Abstract
Background/Aim: To assess the baseline inflammatory markers modified Glasgow Prognostic Score (mGPS), systemic immune-inflammation index (SII), and neutrophile-to-lymphocyte ratio (NLR) as pragmatic tools for predicting response to chemohormonal therapy (docetaxel plus ADT) and prognosis in men with metastatic hormone-sensitive prostate cancer (mHSPC). Patients and Methods: Male patients who received docetaxel at a tertiary university care center between 2014 and 2019 were screened for completion of 6 cycles. NLR, SII, mGPS, overall survival (OS), three-year survival, and radiologic response were assessed. Complete response (CR), partial response (PR), and stable disease (SD) were analyzed alone and in combination. Results: Thirty-six mHSPC-patients were included. In thirty patients, baseline mGPS was assessed and was either 0 (n=22) or 2 (n=8). In Cochran-Armitage Trend Test, mGPS showed significant association with the combined radiologic endpoint of “CR, PR, or SD” (p=0.01), three-year survival (p=0.02), and OS (p<0.01). Next to prostate-specific antigen (PSA) (HR per 100 units 1.16, 95%CI=1.04-1.30, p<0.01), NLR (HR=1.31, 95%CI=1.03-1.66, p=0.03), and mGPS (2 vs. 0, HR=6.53, 95%CI=1.6-27.0, p<0.01) at baseline showed significant association with OS in univariable cox regression. However, mGPS remained the only independent predictor for OS in multivariable cox regression (p<0.01) and for the combined radiologic endpoint of “CR, PR or SD” (p=0.01) in multivariable logistic regression. SII showed no statistical relevance. Conclusion: Baseline mGPS seems to be a pragmatic tool for clinical decision-making in patients with mHSPC in daily routine.
- Biomarkers
- prognosis
- overall survival
- systemic immune-inflammation index
- neutrophile-to-lymphocyte ratio
In the male population, prostate cancer (PC) is the most common cancer in Europe and the second most common cancer worldwide (1). Moreover, a strong increase of around 27% in PC cases is expected until 2040 (2) due to demographic changes. Most patients are diagnosed in a localized stage (74%), however, in 13% the disease spreads to regional lymph nodes and in 7% of cases it progresses to metastatic disease (3).
Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) is based on long-term androgen deprivation therapy (ADT). In recent years, the STAMPEDE and CHAARTED studies have shown a benefit for the addition of docetaxel to the first-line treatment of mHSPC (4, 5). Later, combination strategies including one of the novel hormonal agents abiraterone, enzalutamide or apalutamide were introduced to the first-line treatment of mHSPC.
To our knowledge, despite the years of clinical experience in treating mHSPC with combined hormonal therapy and chemotherapy and a large number of biomarkers in PC, no tool for predicting therapy response and prognosis in these patients has been brought to clinical routine. At the same time, the number of biomarkers has led to the development of combined prognostic scores such as for example the combination of TMPRSS2: ERG and PCA3 in urine with serum prostate-specific antigen (PSA) (6). Moreover, the body’s inflammatory response in cancer disease has been shown and established in observational studies (7, 8). Therefore, in the last decade, further combined prognostic scores like the modified Glasgow Prognostic Score (mGPS), the neutrophile-to-lymphocyte ratio (NLR) and the systemic immune-inflammation index (SII) have been established (9–11).
The mGPS is a combined score including serum elevation of C-reactive protein (CRP) and hypoalbuminemia and has been studied and shown to be linked to clinical outcomes in several cancers including PC (9, 12). In recent studies, mGPS could be linked to overall survival (OS) (13) and disease progression (14) in metastatic castration-resistant PC (mCRPC).
An elevated NLR has also been linked to poorer OS and progression-free survival (PFS) (11) in mCRPC as has the SII (15). The SII is based on peripheral lymphocyte, neutrophil, and platelet counts and was associated with higher risk of biochemical recurrence after radical prostatectomy for localized PC (16).
However, to our knowledge no peer-reviewed and Medline listed study investigated the prognostic value of mGPS and SII in patients with mHSPC. Regarding NLR in patients with mHSPC, we only found one study addressing NLR as a predictor for time to castration resistance (17).
