Using a retrospective cohort design, the present study examined the efficacy of chemotherapy in patients with UC of the pancreas. The most frequently used first-line treatment regimens were gemcitabine, S-1, and gemcitabine plus nab-paclitaxel. Although there was no significant difference in OS among these first-line regimens, gemcitabine plus nab-paclitaxel significantly improved PFS compared with gemcitabine, and it showed a significantly higher ORR compared with both gemcitabine and S-1. In addition, one complete response was observed in a patient treated with paclitaxel. A paclitaxel-containing first-line regimen significantly improved OS compared with a non-paclitaxel-containing regimen. After adjustment, use of a paclitaxel-containing regimen in any line was still an independent predictor of OS. All these observations indicate that a paclitaxel-containing regimen is a reasonable option for treatment of patients with unresectable UC of the pancreas.
The present study showed that most UC patients were diagnosed at the age of 60-70 years, with a slight male predominance. These clinical features were similar to those of PC [2], but median OS for UC patients treated with chemotherapy did not exceed 5 months. In recent phase 3 trials for metastatic PC [14] [15], the median OS reached approximately 1 year. The present study clearly showed that UC was refractory to chemotherapy. Of the chemotherapeutic regimens used for UC, gemcitabine monotherapy was the most frequently used regimen for unresectable UC in the present study; it provided a limited response, with median PFS and an ORR of 1.61 months and 3.7%, respectively. Most patients with unresectable UC had lower ECOG PS at the time of diagnosis, and the majority of patients received only one line of treatment. Although gemcitabine monotherapy still remains a therapeutic option for frail and elderly patients with PC [16] [17] [18], the benefit of gemcitabine monotherapy may be limited for UC patients. On the other hand, paclitaxel-containing regimens may have a relatively high anti-tumor effect in UC. Paclitaxel has shown activity in anaplastic carcinoma of the thyroid [19] [20] and sarcoma (e.g. angiosarcoma and Kaposi's sarcoma) [21] [22] [23] [24]. It has been reported that UC of the pancreas expressed epithelial-mesenchymal transition (EMT) markers (e.g. Slug, Twist, Zeb1), as in anaplastic carcinoma of the thyroid and sarcoma [8] [25]. Drug sensitivity of UC of the pancreas may be similar to these neoplasms because they show similar pathological features and expression of EMT markers.
EMT is a complex process by which epithelial cells lose their cell polarity and cell-cell adhesion, and they gain migratory and invasive properties to mesenchymal cells. Accumulating evidence indicates that EMT plays a crucial role in cancer-related events, including cancer invasion and metastasis. EMT is known to be associated with a poor prognosis in various cancers, and this fact may contribute to the aggressive clinical course of UC. On the other hand, the mechanism of the effect of paclitaxel on UC is unclear. Paclitaxel, including nab-paclitaxel, is a widely used chemotherapy drug for various cancers, including PC [26] [27] [28]. However, many studies have reported that the EMT is associated with acquired resistance to chemotherapy drugs [29] [30] [31], including paclitaxel [32]. The EMT is known as a heterogeneous phenomenon and the progression of cancer varies depending on the EMT phenotype [33]. Mattiolo et al. reported that the EMT was also expressed in UC, both with and without OGCs [23]. Ishida et al. categorized UC into 2 subgroups based on the expression patterns of EMT markers and E-cadherin. They suggested that these differences in EMT phenotypes may have an impact on the prognosis of UC [24]. Given these findings, the EMT status may have an impact on the response to paclitaxel in UC. However, further elucidation is required to understand differences in drug responses.
In addition to the efficacy of paclitaxel-containing regimens, a multivariate Cox proportional hazard model showed that age ≥65 years was an independent predictor of OS in patients treated with chemotherapy. Fundamentally, chemotherapy provides a modest survival benefit in patients with unresectable UC. However, some patients had a good response to chemotherapy and achieved relatively long survival. In such a situation, there is a critical need to identify high-risk patients and select patients who will potentially benefit from treatment based on predictors. For example, for patients who are not expected to respond to chemotherapy, it is possible to avoid highly invasive treatments and focus on quality of life. By predicting the chemotherapeutic response, it makes a significant contribution to the selection of treatment for UC. Age is a widely accepted prognostic factor for PC, and Clark et al. reported that age was an independent prognostic factor for survival in UC (HR per 10 years, 1.1; 95% CI, 1.04 - 1.2) in their population-based study [6]. This report supports the present findings. It should be noted that the survival benefit of chemotherapy for UC may be limited in patients aged ≥65 years.
Future directions in research on UC will lead to identification of biomarkers for therapeutic stratification, such as microsatellite instability-high in various types of cancers [34] and EGFR in lung cancer [35]. Currently, there is no established treatment specific to UC. Thus, most UC patients were treated by chemotherapy in accordance with PC, but the result of the present study showed limited survival benefit of chemotherapy. Presently, precision medicine, tailoring treatment based on an individual’s genetics, lifestyle, and environment, has emerged. Development of technologies can provide a comprehensive view of an individual patient's cancer [36] [37], which can impact real-time clinical decision-making. For UC patients, precision medicine has not been well established. However, newer technologies [38] can unveil various potential predictive biomarkers for possible development of new treatments and precision medicine.
This study has some limitations. The first limitation is the fact that the present analysis was a retrospective study that lacked adequate statistical power due to the small sample size. Therefore, the study should be considered only an exploratory investigation. However, UC of the pancreas is a rare malignant neoplasm, and this could complicate the recruiting for and completion of clinical trials for UC of the pancreas. The retrospective design and relatively small sample size limit the strength of this study, and the effects of chemotherapy need to be evaluated in a larger patient cohort. However, the result is not negligible because the results will benefit patients with UC for whom it has been difficult to establish therapeutic strategies. The second limitation is missing values. Due to the retrospective nature of this study, missing data were unavoidable, which may lead to bias and loss of information in the study [39]. It may undermine the value of such a small-sized study for a rare disease. Thus, multiple imputation was used to account for missing values. The prognostic factors obtained by multiple imputation may be useful in decision-making for the treatment of UC of the pancreas. The final limitation is the small number of patients treated with FOLFIRINOX. Of the 4 patients treated with FOLFIRINOX, two had partial response. FOLFIRINOX may be potentially effective for UC of the pancreas. However, even so, UC patients are often in poor condition. Thus, less invasive treatment than FOLFIRINOX, gemcitabine plus nab-paclitaxel, is a reasonable choice for UC of the pancreas [16].