-effects of chemotherapy commonly result in dose reductions and/or treatment delays, the paucity of reports in the literature about how this affects outcome is somewhat surprising. Whether the dose should be reduced or the treatment delayed, in case of non-manageable toxicity, is a clinically very common and important question that needs to be further addressed, not only in this specific disease setting, but also in other malignancies and treatment situations.