This study aimed to evaluate mGPS, NLR and SII as predictive and prognostic biomarkers for radiologic response and OS in men with mHSPC.
Patients and Methods
All patients who received docetaxel at a tertiary university care center (University Medical Center Mannheim, Heidelberg University) in Germany between January 2014 and December 2019 were screened for completion of 6 cycles of therapy. Next to clinical and oncologic variables, hemoglobin (Hb), alkaline phosphatase (AP), lactate dehydrogenase (LDH), albumin, CRP, leukocyte, and thrombocyte values were recorded as analyzed in the center’s department for clinical chemistry. OS, three-year survival (death/alive), as well as radiologic response were assessed binary for Cochran-Armitage Trend and uni- and multi-variable logistic regression analysis. Radiologic response [complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD)] to docetaxel was assessed by comparison of baseline staging with imaging 4-6 weeks after docetaxel application. CR, PR, and SD were analyzed alone and in combination. The SII and mGPS were calculated as shown in Table I (18). To assess survival status the death register query was carried out in April 2020, which thereby marks the endpoint of survival analysis. This study was conducted according to the Declaration of Helsinki. Ethical approval was obtained from the University of Heidelberg’s Ethics Committee II (Medical Faculty Mannheim, reference number 2015-549N-MA).
The modified Glasgow prognostic score (mGPS) and systemic immune-inflammation index (SII).
Statistical analysis. Frequencies and proportions were assessed for categorical variables, while medians and interquartile ranges were computed for continuous variables. Cochran-Armitage Trend Test was used to assess mGPS as a predictor for survival (OS) and radiologic response. To test the impact of PSA values and other continuous variables or categorical factors on binary outcomes (e.g., OS or the combined radiologic endpoint of “CR, PR, or SD”), univariable logistic regression analyses were performed. Multivariable logistic regression analysis using backward selection method initially including “age at initial administration”, “visceral disease”, “PSA at initial administration”, “Gleason score ≥8”, “AP”, “LDH”, “SII”, “NLR”, and “Hb” (all at initial administration) was performed to evaluate mGPS as an independent prognostic marker. Additionally, for OS uni- and multi-variable Cox regression analysis was performed. Furthermore, log rank test was conducted to compare the mGPS level regarding OS time and time to the combined radiologic endpoint. All tests comparing 2 groups were two-sided. In general, statistical significance level was set to α=0.05. Statistical calculations were performed using the software SAS® (SAS Institute Inc., Cary, NC, USA), release 9.4 and GraphPad Prism9 (GraphPad Software, Inc, San Diego, CA, USA).
Results
After screening, forty patients with mHSPC under chemohormonal treatment were identified, 36 of whom had completed 6 cycles of docetaxel and were included. Out of these patients, thirty-five received a docetaxel dose of 75 mg/m2, whereas one patient received 50 mg/m2. The median age at initiation of combined hormonal therapy and chemotherapy was 63 years [interquartile range (IQR)=59-69 years] and initial PSA was 145 ng/ml (IQR=27-304 ng/ml). Twenty-eight patients (80.0%) showed osseous, 22 (62.9%) lymphatic, and 5 (13.9%) visceral metastases. Baseline characteristics of the study cohort are shown in Table II.
Baseline characteristics of study cohort.
In 30 patients, baseline mGPS was assessed and was either 0 (n=22) or 2 (n=8). In Cochran-Armitage Trend Test, mGPS showed significant association with OS (p<0.01), three-year survival (p=0.02), and the combined radiologic endpoint of “CR, PR, or SD” (p=0.01).
