Predictors of the therapeutic effect of Nab-paclitaxel plus gemcitabine therapy for patients with recurrent pancreatic cancer after pancreatectomy

doi:10.21203/rs.3.rs-3201226/v1

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Predictors of the therapeutic effect of Nab-paclitaxel plus gemcitabine therapy for patients with recurrent pancreatic cancer after pancreatectomy

https://doi.org/10.21203/rs.3.rs-3201226/v1

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Background/Aim

Nab-paclitaxel plus gemcitabine (GnP) is one of the standard chemotherapeutic schemes of treatment of advanced pancreatic cancer (PC). The current study has the aim to outline the predictors of therapeutic effect of GnP in the cases with recurrent PC after pancreatectomy.

Patients and Methods

We retrospectively evaluated the clinicopathological characteristics of patients with recurrent PC after pancreatectomy who received GnP at our institution from January 2016 to February 2021. We examined various inflammatory markers [neutrophil lymphocyte ratio (NLR), lymphocyte monocyte ratio (LMR), platelet lymphocyte ratio (PLR), C-reactive protein albumin ratio (CAR)] and a nutritional marker [ prognostic nutritional index (PNI) ] in addition to common clinicopathological characteristics as possible predictors of the chemotherapeutic effects of GnP.

Results

Univariate analysis identified PLR, CAR, and histological differentiation as significant predictors of better chemotherapeutic effects. Meanwhile, multivariate analysis identified only histological differentiation as an independent predictor of better chemotherapeutic effects. Accordingly, patients with well-differentiated adenocarcinoma showed better overall survival after recurrence than those with other histological types.

Conclusion

Histological differentiation can be a useful predictor of the therapeutic effects of GnP in the clinical cases of recurrent PC after pancreatectomy.

Nab-paclitaxel plus gemcitabine

pancreatic cancer

histological differentiation

Pancreatic cancer (PC) is considered one of the most aggressive malignant tumors (1, 2) with one of the highest mortality rates. The incidence rate of PC is approximately equal to the latter estimated per year, with an overall 5-year survival rate of approximately 8% (1). Moreover, only between 10% and 20% of the patients have resectable PC (3–7), among whom 50–86% will experience recurrent tumors despite curative resection, with a resulting 5-year survival rate of approximately 10–20% (3–6). Therefore, chemotherapy is required for many patients who have undergone pancreatectomy for PC.

Since the first publication of the effects of gemcitabine in 1997 (8), several chemotherapy schemes have been developed and assessed for the treatment of PC. Among them, Nab-paclitaxel plus gemcitabine (GnP) has become one of the standard therapies for patients with unresectable PC based on superior efficacy results compared to gemcitabine monotherapy in the MPACT trial (9).

Previous reports regarding chemotherapeutic treatment have focused mainly on patients with unresectable PC given that lethal diseases were mostly detected in patients with unresectable cancer. In recent years, advances in diagnostic modalities as well as the widespread use of medical screening has facilitated the relatively early detection of PC, consequently increasing the number of patients who undergo surgical resection. Most patients, however, experience recurrent cancer, even after apparently curative resection for the disease. Although patients who have relapse have more clinicopathological information than those with unresectable PC, no previous reports have identified predictors for chemotherapeutic effect.

Therefore, the current study sought to clarify the predictors of therapeutic effect of GnP in clinical cases of recurrent PC after pancreatectomy.

Patients

We investigated 48 cases of relapsed PC after pancreatectomy involving the chemotherapy with Nab-paclitaxel plus gemcitabine at our institution from January 2016 to February 2021. Patients’ characteristics, laboratory data, and pathological results were then determined from the electronic medical records.

Patients with resected PC received S-1 [40, 50, or 60 mg determined by body surface area for oral intake twice a day for 28 days with a 14-day rest period, during 6 weeks per cycle (for up to four cycle)] (10) or gemcitabine doses [(1000 mg/m²) for intravenous administration on days 1, 8, and 15, for 4 weeks per cycle, the number of which was up to six cycles], (8) as adjuvant therapy.

Regarding tumor markers, the levels of carbohydrate antigen 19 − 9 (CA19-9), carcinoembryonic antigen (CEA) and duke pancreatic monoclonal antigen type 2 (DuPAN-2) were estimated every 4 weeks, and computed tomography (CT) was carried out every 3 months after surgery.

Recurrence of PC was defined as tumor appearance on CT.

This study received the approval from the Human Research Ethics Committee of Faculty of Medicine, University of Yamanashi (No. H30186).

