Chemotherapy following immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma: clinical effectiveness and influence of inflammatory and nutritional factors

Objective This study aimed to evaluate the clinical effectiveness of chemotherapy following immune checkpoint inhibitors (ICI). The association between inflammatory and nutritional factors and prognosis has also been investigated. Methods We retrospectively reviewed the medical records of recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) patients who received chemotherapy following ICI therapy. The response rate and survival after chemotherapy, and nutritional and inflammatory factors, were examined. Results The ICI before chemotherapy was nivolumab in 36 patients (70.6%) and pembrolizumab in 15 patients (29.4%). The chemotherapy regimens consisted of PTX in 32 patients (62.7%), PTX + Cmab in 9 (17.6%), and S1 in 10 (19.6%). The median overall survival (OS) was 20 months (95% CI 12–25), the estimated 12-month OS rate was 63.3%, the median progression-free survival (PFS) was 5 months (CI 4–6), and the 12-month PFS estimate was 8.9%. Univariate analysis significantly correlated Neutrophil-to-Lymphocyte Ratio (NLR), platelet-to-lymphocyte ratio (PLR), controlling nutritional status score (CONUT), and prognostic nutrition index (PNI) with OS and PFS. Additionally, these factors were significantly correlated with OS and PFS in the log-rank tests. Conclusions Chemotherapy following ICI is highly effective. There were no significant differences in the chemotherapy regimens. Inflammatory and nutritional factors may associate with patient prognosis after chemotherapy.

This study aimed to evaluate the clinical effectiveness of chemotherapy following ICI therapy.In addition, the effectiveness and response rates of each regimen were examined.Moreover, we investigated whether inflammatory and nutritional factors were associated with the effectiveness of chemotherapy following ICI in RMHNSCC, and also examined their correlation with the prognosis.1 3 the three groups.Cutoff values for nutritional and inflammatory factors were determined by referring to ROC curves and were classified into two groups (high and low).The association between ORR, DCR, and each factor was assessed using the univariate logistic regression model.A Cox regression model analyzed the relationship between nutritional and inflammatory factors and OS or PFS.Logistic regression model and Cox regression model analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Japan), and other statistical analyses were performed using GraphPad Prism 8 software (GraphPad Software Inc., San Diego, CA, USA).Statistical significance was set at p < 0.05.

Patient characteristics
From June 2017 to June 2022, 51 of the 110 RMHNSCC patients treated with ICI were eligible for treatment evaluation after chemotherapy following ICI.Their characteristics are summarized in Table 1.There were 48 males and three females with a median age of 66 years (range: 47-83 years).In 24 cases, the primary site was the hypopharynx, the oropharynx in 11 cases, and the larynx in 7 cases.The ECOG was 0-1 in almost all cases.The disease sites evaluated were locoregional recurrence in 32 cases and distant metastases in 19 cases.Regarding the line of chemotherapy, 43 cases received chemotherapy as second-line treatment after ICI, 7 cases for 3rd, and 1 for 4th.The type of ICI before chemotherapy was nivolumab in 36 patients and pembrolizumab in 15 patients.Regarding prior cetuximab treatment

Adverse event
The adverse events observed during chemotherapy are listed in Table 3.The most common AE was peripheral neuropathy in 6 patients (11.5%).The most common was thyroid dysfunction, pneumonia, liver dysfunction, and skin toxicity.Grade 3 or higher adverse events were observed in 10 patients (19.6%), and one died of interstitial pneumonia.

