In this case report, we present a rare case of liver metastases following curative resection of early gastric cancer in which a complete clinical response was achieved to nivolumab as third-line therapy. Although a recent randomized double-blind placebo-controlled phase 3 trial has demonstrated that the objective response rate to nivolumab for metastatic gastric cancer was 11.2%, there were no patients that confirmed complete response [6]. To the best of our knowledge, the present case report is the first case reported in the English literature of a gastric cancer patient achieving a complete clinical response to nivolumab therapy.
Although the liver is a common metastatic site of gastric cancer, the treatment for liver metastasis of gastric cancer has not been well established. According to Japanese gastric cancer treatment guidelines [7], chemotherapy is indicated for patients with unresectable or recurrent gastric cancer, including liver metastases. Despite the generally excellent outcome after curative surgery in patients with early gastric cancer, cancer recurrence is a rare event that can occur even after curative gastrectomy, with an incidence of 1.4–2.7% [10,11,12].
In previous randomized clinical trials, the rates of complete responses, as defined by RECIST, to drug treatment using chemotherapy and molecular targeted therapy were reported as 0.7–5.4% for first-line therapy [13, 14], 0.4–0.6% for second-line therapy [3, 4], and 0% for third-line therapy [6]. The objective response rate was lower for later than first-line therapy. The therapeutic efficacy of treatment regimens may have declined in patients who had undergone prior treatments as a result of decreased physical strength due to disease progression and/or cumulative cytotoxicity of the cytotoxic agents administered.
Recent studies have demonstrated that systemic inflammatory response markers, including GPS and NLR, are associated with prognosis in cancer patients [15, 16]. Previous investigators demonstrated that the unresectable advanced gastric cancer patients with high NLR were significantly associated with worse overall survival when the cut-off values were set at 3.0–4.0 [16,17,18,19]. In the present case, NLR was low and GPS was 0, which indicate maintained host immune responses to the tumor. Neutrophilia is an inflammatory response that inhibits the immune system by suppressing the cytolytic activity of immune cells, whereas lymphopenia is a surrogate for impaired cell-mediated immunity. NLR, calculated as neutrophil counts/lymphocyte counts, has been suggested as a marker for the general immune response to various stress stimuli [16, 20]. Furthermore, systemic inflammatory responses can indicate nutritional decline, which could contribute to tumor progression [21].
Ameratunga et al. reported shorter overall survival in patients with advanced solid tumors using an NLR cut-off value of 5.0 [22]. Similarly, Nakaya et al. reported that progression-free survival was worse in advanced non-small-cell lung cancer patients with a high NLR when the cut-off value was set at 3.0 [23], Furthermore, meta-analysis to investigate the prognostic utility of baseline NLR in patients receiving immune checkpoint inhibitors showed that a high NLR was associated with poorer outcomes [24]. Therefore, the host inflammatory response markers including NLR may be important not only in the development and progression of cancer but also in predicting responses to immune checkpoint inhibitors.
Immune checkpoint-targeted therapy has emerged as a promising treatment strategy with considerable benefits in many cancer types; however, it is not suitable for all patients [5, 6]. Although the expression of PD-1, and its ligands PD-L1 and PD-L2, or microsatellite instability (MSI) profiles are frequently used to select patients for immunotherapy trials and appear to be correlated with treatment response, a universal biomarker has not been identified as yet that can accurately predict patients who are more likely to respond to immunotherapy [5, 25]. In order to improve the efficacy of immune checkpoint-targeted therapy, biomarkers that can predict patient responses to immunotherapy need to be developed [25, 26].
When a clinical complete response is achieved, the significance in the continuation of treatment is unknown. Cho et al. reported that three patients developed recurrence among 22 patients who achieved a pathological complete response with neoadjuvant chemotherapy [27]. Although a complete response induced by drug treatment is associated with the better prognosis of patients, the continuation of treatment seems to be necessary to aim long-term survival at this time.