PSA at baseline (p=0.05, OR=0.55, 95%CI=0.30-0.99) and after completing 6 cycles (p=0.02, OR=3.78, 95%CI=1.21-11.83) was found to be significantly associated with OS in univariable logistic regression. However, in multivariable logistic regression, mGPS remained the only independent predictor for reaching the combined radiologic endpoint (mGPS 2 vs. 0, OR=0.07, 95%CI=0.01-0.55, p=0.01) and OS (mGPS 2 vs. 0, OR=19.00, 95%CI=2.54-141.9, p<0.01). For survival at 3 years, mGPS (mGPS 2 vs. 0, outcome: death, OR=10.56, 95%CI=1.61-69.12, p=0.01) was found to be the only variable significantly associated in univariable logistic regression, whereas patients’ age (p=0.07), AP at initial administration (p=0.05), baseline PSA (p=0.09) and Gleason score ≥8 (p=0.09) did not reach significance. In multivariable logistic regression, mGPS remained the only independent predictor for three-year survival (p=0.01). Results of univariable logistic and multivariable logistic regression analysis regarding radiologic response as assessed by the combined radiologic endpoint, three-year survival and OS are shown in Table III, Table IV, and Table V.
Univariable logistic and multivariable logistic regression in order to detect variables associated with the radiologic response of the study cohort.
Univariable logistic and multivariable logistic regression in order to detect variables associated with the 3-year survival.
Univariable logistic and multivariable logistic regression in order to detect variables associated with overall survival (OS).
Kaplan–Meier analysis (Figure 1) revealed longer OS of patients with mGPS=0 than in those with mGPS=2 (median survival not reached vs. 19.5 months, HR=6.53, 95%CI=1.60-27.0, log rank test: p<0.01). Additionally, multivariable Cox regression analysis (backward selection method) was performed for OS including the same variables. mGPS was confirmed as the only prognostic factor (p<0.01). Furthermore, univariable Cox regression showed significant results for NLR (HR=1.31, 95%CI=1.03-1.66, p=0.03), PSA per 100 units (HR=1.16, 95%CI=1.04-1,30, p<0.01) and mGPS 2 vs. 0 (HR=6.53, 95%CI=1.6-27.0, p<0.01) at initial administration. For SII no significant results could be shown regarding prediction for therapy response or prognosis.
Kaplan–Meier analysis of OS [months] depending on mGPS (Modified Glasgow Prognostic Score). mGPS available for n=30 patients. Hazard ratio (HR)=6.53, 95% confidence interval (CI)=1.6-27.0, log rank test p<0.01.
Discussion
Inflammatory response markers are well studied in mCRPC. In contrast, evidence regarding mGPS, SII and NLR is sparse in men with mHSPC receiving treatment with combined hormonal therapy and docetaxel chemotherapy. In this retrospective study, we aimed to elucidate the prognostic value of these markers on oncologic outcomes.
Evaluating mGPS, SII and NLR as tools to predict treatment response, we found mGPS to be significantly associated with OS, three-year survival, and radiologic response and baseline NLR and PSA to be significantly associated with OS. In multivariable logistic and Cox regression analysis only mGPS showed to be an independent predictor of OS. This makes mGPS a promising tool for prediction of therapy response in patients with mHSPC under treatment with chemohormonal therapy.
Inflammatory markers offer the advantage that they are usually included in routine laboratory analysis in patients with PC under systemic therapy. Therefore, they can be considered as an inexpensive measurement, that is easy to integrate into pre-treatment and treatment evaluation in daily clinical routine.
In a systematic review based on 36 randomized clinical trials in mostly advanced inoperable cancer (colorectal, non-small cell lung, oesophageal, nasopharyngeal, pancreatic, prostate, and breast cancer), Dolan et al. investigated combined markers of the systemic inflammatory response (9). They confirmed the value of systemic inflammation-based prognostic scores and that the mGPS, which had been analyzed in 7 studies, has not been as well studied as the NLR, which has been investigated in 33 trials (9). However, recently more and more studies reveal the potential of mGPS in cancer treatment in general and especially in urologic cancers. In mCRPC, mGPS has been shown to be independently associated with disease progression (14), OS (12, 13) and poorer five-year survival and relative survival independent of age (19). In other urologic cancers, mGPS also has been assessed recently: A study by Draeger et al. showed mGPS as clinical predictor for OS in penile cancer (20) and Nagai et al. revealed high mGPS as a risk factor for poor cancer-specific survival in metastatic urothelial carcinoma for patients that receive either gemcitabine/cisplatin or pembrolizumab (21). In metastatic renal cell carcinoma patients who received immune checkpoint inhibitor treatment, mGPS showed a discrimination power to predict OS and PFS comparable to the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk score (22).