Discussion
Immunotherapy, a breakthrough treatment for head and neck cancer, has become more widely used, and treatment outcomes and prognoses are gradually becoming clearer [10,15,38].In addition, many studies have reported relatively better results with chemotherapy after ICI compared to conventional chemotherapy for RMHNSCC [12,13,15,39] Our department employs three regimens: PTX, PTX + Cmab, and S1, but the single agent, PTX regimen, is primarily used.However, this was because many patients had a history of cetuximab when nivolumab was started in our department, and we wanted to avoid duplication of cetuximab.After its initiation, the PTX regimen was clinically effective and had few adverse events; therefore, the PTX monotherapy regimen has been used as a general rule.In this study, the ORR and DCR for patients treated with chemotherapy following ICI were 71.2% and 84.6%, respectively, and the ORR after chemotherapy was 78.1%, 88.9%, and 40.0% for PTX, PTX + Cmab, and S1, respectively.The highest ORR for PTX + Cmab and lowest ORR for S1 were observed.PTX + Cmab had the best response rate but was not significantly different from that of PTX.In addition, a study on the estimated OS and PFS from the first dose of chemotherapy after ICI showed favorable results, with a median OS of 10 months (95% CI 6-18), an estimated 12-month OS rate of 44.5%, a median PFS of 5 months (95% CI 4-6), and an estimated 12-month PFS rate of 8.9%.Compared to reports of patients receiving PTX + Cmab [14], we found no significant difference in OS, although PFS was slightly lower.In addition, there were no significant differences among the three groups by regimen, similar to the results reported by Yasumatsu et al. [15].Although the effects between regimens vary from report to report [12][13][14][15][40][41][42][43], all reports indicate that chemotherapy after ICI is effective.Our results also showed that chemotherapy was effective regardless of regimen, and the results were comparable to previous reports [14,15,41].Due to the small number of cases and some biases in our study, it was difficult to describe the differences in efficacy between regimens.However, as more patients accumulate, it is expected to become clearer which regimen is more effective.Regarding safety, although there was a concern about an increase in adverse events with chemotherapy after using ICIs, this study showed no particular increase in adverse events.However, there was one case of serious interstitial pneumonia.Matsuo et al. stated that patients treated with nivolumab followed by Cmab-containing chemotherapy have a higher risk of drug-induced interstitial lung disease compared to other regimens [44].In patients with documented pulmonary dysfunction, Cmab-containing chemotherapy should be administered with careful monitoring.
Although several factors may be associated with the prognosis or efficacy of chemotherapy after ICI in RMHNSCC, few studies have examined those factors [25].Recently, nutritional and inflammatory factors have been reported to be  associated with prognosis [17,19,[21][22][23][24][25], and we investigated whether these factors were associated with prognosis after chemotherapy in RMHNSCC.
The results of this study showed no significant differences between the ORR or DCR and each factor.However, there was a trend suggesting that ORR might be associated with age, whereas DCR might be associated with NLR and PLR.Matsuki et al. reported that hematological inflammatory markers, specifically elevated NLR and modified GPS, were significantly associated with DCR, but not with ORR, in patients with RMHNSCC treated with nivolumab [45].Our previous study found no significant correlation between inflammatory and nutritional factors and the ORR in patients receiving ICI therapy [46].However, DCR showed a significant correlation with the systemic immune-inflammation index and a trend associated with other factors such as PLR.Clinical studies examining the association between ORR or DCR and survival after chemotherapy have reported that ORR is not associated with prognosis and that DCR is associated with prognosis [47].These results suggest that inflammatory and nutritional factors may be associated with DCR rather than ORR, which may be correlated with long-term prognosis.
Furthermore, we examined the associations between these inflammatory and nutritional factors and prognosis.Univariate Cox regression analysis for OS and PFS by factor showed that Alb, NLR, PLR, CAR, CONUT, GPS, and PNI were significantly correlated with OS, and NLR, PLR, CONUT, and PNI were significantly correlated with PFS.Additionally, these four factors (NLR, PLR, CONUT score, and PNI) were significantly correlated with OS and PFS in the log-rank test.
And reflect prognosis, with better nutritional status and lower inflammatory status associated with better prognosis.Wakasaki et al. reported that CRP and NLR were prognostic factors for chemotherapy after nivolumab in RMHNSCC [25].The NLR is a well-known biomarker that has been reported to be an independent prognostic factor in head and neck cancer [26].The results of the present study, as well as previous reports, showed that NLR is associated with the prognosis of chemotherapy after ICI.However, to date, no other studies have examined the prognostic value of inflammatory and nutritional factors for chemotherapy after ICI, and the role of these factors remains unclear.Our results also demonstrated that PLR, CONUT score, and PNI were significantly associated with prognosis.PLR is defined as the platelet-to-lymphocyte ratio.Increased platelet counts have been implicated in increased cancer invasiveness and indirect interactions between cancer cells and platelets through secreted molecules, making them more aggressive [48].In contrast, lymphocytes constitute a significant component of the host immune system and can eliminate cancer cells and prevent tumor progression [49].In other words, relatively high platelet and low lymphocyte counts may predict a poor prognosis.Takenaka et al. [50] reported that PLR was associated with poor survival in patients with HNSCC.Additionally, PLR is reportedly associated with poor prognosis in various carcinomas [24,51,52].These results showed that PLR was also a prognostic factor for the patients in ICI after chemotherapy.
The CONUT score is a nutritional scoring tool used to screen and identify hospitalized patients with malnutrition [34].This score, calculated from serum albumin, total lymphocyte count, and total cholesterol, has recently emerged as a tool to assess the nutritional and immunological status of patients with malignancies [18,21,53].The PNI, which is calculated based on the serum albumin concentration and peripheral blood lymphocyte count, is a nutritional scoring tool that is used to assess the nutritional and immune status of patients with cancer [19].The PNI has been shown to be a useful prognostic tool in predicting survival and guiding treatment decisions in patients with various types of cancer [20,23].The CONUT score and PNI are indicators of nutritional status.However, Lin et al. demonstrated that the CONUT score has a superior prognostic value compared to the NLR, PLR, and LMR [18].This finding further emphasizes the correlation between nutritional status, immune status, and prognosis.Notably, they also revealed that the prognostic value of the CONUT score was superior to that of the PNI score, suggesting an important role of cholesterol in determining the prognosis of tumors.Our results revealed no significant differences between the two factors.However, both factors were associated with prognosis, suggesting they could be useful tools for chemotherapy following ICI treatment.
In summary, our results showed that several inflammatory and nutritional factors are correlated with the prognosis of patients treated with chemotherapy after ICI.Although the usefulness of these factors differs among reports, they all indicate that inflammatory and nutritional factors are associated with cancer patient prognosis.In the future, these factors are expected to contribute to the prognosis of cancer patients by providing nutritional support at an early stage concurrently with cancer treatment.
This study had several limitations.First, this was a single-center retrospective study that evaluated a small number of patients.Second, the PTX + Cmab and S1 groups were small, making it difficult to assess the usefulness of the regimen and possibly causing bias in drug selection.Third, nutritional and inflammatory factors must be interpreted cautiously because of the many factors involved.Finally, randomized prospective trials are needed to optimize chemotherapy after ICI treatment for RMHNSCC.

