Chemotherapy-Induced Thrombocytopenia in Nasopharyngeal Carcinoma
Overview
This study aimed to investigate serious chemotherapy-induced thrombocytopenia (CIT) in nasopharyngeal carcinoma (NPC), focusing on its incidence, consequences, and predictors.
The retrospective analysis of NPC patients from 2013 to 2015 revealed a 5.21% incidence of serious chemotherapy-induced thrombocytopenia. Patients experiencing severe thrombocytopenia had notably worse long-term prognoses, although the impact on short-term survival was minimal. Predictors of serious chemotherapy-induced thrombocytopenia included specific chemotherapy regimens (gemcitabine and platinum, 5-fluorouracil and platinum, taxane and platinum), as well as serum potassium ion concentration, serum lactate dehydrogenase levels, platelet count, red blood cell count, and estimated glomerular filtration rate.
Introduction
In 2020, nasopharyngeal carcinoma (NPC) accounted for 0.7% of all new cancer cases, totaling 133,354 cases. The primary treatment modalities for NPC involve radiotherapy and chemotherapy. Clinical trials have highlighted the benefits of concurrent chemotherapy and induction chemotherapy, particularly for locally advanced NPC, compared to radiotherapy alone. Induction chemotherapy regimens commonly include platinum-based combinations such as gemcitabine and cisplatin, docetaxel and cisplatin, cisplatin and 5-fluorouracil, or docetaxel plus cisplatin and 5-fluorouracil.
Since many NPC patients present with locoregionally advanced disease, chemotherapy is often a crucial component of their treatment. Unlike radiotherapy for head and neck cancers, which generally doesn’t result in serious thrombocytopenia, chemotherapy has been associated with inducing severe thrombocytopenia during NPC treatment. Thrombocytopenia caused by chemotherapy, referred to as chemotherapy-induced thrombocytopenia (CIT), can be costly and may lead to dose reductions, delays, alterations, or discontinuations in chemotherapy. A platelet count of ≤10 × 10^9/L increases the risk of significant bleeding.
Notably, chemotherapy-induced thrombocytopenia doesn’t solely impact chemotherapy but also affects radiotherapy. Thus, it becomes imperative to investigate the incidence, consequences, and predictive factors of serious chemotherapy-induced thrombocytopenia to enhance the management and outcomes of NPC patients undergoing these combined treatments.
Methods
In this retrospective study conducted at the Sun Yat-Sen University Cancer Center (SYSUCC) between 2013 and 2015, the research focused on newly diagnosed patients with non-metastatic nasopharyngeal carcinoma (NPC). The study’s inclusion criteria encompassed individuals aged 18 to 75 years at the time of diagnosis, with pretreatment white blood cell (WBC) counts of ≥4 × 10^9/L and platelet counts of ≥100 × 10^9/L. All eligible patients received a combined treatment regimen involving radiotherapy and platinum-containing chemotherapy. Importantly, patients with concurrent malignant diseases were excluded from the study. Additionally, exclusion criteria applied to cases where a change in the chemotherapy regimen occurred for reasons unrelated to thrombocytopenia.
To assess and categorize thrombocytopenia, the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) was employed. Grade 3 thrombocytopenia was defined as a platelet count ranging from 25 × 10^9/L to 50 × 10^9/L, while grade 4 thrombocytopenia was characterized by a platelet count of <25 × 10^9/L. The study’s primary focus was on identifying and analyzing cases of serious chemotherapy-induced thrombocytopenia (CIT), denoted as grades 3–4 thrombocytopenia occurring within 120 days from the initiation of treatment.
It’s important to note that this retrospective study was conducted following approval from the institutional ethics review board of SYSUCC, bearing the approval number [B2022- 684- 01].
