Abstract
Background/Aim
Cancer-induced pain (CIP) exacerbates patient’s quality of life. However, it is unknown whether CIP is associated with survival in urothelial carcinoma (UC) patients treated with enfortumab vedotin (EV). This study retrospectively investigated the prognostic significance of CIP in EV-treated UC patients.
Patients and Methods
We analyzed clinical data from patients with locally advanced or metastatic UC who received EV treatment, assessing various factors such as age, metastasis site, ECOG Performance Status (PS), and CIP status prior to treatment. CIP was determined based on clinical records cancer-related pain or the use of analgesics for pain management.
Results
A total of 114 patients (78 males and 36 females) were included in the study. The group with CIP included significantly higher number of patients with bone metastasis. Progression-free survival of the patients with CIP was not significantly different from those without CIP. However, the patients with CIP showed worse overall survival (OS) than those without CIP. Cox proportional regression analysis showed that CIP, liver metastasis, and ECOG PS were significant predictors of poorer OS.
Conclusion
CIP before the treatment of EV was a significant predictor of reduced OS in patients with UC. Early management of CIP or initiation of EV therapy before CIP development may improve survival outcomes.
Keywords: Cancer-induced pain, urothelial carcinoma, Enfortumab Vedotin
Introduction
The prognosis of metastatic or locally advanced urothelial carcinoma (m/laUC) had been poor; however, the emergence of immune check point inhibitors (ICIs) and antibody-drug conjugates (ADCs) has significantly shifted the treatment landscape, leading to unprecedented improvements in survival outcomes (1). Despite these advancements, cancer-induced pain (CIP) continues to have a significant negative impact on patients’ quality of life (QOL) (2). Furthermore, CIP has been associated with overall survival (OS) in several malignancies including breast, colon, and lung cancer (3). However, its prognostic significance in UC patients remains unclear.
Enfortumab vedotin (EV) is an ADC targeting nectin-4 expressed on UC (4,5), which has shown remarkable efficacy in m/laUC patients (6-13). Systemic therapy with EV could lead to pain relief (14,15). However, no studies have investigated the relationship between CIP and prognosis in UC patients treated with EV. The aim of this study was to analyze the effect of CIP on the prognosis of patients with m/laUC treated with EV.
Patients and Methods
This is a multi-institutional retrospective study conducted in Kindai University Faculty of Medicine (Osaka, Japan), Osaka Medical and Pharmaceutical University (Osaka, Japan), the Jikei University School of Medicine (Tokyo, Japan), Tokyo Medical University (Tokyo, Japan), and Fujita-Health University School of Medicine (Aichi, Japan) between January 2018 and July 2023. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The institutional ethical review board approved this study protocol (approval number: R02-155). Inclusion criteria included patients with m/laUC who received EV treatment following disease progression after chemotherapy and ICI therapy. EV was administered intravenously on days 1, 8, and 15 of each four-week cycle, until they experienced progressive disease based on radiological examinations.
Radiological assessments were typically conducted via computed tomography prior to and following every three to six cycles of EV treatment. Additionally, evaluations were carried out as deemed necessary by clinicians. The radiological analysis adhered to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as outlined by previous researchers (16). The assessment of the best response for each metastatic lesion was categorized into four classifications: 1) complete response (CR), defined as the complete disappearance or a reduction in the short-axis diameter to less than 10 mm for all lymph node metastases; 2) partial response (PR), characterized by a reduction exceeding 30%; 3) stable disease (SD), indicating that the response did not meet the criteria for CR, PR, or progressive disease (PD); and 4) PD, identified by an increase greater than 20%. Laboratory data were gathered within one month prior to initial administration of EV therapy. The EV was administered at a dosage of 1.25 mg per kilogram of body weight as a single intravenous infusion over a duration of 30 minutes on days 1, 8, and 15 within a 4-week treatment cycle. CIP was determined based on clinical records, where patients either reported cancer-related pain or used analgesics for pain management. Patients were then divided into two groups: Group A, with CIP, and Group B, without CIP.
Kaplan-Meier analysis and the log-rank test were employed to assess and compare overall survival (OS) and progression-free survival (PFS) between the two groups. A multivariate analysis was conducted to identify independent prognostic factors influencing the OS or PFS of all patients, utilizing a cox proportional-hazards regression model. The relationship between variables across two groups was examined utilizing the chi-square test, Fisher’s exact test, or Mann-Whitney U-test. All statistical analyses were executed using EZR as reported previously (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (17). In this study, parameters with a p-value of less than 0.05 were deemed statistically significant.
Results
A total of 129 patients received EV treatment. Among them, the patients who did not undergo radiographic examinations after the initiation of EV therapy (n=15) were excluded. Finally, one-hundred fourteen patients were analyzed in this study. One-hundred nine patients received full dosage of EV therapy; however, 1 and 6 patients started at a reduced dosage of 0.75 and 1.00 mg per kilogram of body weight, respectively. Among the analgesics used in Group A, 53 patients used acetaminophen, 42 patients used NSAIDs, and 29 patients used opioids for CIP management. Most of the patients with bone metastasis experienced CIP (n=30/32, 93.7%). Patients’ demographics are summarized in Table I. Patients in group A had significantly higher frequency of bone metastasis, higher levels of ALP, and worse ECOG performance status than those in Group B (Table I). The best overall response rate of EV treatment is shown in Table II. PD rate was significantly higher in Group A compared with Group B (p=0.007) and overall response rate was significantly worse in Group A compared with Group B (p=0.003). PFS did not differ significantly between Group A (median, 4.9 months) and Group B (median, 9.57 months) (Log-rank test, p=0.09; Figure 1). However, the OS of Group A (median, 8.6 months) was significantly worse than that of Group B (median, NA months) (Log-rank test, p=0.001, Figure 1). Cox proportional hazards regression analysis showed that liver metastasis (HR=2.11; 95%CI= 1.22-3.67; p=0.008) and ECOG performance status (HR=2.74; 95%CI=1.55-4.85; p=0.001) were significant predictors of PFS (Table III). In contrast, CIP (HR=3.16; 95%CI=1.61-6.18; p=0.0007), liver metastasis (HR=2.32; 95%CI=1.26-4.28; p=0.007), and ECOG performance status (HR=4.02; 95%CI=2.17-7.45; p=0.00001) were significantly associated with OS (Table IV).