Fig. 3
Fig. 3 Kaplan-Meier curves of overall survival (a) and progression-free survival (b) for patients by nutritional and inflammatory factors divided by cutoff values.Significant differences in OS and PFS were observed between the two groups

Table 4
Prognostic analysis of objective response rate and disease control rate in patients who received chemotherapy following immune checkpoint inhibitor therapy ORR: objective response rate; DCR: disease control rate; CI: confidence interval; BMI: body mass index; Alb: albumin; CRP: C-reactive protein; LMR: lymphocyte-to-monocyte ratio; NLR: neutrophil-to-lymphocyte ratio; PLR: platelet to lymphocyte ratio; CAR: CRP to albumin ratio; CONUT: controlling nutritional status; GPS: Glasgow Prognostic Score; PI: prognostic index; PNI: prognostic nutrition index † p < 0.01

Table 5
The univariate analysis of nutritional and inflammatory factors associated with overall survival and progression-free survival after chemotherapy Bold indicates statistically significant p-values OS: overall survival; PFS: progression-free survival; CI: confidence interval; BMI: body mass index; Alb: albumin; CRP: C-reactive protein; LMR: lymphocyte-to-monocyte ratio; NLR: neutrophil-to-lymphocyte ratio; PLR: platelet to lymphocyte ratio; CAR: CRP to albumin ratio; CONUT: controlling nutritional status; GPS: Glasgow Prognostic Score; PI: prognostic index; PNI: prognostic nutrition index