Association of the Geriatric Nutritional Risk Index with the survival of patients with non-small-cell lung cancer after platinum-based chemotherapy

This was a retrospective observational study conducted in accordance with the ethical standards of the Declaration of Helsinki. Chemotherapy-naïve patients with pathologically confirmed advanced NSCLC who received first-line platinum-based chemotherapy at Hamamatsu University Hospital between January 1, 2000 and December 31, 2020 were included. Eligible patients were required to have stage IIIB without an indication for definitive radiotherapy, stage IV disease, or recurrent disease. Patients who received platinum-based chemotherapy as adjuvant treatment after surgery or in combination with radiotherapy (chemoradiotherapy), those who received combination therapy with platinum-based therapy and ICIs, those who received non-platinum therapy in the first-line setting, those with histories of previous chemotherapy including adjuvant chemotherapy, or those with missing pretreatment serum albumin and body weight data were excluded. Patient consent was waved because this was a retrospective study. The study protocol was approved by the Institutional Review Board of Hamamatsu University School of Medicine (No. 21-151).

Clinical data including age, sex, smoking status, height, weight, serum albumin levels before the administration of platinum-based chemotherapy, tumor histology, active driver mutations, clinical stage, Eastern Cooperative Oncology Group performance status (ECOG-PS), comorbidities, and treatment regimens were retrospectively evaluated via medical record reviews. Comorbidities were recorded according to the Charlson comorbidity index [30]. Response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were evaluated from the time of treatment initiation. The data cutoff date was August 31, 2021.

The GNRI was calculated as follows:Ideal weight was calculated using body mass index as follows:Originally, the GNRI was divided into four levels: < 82, ≥ 82 to < 92, ≥ 92 to < 98, and ≥ 98 [15]. However, in the current study, the GNRI was categorized as low (< 92) or high (≥ 92) because the overall response rate (ORR), PFS, and OS did not differ among the four GNRI categories (Additional file 1: Fig. S1).

Fisher’s exact test and Wilcoxon’s rank sum test were used to compare categorical and continuous variables, respectively. Pearson’s correlation coefficient was used to evaluate the correlations between age and the GNRI. The Jonckheere–Terpstra trend test was used to evaluate the trend between the GNRI and ECOG-PS. Wilcoxon’s signed-rank sum test was used to compare the GNRI between first- and second-line therapy. PFS and OS were evaluated using the Kaplan–Meier method, and the log-rank test was used to compare survival curves. Logistic regression analysis was used to determine predictive factors for ORR, and Cox proportional hazard analysis was used to determine predictive factors for PFS and OS. The variables significant at p < 0.100 in univariate analyses were employed for multivariate analyses. p < 0.05 (two-sided) denoted significance. All values were analyzed using JMP v13.2.0 (SAS Institute Japan, Tokyo, Japan), excluding the Jonckheere–Terpstra test, which was performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).

In total, 412 patients were screened, and 264 were excluded because they did not receive chemotherapy (n = 102), they received non-platinum-based chemotherapy (n = 71), they had insufficient available data (n = 53), or they received platinum-based chemotherapy in combination with other treatments (n = 38). As the results, 148 patients were included in this study (Fig. 1). The characteristics of the patients are presented in Table 1. The cohort had a high proportion of men (73.6%), smoking history (75.0%), and good ECOG-PS of 0–1 (89.2%). Sixty-seven (45.2%) patients were ≥ 65 years old. Ninety-five (64.1%) patients had normal BMI (≥ 18.5 to < 25.0 kg/m²), and 26 (17.6%) and 27 patients (18.2%) were underweight and overweight, respectively. The median GNRI was 100.6 (range 56.6–124.6), and 19 (12.8%), 19 (12.8%), 22 (14.9%), and 88 (59.5%) patients had GNRIs of < 82, ≥ 82 to < 92, ≥ 92 to < 98, and ≥ 98, respectively. All patients received at least one cycle of platinum-based chemotherapy, and 119 (80.4%) and 29 patients (19.6%) received carboplatin and cisplatin, respectively. Concerning combination regimens featuring platinum agents, 61 (41.2%), 58 (39.1%), and 29 patients (19.6%) received pemetrexed, taxanes, and other agents, respectively. Thirty-one patients (20.9%) received bevacizumab in addition to platinum-based chemotherapy. The overall ORR was 37.1% (95% confidence interval [CI] 29.8%–45.2%), and median PFS and OS were 5.6 (95% CI 5.1–6.2 months) and 17.0 months (95% CI 14.6–22.9 months), respectively. The numbers of events for PFS and OS were 115 and 94, respectively. The median observation time was 13.3 months (95% CI 17.2–25.3 months).