Treatment

Patients received intravenously Nab-paclitaxel at a dose of 125 mg/m² followed by gemcitabine (Gem) at a dose of 1000 mg/m² on days 1, 8, and 15 every 4 weeks(9). 5-HT3 antagonist plus dexamethasone was administered for all patients. To patients who had grade 3 peripheral sensory neuropathy or grade 4 hematologic toxicities, the dosage of Nab-paclitaxel and Gem was decreased to 100 and 800 mg/m², respectively (9). Treatment was continued until disease progression. It was discontinued if adverse events happened including toxicity characterized by National Cancer Institute-Common Toxicity Criteria version 4.0.

The criteria of the treatment were Eastern Cooperative Oncology Group performance status (PS) < 3 and adequate hematological, cardiac, respiratory, hepatic, and renal function.

Evaluation factor

Response rates to chemotherapeutic treatments remain moderate in relapsed pancreatic cancer, and patients with progressive disease show extremely poor prognosis. Therefore, effective cases were shown as those who achieved disease control (DC) following treatment (DC group), whereas ineffective cases were outlined as those with progressive disease (PD group). Disease control group consisted of patients with complete response (CR), partial response (PR), and stable disease (SD) for 12 weeks or longer. Enrolled patients provided informed consent for treatment.

Apart from common clinicopathological characteristics, various inflammatory markers [neutrophil lymphocyte ratio (NLR), lymphocyte monocyte ratio (LMR), platelet lymphocyte ratio (PLR), and C-reactive protein albumin ratio (CAR)] and a nutritional marker [the prognostic nutritional index (PNI)] were examined at the start of chemotherapeutic treatment. We also examined the predictive value of histological differentiation in the resected specimen, timing of recurrence after pancreatectomy (the early recurrence group during adjuvant chemotherapy and late recurrence group after adjuvant chemotherapy).

Study evaluations

Objective response of target lesion was graded using the Response Evaluation Criteria in Solid Tumors (version 1.1) criteria, and radiological responses were investigated at our institution, including a radiologist. The response of tumor marker was detected as a greater than 50% decrease from baseline for response and greater than 20% increase from baseline for progression (3–6).

Statistical analysis

Statistical analyses of data were carried out with Student’s t-test and chi-square tests. PFS from the start of GnP was assessed by Kaplan-Meier method and analyzed using the log-rank test. Cut-off values were determined by receiver operating characteristics curve analysis. Multivariate prognostic analysis was performed using factors that had a p-value < 0.05 obtained during univariate analysis. EZR software was used for all statistical analyses (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).

Patients’ characteristics and univariate analysis

Two groups of patients were formed according to their therapeutic effect. There were 31 cases who achieved disease control (DC group) and 17 cases with progressive disease (PD group), resulting in a disease control rate of 65.6%. The median age was 67 and 71 years in DC and PD groups, respectively. The DC group had a relatively higher proportion of males, although the difference was not significant. Regarding inflammatory markers, the significant differences in PLR and CAR were detected between study and control groups (p = 0.021 and 0.009, respectively). However, no significant difference in NLR, LMR, and PNI, as well as CA19-9, were noted between the two groups.

Regarding tumor histological differentiation, the patients with well-differentiated adenocarcinoma showed a significantly better response than those with other histological types, which consisted of 22 moderately differentiated, 5 poorly differentiated, 1 anaplastic, and 1 mucinous adenocarcinoma (p < 0.001). The recurrence pattern was similar between the two groups. After comparing the timing of recurrence, we found that the late recurrence group tended to show better therapeutic effects compared to the early recurrence group, although no significant difference was noted (p = 0.065). Regarding previous use of gemcitabine, no significant difference was detected between the two groups. All data are summarized in Table 1.

