The current standard of care for medically fit patients with potentially resectable LAGC is comprised of perioperative ChT with the FLOT regimen. Previous trials tested combinations of preoperative and postoperative chemotherapy and radiotherapy, providing alternative treatment options for various clinical scenarios. However, in all of the prospective trials, patients were treated in a pre-planned sequence, without taking the tumor response to preoperative treatment into account. Although the idea of modifying the treatment agent or modality in order to overcome tumor resistance is appealing, data supporting a response-adaptive treatment approach are currently lacking. Therefore, in the present study, we evaluated treatment outcomes in patients with a poor pathologic response to preoperative ChT who received postoperative CRT.
We found that with a median follow-up of 29 months (range 9-140), median PFS for the entire cohort was 23 months, and median OS was not reached. Five-year PFS and OS rates were 42% and 54%, respectively. The locoregional recurrence rate was 12%. An exploratory comparison between our results and those of pivotal earlier randomized studies [3, 5, 6, 10] is presented in Table 3. Both 5-year and median OS in our study compared favorably with previous ones which reported a range of 36–45% and 36–50 months, respectively. Five-year PFS was reported only in the CRITICS trial and was 39%, similar to our result. Median PFS was shorter in our study than the reported range of 28–30 months. Recurrence rates should be interpreted carefully, as they were reported at different time points. However, the locoregional recurrence rate in our study seems to be in line with values reported by others (7–24%).
Table 3
Comparison of present study to pivotal trials in the literature
Study | 5-yr PFS | 5-yr OS | Median PFS | Median OS (mo) | Locoregional recurrence (%) | Non-locoregional recurrence (%) |
INT-01163 | NA | NA | 30 | 36 | 24 | 27 |
MAGIC5 | NA | 36 | NA | NA | 14 | 24 |
CRITICS10 | 39 | 41 | 28 | 43 | 7 | 54 |
FLOT46 | NA | 45 | 30 | 50 | NA | NA |
Present study | 42 | 54 | 23 | NR | 12 | 42 |
OS, overall survival; PFS, progression-free survival; NA, not available, NR, not reported |
The favorable long-term PFS and OS results in the present trial using an adaptive approach may point to a successful salvage attempt and a better outcome than expected for poor-risk patients. The low number and proportion of locoregional recurrences in our study, with only one in-field recurrence, support the concept that salvage radiation therapy in poor responders may prevent loco-regional disease recurrence and improve results overall. The relatively shorter median PFS in our study may be attributed mostly to patients in whom metastatic disease emerged a short while after treatment completion, reflecting the dismal prognosis of this high-risk population.
The studies cited in the above comparison included unselected patients, whereas our cohort consisted solely of poor responders to preoperative ChT. An exploratory study of the prognostic value of a pathologic response in the MAGIC trial cohort found that median OS in the CHT-treated patients with a poor pathologic response (Mandard tumor regression grade 3–5) was 20.47 months, notably shorter than reported for unselected patients in other trials. On multivariate analysis, only lymph node status was predictive of OS. The high-risk population with positive lymph nodes was well represented in our study, accounting for 73% of the patients who received preoperative ChT [13].
The main limitations of the present study are the small number of patients included, the retrospective design, and the inherent bias of limiting the cohort to high-risk poor responders who recovered from preoperative ChT and surgery and could tolerate postoperative CRT. The main strength of this study is the novel exploratory approach in a real-life clinical setting, with a complete dataset allowing for accurate evaluation of the benefit of adaptive treatment for selected patients.
In conclusion, in this small retrospective study, patients with LAGC who had a poor pathologic response to neoadjuvant ChT achieved a relatively good outcome following postoperative CRT. These results support the consideration of individualized, adaptive treatment for LAGC in highly selected patients according to pathological response to neoadjuvant ChT. This approach is still exploratory and warrants evaluation in future randomized studies in this setting.