To evaluate the influence of advances in cancer therapy during the observation period, the patients were divided into two groups according to the date of administration of platinum-based chemotherapy: first decade (from January 2000 to December 2010, n = 61) and second decade (from January 2011 to December 2020, n = 87). The patients treated in the second decade were significantly older (median, 66 years) than those treated in the first decade (median, 64 years; p = 0.038). Patients in the second decade had a significantly higher rate of pemetrexed-based regimen treated (62%) and lower rates of treatment with taxane-based (25%) and other regimens (13%) than those treated in the first decade (11%, 59%, and 30%, respectively; p < 0.001). Thirty-one (36%) patients treated in the second decade received bevacizumab in addition to platinum-based chemotherapy, whereas no patient received these treatments in the first decade (p < 0.001). The patients treated in the second decade exhibited significantly longer PFS (median, 6.0 months) than those treated in the first decade (median, 4.9 months; p = 0.004). There was no significant difference in ORR and OS between the first (ORR = 42.5%, median OS = 19.3 months) and second decades (ORR = 29.5%, p = 0.122; and median OS = 16.8 months, p = 0.521).

There was a significant stepwise decrease in the GNRI according to the deterioration of ECOG-PS. Specifically, the median GNRIs (range) in the ECOG-PS 0, 1, and ≥ 2 groups were 104.6 (65.8–124.6), 98.3 (56.6–121.7), and 82.0 (69.4–112.9), respectively (p < 0.001). The GNRI was not associated with sex, age, smoking status, tumor histology, clinical stage, or the time of the start of platinum-based chemotherapy. The patients with a high or low GNRI had comparable demographics including comorbidities excluding the significantly better ECOG-PS, higher BMI, and serum albumin level in patients with a high GNRI (all p < 0.001; Table 1).

Patients with a high GNRI had significantly longer median PFS (6.3 months, 95% CI = 5.6–7.2 months) than those with a low GNRI (3.8 months; 95% CI = 2.5–4.7 months, p < 0.001; Fig. 2a). In univariate Cox proportional hazard analyses, an increased GNRI was predictive of longer PFS, similarly as age < 65 years, good ECOG-PS, receipt of cisplatin, receipt of pemetrexed, and the time of the start of platinum-based chemotherapy (Table 2). In multivariate Cox proportional hazard analyses, only an increased GNRI was an independent predictive factor for longer PFS (Table 2).

Likewise, patients with a high GNRI had significantly longer median OS (22.8 months, 95% CI = 16.7–27.2 months) than those with a low GNRI (8.5 months, 95% CI = 5.4–16.0 months, p < 0.001; Fig. 2b). In univariate Cox proportional hazard analyses, an increased GNRI was predictive of longer OS, similarly as age < 65 years, no smoking history, and good ECOG-PS (Table 3). In multivariate Cox proportional hazard analyses, an increased GNRI was predictive of longer OS, similarly as no smoking history and good ECOG-PS (Table 3).

Patients with a high GNRI displayed significantly higher ORR (44.5%, 95% CI = 35.6%–53.9%) than those with a low GNRI (15.8%, 95% CI = 7.4%–30.4%, p = 0.002). In univariate logistic regression analyses, an increased GNRI, good ECOG-PS, receipt of pemetrexed were predictive of higher ORR. In multivariate logistic regression analyses, an increased GNRI was predictive of the ORR (Table 4).

Patients with a high GNRI completed significantly more cycles of platinum-based chemotherapy (median, 4 cycles) and had a higher rate platinum-based chemotherapy completion (75.5%) than those with a low GNRI (median, 2.5 cycles, p < 0.001; and 39.5%, p < 0.001, respectively; Table 5). Patients with a low GNRI tended to have higher rates of grade ≥ 3 adverse events (55.3%) and dose reduction (39.5%) than those with a high GNRI (38.2%, p = 0.087; and 21.8%, p = 0.053, respectively).

Among the 148 patients who received first-line platinum-based chemotherapy, 71 (48.0%) received second-line non-platinum therapy (2L group). Of those, 47 patients (63.6%) received docetaxel (monotherapy, n = 42; combination with bevacizumab, n = 6; and combination with ramucirumab, n = 1), 12 patients (16.9%) received S-1 (tegafur/gimeracil/oteracil potassium), 4 patients received (5.6%) pemetrexed, and 8 patients (11.3%) received other non-platinum monotherapies. The 2L group had a median GNRI of 101.6 (range 69.7–129.7) at the beginning of the second-line therapy, which was comparable to that at the beginning of first-line therapy (p = 0.941; Fig. 3). The patients with a high GNRI at the beginning of second-line therapy exhibited significantly longer median PFS during second-line therapy (3.3 months, 95% CI 2.6–4.2 months) than those with a low GNRI (1.2 months, 95% CI 0.6–2.1 months, p < 0.001; Fig. 4a). Likewise, the patients with a high GNRI at the beginning of second-line therapy displayed significantly longer median OS during second-line therapy (18.5 months, 95% CI 11.0–28.7 months) than those with a low GNRI (4.4 months, 95% CI 1.4–14.8 months, p < 0.001; Fig. 4b). There was no significant association between the GNRI and ORR during second-line therapy (p = 0.324).

On the contrary, among 77 patients who did not receive second-line chemotherapy, 59 evaluable patients had a median GNRI of 91.6 (range 59.0–112.6) at the time of disease progression after first-line chemotherapy, which was significantly lower than that at the beginning the first-line chemotherapy (p < 0.001) and significantly lower than that at beginning of the second-line therapy in the 2L group (p < 0.001; Fig. 3).