Introduction
Advanced urothelial carcinoma (aUC), consisting of locally progressive and metastatic disease, is generally considered incurable (1). Since the 1980s, cisplatin-based chemotherapy has been the standard of care for aUC. A landmark regimen in systemic chemotherapy was the development of a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) (2). Patients on MVAC demonstrated a good response against aUC, but its toxicity has been known to be severe. A randomized control study on gemcitabine and cisplatin (GC) vs. MVAC revealed the lower toxicity of GC compared to standard MVAC, which resulted in GC becoming a new standard regimen (3). Although the majority of patients with metastatic UC initially respond to these chemotherapy regimens, most such cancers eventually progress. To establish systemic salvage therapy for patients who have progressed after first-line chemotherapy is one of the unmet needs in the field.
Pembrolizumab, a programmed death 1 inhibitor, was approved as second-line therapy for aUC that had progressed after chemotherapy. A randomized phase 3 KEYNOTE-045 trial showed a superior overall survival (OS) benefit of pembrolizumab vs. chemotherapy (paclitaxel, docetaxel or vinflunine) in patients with aUC that progressed on platinum-based chemotherapy (4). However, its survival benefit was relatively short (10.3 vs. 7.4 months). The objective response rate [complete response (CR)+ partial response (PR), 21.1%] was also unsatisfactory although it was significantly higher than that of the chemotherapy group (11.4%). Unfortunately, only a minority of patients benefits from pembrolizumab. Establishing biomarkers to predict the efficacy of this drug is therefore an important challenge (5).
Recently, the prognostic nutritional index (PNI) has been studied as a potential biomarker that predicts patients' response to immunotherapy for various cancers (6,7). These works demonstrated that a low pretreatment PNI value was a candidate prognostic biomarker of a poor objective response and adverse prognosis in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). In the field of aUC, a small number of publications exist on PNI and pembrolizumab treatment outcomes (8,9). However, their findings on the predictive impact of a survival benefit were inconsistent. Therefore, we planned a retrospective observational study of PNI before and after the induction of pembrolizumab in our cohort. In the present study, we elucidated that early posttreatment PNI after the induction of pembrolizumab therapy predicts better clinical outcomes in patients with aUC.
Discussion
The era of cancer immunotherapy for the treatment of aUC commenced with the introduction of pembrolizumab (4). In the first report of the KEYNOTE-045 trial, median OS and PFS were 10.3 and 2.1 months for a pembrolizumab treatment group compared with 7.4 and 3.3 months for a chemotherapy group, respectively. The trial revealed longer OS for the pembrolizumab group compared to the chemotherapy group (hazard ratio = 0.73). After >2 years of follow-up, the long-term results were consistent with those of previously reported analyses, which showed that median OS and PFS were 10.1 and 2.1 months, respectively (13). Our cohort yielded similar results to those of the KEYNOTE-045 trial; the median OS and PFS were 10.2 and 3.5 months, respectively. Although our sample size was very small, the clinical outcome of our cohort is considered standard quality of care.
Not all patients benefit from cancer immunotherapy. Therefore, many researchers have made efforts to identify biomarkers to predict the therapeutic benefit of pembrolizumab. Histological markers, such as programmed death-ligand 1 (PD-L1), are generally used to predict the response during immunotherapy for some types of cancer (14). Bellmunt et al have shown that multiple biomarkers that characterize the tumor microenvironment, such as PD-L1, tumor mutational burden, and the T-cell-inflamed gene expression profile (TcellinfGEP), may be clinically useful in better selecting patients with UC in KEYNOTE-045 and 052 cohorts for treatment with pembrolizumab (15). However, the role of PD-L1 expression as second-line immunotherapy for aUC is uncertain. In a subgroup analysis of KEYNOTE-045, a survival benefit was observed in patients who had a tumor PD-L1 combined positive score of less than 1% as well as 1% or more (4). PD-L1 thresholds vary due to tumor types and the use of different assays. PD-L1 expression was also measured in a variable fashion either on tumor cells, tumor-infiltrating immune cells, or both. To date, PD-L1 expression as a predictive biomarker appears to have limitations (14).