In meta-analyses, mGPS could be associated to poor prognosis in pancreatic, gastric, gynecologic, colorectal, and lung cancers and hepatocellular carcinoma.
In patients with mHSPC several other prognostic factors have been identified in previous studies: hemoglobin values <13 g/dl, visceral metastases, bone metastases, the extend of bone disease, a combined Gleason score ≥8 or ≥9, elevated AP values, LDH above 230 U/l and a high initial PSA have been reported to be associated with significantly poorer OS of patients with mHSPC. Further predictors include age, the nutritional status (23), ECOG ≥2 (24), high-volume disease as defined by the CHAARTED criteria (25), and the amount of circulating tumor cells.
In combined scores or ratios, it is usually not clear which component is abnormal. However, in our cohort, patients either showed mGPS of 0 or 2, which means that the inflammation response, represented by an increase in CRP, and the hypoalbuminemia occurred simultaneously. It has been shown that hypoalbuminemia not only reflects the nutritional but also the chronic inflammation status (26). Additionally, it is well known that hypoalbuminemia is a poor prognostic biomarker in oncologic diseases (27). Furthermore, in patients with PC the ADT leads to a gain of fat mass and loss of lean mass, which is associated with all-cause and cancer-specific mortality (28). Therefore, at the time of diagnosis patients with mHSPC should also be assessed for their nutritional status and nutritional support by a multidisciplinary team as already suggested for other tumor entities (29). In addition, specific exercise and nutrition programs can lead to an improved quality of life in patients with PC (28).
Limitations. This study is limited by its design, which is retrospective and monocentric. In addition, the sample size is relatively small, which limits the power of our study and also the generalizability of our findings.
Additionally, we only focused on disease-specific characteristics and did not include other diseases, which could have affected OS, in our analysis. On the other hand, this could strengthen mGPS as a prognostic factor and make it an even more pragmatic biomarker. Furthermore, there was no control over further therapies that patients might have received after their chemotherapy with docetaxel was completed or patients experienced castration resistance. In addition, the performed death register query registered death from any cause. Therefore, the results might be biased because patients could have died from (prostate) cancer unspecific causes.
Conclusion
In this study, we evaluated the potential of mGPS, SII, and NLR as prognostic factors in patients with mHSPC, who receive docetaxel chemohormonal therapy. Baseline mGPS seems to be an independent biomarker for mHSPC patients receiving first-line treatment with ADT plus docetaxel in daily clinical routine. This finding from a retrospective study needs prospective and multicentric validation.
Acknowledgements
The Authors would like to thank the patients who participated in the study.
Footnotes
Authors’ Contributions
Manuel Neuberger: Conceptualization, formal analysis, methodology, writing original draft, review & editing, visualization, project administration. Janina Skladny: Investigation, data curation, review & editing. Nora Goly: Investigation, data curation, review & editing. Christel Weiß: Methodology, formal analysis, visualization, review & editing. Frederik Wessels: Visualization, review & editing. Philipp Erben: Review & editing. Luisa Egen: Resources, review & editing. Matthias Groß-Weege: Data acquisition, resources, review & editing. Britta Grüne: Resources, review & editing. Friedrich Hartung: Resources, review & editing. Jonas Herrmann: Data acquisition, resources, review & editing. Patrick Honeck: Review & editing. Jonas Jarczyk: Resources, review & editing. Karl Friedrich Kowalewski: Formal analysis, Review & editing. Julia Mühlbauer: Resources, review & editing. Malin Nientiedt: Data acquisition, review & editing. Katja Nitschke: Writing - review & editing, data acquisition, resources. Margarete Theresa Walach: Resources, review & editing. Frank Waldbillig: Resources, review & editing. Niklas Westhoff: Resources, review & editing. Jost von Hardenberg: Resources, review & editing. Maximilian Kriegmair: Review & editing. Thomas Stefan Worst: Review & editing. Philipp Nuhn: Conceptualization, resources, supervision, review & editing, project administration.
Conflicts of Interest
The Authors have no competing interests to declare that are relevant to the content of this article.
- Received February 18, 2022.
- Revision received March 1, 2022.
- Accepted March 3, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
