How would you treat a patient with T4N1M0 GEJ adenocarcinoma with local progression after concurrent chemoRT who still has resectable disease?
This is a tricky but thankfully rare scenario.
My answer depends on the nature of the local progression. The more favorable situation involves local persistence of the primary tumor with a modest increase in locoregional lymph nodes. This situation would essentially represent a lack of response to chemoradiation but not dramatic progression. In this case, I think it remains defensible to proceed with surgical resection and to hope that adjuvant nivolumab (based on the CheckMate 577 study by Kelly et al. in the NEJM) is able to improve what would otherwise be a potentially dismal progression-free survival. The value of adjuvant nivolumab seems to differ somewhat by histology as well as by PD-L1 CPS (>5 vs. <5) but I would offer adjuvant nivolumab irrespective of PD-L1 CPS.
The more serious situation is if there are new locoregional lymph nodes, which can technically still be resected. This would represent progression on chemoradiation and could hint at an even worse outcome than the scenario above. In this case, I would be strongly inclined to consider more/different systemic therapy in an attempt to better determine the behavior of the cancer prior to surgery. For example, in a patient who received carboplatin/paclitaxel and RT, I would consider FOLFOX. Based on the biomarker status of the tumor cells, I might even consider adding an immune checkpoint inhibitor and/or trastuzumab based on the premise that this might represent a locally advanced/unresectable tumor. If there is disease control after several months of chemotherapy, we could then re-evaluate the role of surgery.
Clearly, none of these situations is one-size-fits-all and a multidisciplinary discussion is critical to try to tailor treatment to try to mitigate what will generally be an unfavorable outcome.
On a somewhat related note, I would make an unabashed plug for the use of PET-directed chemoradiation based on the CALGB 80803 study (Goodman et al., PMID 34077237). I absolutely acknowledge that this is not a randomized study and the value of PET imaging to guide the choice of chemotherapy is not definitively proved. We did perform a retrospective analysis of 451 patients treated at MSKCC with standard carboplatin/paclitaxel and RT vs. induction chemotherapy (FOLFOX vs. carboplatin/paclitaxel) prior to PET-directed therapy (Carr et al., PMID 34387205). Our data suggest that patients treated with induction FOLFOX and PET-directed chemoradiation seemed to have better pathologic response and disease-free survival than those treated with CROSS-type carboplatin/paclitaxel and RT. Therefore, the use of induction chemotherapy may identify patients who will develop frank progression and allow a switch to alternative chemotherapy during RT.