Along with the search for histological biomarkers, hematological biomarkers have also been explored (5). Pretreatment baseline hematological parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), have been studied (16–19). Such prior works described how low NLR and PLR were associated with a favorable outcome of pembrolizumab therapy. With regard to the correlation between pretreatment PNI and the outcome of pembrolizumab treatment in aUC, several studies have been reported (8,9). Ishiyama et al described how a low PNI group showed significant shorter OS and PFS; they concluded that PNI is a useful predictor of prognosis in patients with aUC treated with pembrolizumab (9). Ni et al performed a meta-analysis of several types of cancers (gastric, lung, esophageal, urothelial, among others) and reported that low PNI might be an effective biomarker of poor outcome in patients with advanced cancer administered ICIs (6). Chemotherapy suppresses the numbers of neutrophils, platelets, and monocytes severely, and the use of granulocyte colony-stimulating factor and platelet transfusion may influence NLR/PLR/LMR before the start of salvage pembrolizumab. In comparison, serum albumin levels and lymphocyte counts change moderately. Therefore, we considered that PNI to be suitable as a prognostic biomarker after chemotherapy.
Recently, several reports have focused on the early hematological response after the induction of pembrolizumab therapy (19–22). These studies demonstrated that changes between pre- and posttreatment NLR, or the absolute value of NLR after treatment, were significantly associated with patient outcomes. We observed trends in PNI values for our patients, before and during pembrolizumab treatment. In cases with a good prognosis, PNI values increased soon after the start of treatment, even when the pre-PNI value was low. Thus, we speculated that the PNI value after pembrolizumab initiation was a good prognostic indicator. In previous reports regarding posttreatment NLR, observation points varied according to investigator: Three weeks, six weeks, and two cycles (approximately 4 weeks) after the start of pembrolizumab (18–21). Although the timing of a rise in post-PNI values in our patients with good outcomes showed a wide distribution, most were observed within two months (8–58 days, median 25.5 days). Therefore, we designated the observation point as within two months after the initiation of pembrolizumab. To our knowledge, the present study is the first report regarding post-PNI in patients with aUC treated with pembrolizumab.
The exact reason why a low PNI value was associated with a poor outcome in cancer immunotherapy has not been fully elucidated (6). Ryman and Meibohm stated that the increased catabolism associated with malnutrition might accelerate the clearance of monoclonal antibodies, which are eliminated primarily by catabolic degradation (23). Turner et al also reported that patients showing high clearance of pembrolizumab were associated with cachexia and increased protein turnover secondary to chronic inflammation; they showed a shorter OS (24). In our patients, the rapid increase in absolute lymphocyte counts mainly contributed to the increase in post-PNI values. Elevation of absolute lymphocyte counts after the induction of ICIs has been reported in several cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma (25–29). These studies demonstrated that higher absolute lymphocyte counts after the start of ICI (3–6 weeks) led to longer survival. We speculated that the induction of an immune response with pembrolizumab leads to an early increase in lymphocyte count. Moreover, an improvement in the patient's nutritional condition results in an increase in albumin levels, which may cause an increase in the post-PNI level.
Several limitations existed in the present study. First, this was a single-institutional retrospective study with a small patient number, and thus may have been prone to selection bias. Further study with a larger and more diverse cohort is required to validate our results. In fact, we are currently planning a multi-institutional validation study using a larger number of patients. Second, the timing of blood tests was not strictly defined, since it varied from physician to physician. The optimal sampling time to determine the best post-PNI value should be validated in future studies. Third, the PNI does not reflect the inflammatory state of the host, although cancer-related inflammation is considered to indicate a worsened prognosis. A comparison in future of PNI with inflammation-based markers, such as NLR, PLR, LMR and c-reactive protein, should be performed in terms of their ability to discriminate prognosis.
In conclusion, higher post-PNI values within two months predict both longer OS and PFS. Our findings may help identify good responders with aUC to salvage pembrolizumab therapy in an early phase of treatment.