Statistical Analysis
The analysis of patient baseline characteristics employed statistical methods as follows: The Mann–Whitney–Wilcoxon test was utilized for count data, while the chi-squared test was applied for categorical data. Univariate and multivariate Cox proportional hazards regression models were employed to assess the impact on overall survival (OS), with the proportional hazards assumption tested using Schoenfeld residuals. To reinforce these findings, survival analysis was conducted using the Kaplan–Meier method and subsequently evaluated through log-rank tests. This analysis was adjusted for potential confounding factors using propensity score matching (PSM).
In addition, univariate and multivariate logistic regression analyses were conducted to identify predictors of serious chemotherapy-induced thrombocytopenia (CIT). To determine the optimal thresholds for these predictors, receiver operating characteristic (ROC) curve analysis was performed, and the area under the curve (AUC) was calculated.
Overall survival (OS) was defined as the duration from the initial diagnosis to the date of death from any cause or the last follow-up date for patients who remained alive or were lost to follow-up. These statistical analyses were carried out using R software (version 4.1.3), utilizing various packages including tableone, MatchIt, survminer, survival, rms, and pROC, to ensure comprehensive and rigorous data analysis.
Results
A total of 27 patients were excluded from the analysis due to modifications in their chemotherapy regimen unrelated to thrombocytopenia. These alterations resulted from various reasons, including poor response to initial chemotherapy, serious neutropenia, preferences for shorter hospital stays, or unknown causes. Consequently, 3933 patients were included in the study, and Table 1 provides an overview of their baseline characteristics. The study observed a 5.21% incidence of serious chemotherapy-induced thrombocytopenia (CIT) occurring within 120 days of treatment initiation. Notably, the incidence of serious chemotherapy-induced thrombocytopenia varied among patients receiving different chemotherapy regimens, with the highest incidence observed in those receiving gemcitabine and platinum (GP), platinum and 5-fluorouracil (PF), and taxane and platinum (TP).
Cox regression survival analyses were conducted to assess the impact of CIT on overall survival (OS). The univariate analysis identified CIT as a significant risk factor (hazard ratio [HR]: 2.07, 95% confidence interval [CI]: 1.49–2.87, p < 0.001). The subsequent multivariate Cox model adjusted for various factors, including age, stage, chemotherapy regimen, sex, pretreatment serum lactate dehydrogenase (LDH), and the occurrence of grade 3–4 CIT, neutropenia, leukopenia, or anemia within 120 days of treatment initiation. Notably, a higher LDH level (LDH ≥ 245 U/L), age, stage IVa, and serious CIT were identified as statistically significant risk factors for OS, while sex, chemotherapy regimen, and grade 3–4 neutropenia, leukopenia, and anemia were not significantly associated with OS.
To further validate the impact of serious CIT on OS, propensity score matching (PSM) was employed to balance potential confounding variables, such as age, stage, chemotherapy regimen, and LDH level. After PSM, a cohort of 587 patients with serious chemotherapy-induced thrombocytopenia was matched to 201 patients without serious CIT. This matching procedure ensured the balance of patient characteristics between the two groups. The analysis revealed that patients with serious CIT had a significantly lower 5-year OS rate compared to those without serious CIT (82.5% vs. 90.9%). The differences in 1-year OS rates were also noted, albeit less pronounced (98.98% vs. 99.1%). These findings were statistically significant (p < 0.05).
The study further investigated the effects of chemotherapy-induced thrombocytopenia on treatment outcomes. Notably, six patients changed their chemotherapy regimen due to CIT, and three of them subsequently passed away. Among the 148 patients who completed planned chemotherapy, 54 experienced either chemotherapy dose reductions or complete treatment cessation. While these patients exhibited poorer OS compared to those without such reductions, this difference was statistically insignificant when adjusted for important factors. Additionally, 64 patients received chemotherapy after CIT, with 32 of them encountering delays in chemotherapy administration. However, these delays did not significantly affect OS, even after adjusting for critical factors.
Regarding radiotherapy, three patients had unplanned interruptions due to side effects unrelated to chemotherapy-induced thrombocytopenia, while one patient discontinued radiotherapy due to chemotherapy-induced thrombocytopenia and experienced poor outcomes. In contrast, 172 patients continued radiotherapy despite experiencing CIT, and 29 of them had interruptions in radiotherapy. Although these interruptions resulted in a longer radiotherapy treatment time (RTT), they did not significantly impact OS, even after adjusting for important factors.