Table I. Patient characteristics.
PS: Performance status; NSAIDs: non-steroidal anti-inflammatory drugs; ICIs: immune check point inhibitors; ALP: alkaline phosphatase; LDH: lactate dehydrogenase. *p<0.05 is considered statistically significant.
Table II. Best overall response, n (%).
CR: Complete response; PR: partial response; ORR: overall response rate; SD: stable disease; PD: progression disease. *Statistically significant.
Figure 1.
The log rank test was performed to compare progression-free survival and overall survival distributions between Group A (with CIP) and Group B (without CIP). A p-value <0.05 was considered significant.
Table III. Cox regression analysis to predict progression-free survival.
*Statistically significant.
Table IV. Cox regression analysis to predict overall survival.
*Statistically significant.
Discussion
This is the first study to demonstrate that CIP along with liver metastasis and ECOG PS before the initiation of EV treatment were significant predictors of a worse OS. The presence of CIP may be associated with worse ECOG PS; however, CIP was found to be an independent predictive factor for OS in this study. Furthermore, we observed a worse overall response rate (ORR) and higher rate of PD in patients with CIP compared to those without. Even though EV is an effective treatment, patients with CIP may exhibit resistance to EV therapy.
In our cohort, the number of patients with bone metastasis was higher among those with CIP than those without. Bone metastasis had been identified as one of the most common causes of pain in cancer-bearing patients. The likelihood of experiencing pain could significantly increases with the development of metastasis compared to progressive disease with localized invasion (18). Thus, if patients experience CIP, clinicians should be particularly vigilant for metastasis, especially bone involvement.
Elucidation of the mechanisms of cancer-induced bone pain can contribute to improving patient’s quality life as well as prognosis. Peripheral and central neural sensitization are identified as the primary mechanisms related to the pathogenesis of neuropathic pain caused by bone metastasis (19). Recently, many researchers have been focusing on the tumor microenvironment, which consists of various components such as immune cells, lymphatic and vascular systems, and the nervous system. Perineural invasion, through the peripheral and central nervous system, including sensory nerves, is a potential pathway for cancer metastasis and is associated with poor survival outcomes. CIP may worsen as perineural invasion leads to increased structural nerve damage. Furthermore, neural modulation by cancer cells may be closely related to treatment resistance (20). Treatment with EV may lead to significant pain relief in UC patients (21). Based on this evidence, we can speculate that EV might slow perineural invasion, achieving pain relief and a survival benefit. However, our study showed that patients with CIP experienced worse OS and ORR, and a higher rate of PD, suggesting a poorer response to EV compared to those without pain. It is also possible that patients with CIP had more advanced disease before the initiation of EV therapy, which could have resulted in an insufficient response to EV treatment. Thus, initiating EV treatment before the emergence of CIP and the establishment of a resistant neural metastatic niche may help prevent CIP and improve the survival of m/laUC patients. Recently, the combination treatment with EV and pembrolizumab as first-line therapy significantly prolonged PFS and OS in untreated m/laUC patients (22). The combination treatment with EV and pembrolizumab was used as an initial therapy, therefore the patients could have had less CIP compared to those treated with several lines of chemotherapy. Thus, EV used as first-line treatment may be more effective in preventing the future progression of CIP and improving OS compared to its use in later lines of therapy.
Study limitations. First, most of the patients with bone metastasis had CIP, with bone metastasis being identified as the primary cause of CIP. However, the cause of CIP in patients without bone metastasis is unknown. Second, we were unable to include data on treatments such as palliative radiotherapy and bone modifying agents, like anti-receptor activator of nuclear factor-κB ligand antibodies. Third, patients with CIP could have a significantly higher tumor burden, which could be a major contributing factor to their poor response to EV therapy. However, we could not incorporate tumor burden into the cox proportional hazards model in this retrospective study. Future prospective studies are warranted to investigate whether the reduction of tumor burden and the improvement of CIP are associated with survival benefits.
Conclusion
CIP before EV treatment was a significant predictor of OS in patients with m/laUC. Administering EV treatment before the onset of CIP may help improve OS.
Authors’ Contributions
Conceptualization: Mamoru Hashimoto and Kazutoshi Fujita; Methodology: Ken Fukiage, Kosei Taniguchi, Yuki Yoshikawa and Takeshi Hashimoto; Formal analysis and investigation: Takafumi Minami, Takafumi Yanagisawa and Takuya Tsujino; Writing-original draft preparation: Mamoru Hashimoto, Masanobu Saruta and Kiyoshi Takahara; Writing-review and editing: Wataru Fukuokaya, Ryoichi Maenosono and Yosuke Hirasawa; Supervision: Yoshio Ohno, Takahiro Kimura, Ryoichi Shiroki, Kazutoshi Fujita. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
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