To explore the predictors of serious chemotherapy-induced thrombocytopenia, the study conducted univariate and multivariate logistic regression analyses involving 15 variables, including age, sex, stage, chemotherapy regimen, and pretreatment data such as LDH, white blood cell count, red blood cell count, lymphocyte count, platelet count, absolute neutrophil count, serum indirect bilirubin, serum potassium ion concentration, serum sodium ion concentration, and estimated glomerular filtration rate (eGFR). Among these variables, RBC, PLT, K+, LDH, eGFR, and chemotherapy regimen were included in the final multivariate logistic regression analysis due to their significant association with serious CIT. ROC curve analysis was employed to determine the threshold values for PLT count and eGFR, yielding cut-off values of 228.75 × 10^9/L and 94.60 mL/min/1.73 m^2, respectively.
These comprehensive findings shed light on the impact of serious CIT on overall survival and the associated treatment effects, as well as identifying important predictors of serious CIT in patients with non-metastatic nasopharyngeal carcinoma.
Conclusion
The study addresses the significance of serious chemotherapy-induced thrombocytopenia (CIT) and its impact on long-term survival. It also identifies higher serum potassium (K+) levels as a novel risk factor for CIT. The influence of neutropenia, leukopenia, and anemia on prognosis was previously debated, but in this study, grade 3–4 neutropenia, leukopenia, and anemia were not found to be prognostic factors. CIT emerged as an independent risk factor for overall survival (OS), affecting long-term survival while having minimal impact on short-term survival rates.
The study examined the effects of CIT on radiotherapy treatment time (RTT) and chemotherapy outcomes. While prolonged RTT has been associated with worse OS in prior studies, the extended RTT observed in patients with CIT did not significantly affect OS. Similarly, despite chemotherapy dose reductions or delays in patients with CIT, these factors did not substantially contribute to decreased OS, although the sample size for subgroup analyses was limited.
Notably, higher estimated glomerular filtration rate (eGFR) was identified as a protective factor against chemotherapy-induced thrombocytopenia, with a threshold value of 94.60 mL/min/1.73 m^2. This suggests that better renal function may facilitate chemotherapy drug excretion, potentially reducing side effects on megakaryocytes. Moreover, elevated serum K+ levels were linked to a higher risk of serious CIT, possibly due to K+ elevation being associated with cell and platelet lysis. Previous studies have also suggested that potassium supplementation can reduce platelet reactivity. The study revealed that higher lactate dehydrogenase (LDH) levels were a risk factor for CIT in solid tumors, expanding on prior findings in diffuse large B-cell lymphoma.
Regarding blood cell counts, higher red blood cell (RBC) and platelet (PLT) counts were protective factors against CIT. This aligns with the conclusion that PLT counts below 150 × 10^9/L are associated with poor survival. The study calls for further research to explore potential genes related to low pretreatment platelet counts.
In the context of chemotherapy regimens, the study reported a notably higher incidence rate of chemotherapy-induced thrombocytopenia (10.17%) in patients receiving platinum and 5-fluorouracil (PF) regimens compared to previous clinical trials. Gemcitabine and platinum (GP) regimens were also identified as risk factors for CIT. Surprisingly, the TP (taxane and platinum) regimen demonstrated lower odds of inducing CIT than PF. This suggests that the three-regimen chemotherapy, TPF (taxane, platinum, and 5-fluorouracil), may have lower toxicity on thrombocytes or megakaryocytes.
However, the study has limitations, such as its single-center focus on nasopharyngeal carcinoma (NPC) patients. Whether the findings can be generalized to other cancer types or patients with lower pretreatment white blood cell (WBC) or platelet (PLT) counts remains to be investigated. Further research is warranted to assess the broader applicability of these conclusions to different cancer populations.
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