Table 1

Patients’ characteristics and univariate analysis
	DC group	PD group	p value
	n = 31	n = 17
Age (mean, range)	66.9 (46–78)	70.5 (57–81)	0.17
Sex
Male	23	8	0.147
Female	8	9	0.147
Inflammatory markers
NLR	2.36 ± 1.47	2.74 ± 1.24	0.378
LMR	4.26 ± 1.90	3.61 ± 1.93	0.27
PLR	137.5 ± 61.3	202.5 ± 127.3	0.021
CAR	0.048 ± 0.044	0.223 ± 0.354	0.009
Nutritional marker
PNI	48.5 ± 4.7	46.4 ± 8.0	0.256
Tumor marker
CA19-9 (U/mL)	455.0 ± 219.6	329.3 ± 135.3	0.691
Performed operation
Total pancreatectomy	2	0	0.666
Pancreaticoduodenectomy	18	11
Distal pancreatectomy	11	6
Histological differentiation
Well-differentiated adenocarcinoma	18	1	< 0.001
Other histological types	13	16	< 0.001
Recurrence formation
Hematogenous metastasis	18	11	0.363
Peritoneal dissemination	4	4
Local recurrence	14	3
Timing of recurrence
Early recurrence group	9	10	0.065
Late recurrence group	22	7	0.065
Gemcitabine naïve	25	12	0.486
receive	6	5	0.486
LMR: lymphocyte-to-monocyte ratio, NLR: neutrophil-to-lymphocyte ratio, PLR: platelet-to-lymphocyte ratio, PNI: prognostic nutritional index, CA19-9: carbohydrate antigen 19 − 9

Table 2

Multivariate analysis
	Odds ratio	95% CI	p
PLR	0.992	0.983–1.0	0.141
CAR	0.5151 × 0^− 3	0. 397 × 10^− 8–66.80	0.208
Well-differentiated adenocarcinoma	0.047	0. 437 × 10^− 2–0.556	0.012
Other histological types	0.047	0. 437 × 10^− 2–0.556	0.012
Early recurrence group	0.83	0.131–5.28	0.844
Late recurrence group	0.83	0.131–5.28	0.844

Multivariate analysis

Based on these results, multivariate analysis was performed on PLR, CAR, histological differentiation, and timing of recurrence. Accordingly, only histological differentiation was identified as an independent predictor of better therapeutic effect (p = 0.012) (Table.2).

Relationship between the histological differentiation and overall survival after recurrence

Survival analysis showed that patients with well-differentiated adenocarcinoma had significantly better overall survival after recurrence than those with other histological types (2-year survival rate: 71.7% vs. 44.8%; median survival term: 30.5 vs. 22.7%, respectively) (Fig. 1).

The combinative therapy of Nab-paclitaxel and gemcitabine had a positive impact on the overall survival rate after recurrence, especially in patients with well-differentiated adenocarcinoma.

Recent comprehensive genomic analyses have clearly demonstrated that various changes in the tumor genomic/epigenomic profile and microenvironment occur during successive tumor evolution, resulting in different clinicopathological features with intra-tumoral heterogeneity among primary, metastatic, and recurrent tumors (11–14). Changes that occur during tumor evolution might determine the potential for drug efficacy and resistance (11, 14). In various studies on chemotherapeutic treatment, however, unresectable locally advanced PCs with/without distant metastases have been lumped together with postoperative recurrent PCs as treatment targets (9, 15–18).

Various chemotherapeutic regimens have been developed and examined for efficacy in PCs, one of the most aggressive type of malignant tumors with high mortality rate. The MPACT trial demonstrated that GnP offered significant survival benefits for both primary pancreatic and metastatic lesions, making it one of the important treatments for patients with PC (9). This trial, however, included patients with both locally advanced PC with/without distant metastases and recurrent cancers. Considering the tumor genomic/epigenomic evolution as well as microenvironmental changes, locally advanced PC with metastases might exhibit different therapeutic efficacy and resistance compare to recurrent cancer. These finding prompted us to examine the predictors of therapeutic efficacy of GnP in patients with recurrent tumors.

Multivariate analysis conducted in the current study identified only histological differentiation as an independent predictor for the efficacy. Recent advancements in diagnostic modalities have allowed us to obtain pathological information in inoperable patients with PC. In fact, there have been many reports of preoperative histological diagnosis by EUS-FNA (19–21); however, precise diagnosis of histological differentiation is sometimes difficult given the small amount of specimens. Moreover, the necessity to include histological types in analysis during a diagnostic biopsy to tailor treatment remains unproved (11, 22, 23). Conversely, all patients who developed recurrent cancer were able to exhibit more accurate and comprehensive histological information, including tumor heterogeneity, from resected specimens. Considering these findings, pathological tumor differentiation can be used to determine the chemotherapeutic strategy for patients with recurrent PCs.

Studies on other gastrointestinal cancers have highlighted the relationship between histological types and prognosis and recurrence patterns (24–27). However, about GnP in patients with recurrent PC, it has not been sufficiently analyzed. We also examined whether recurrence patterns differ depending on the histological type (28), which might result in a difference in therapeutic effect. However, the current study found no difference in recurrence pattern according to histological differentiation.

Increasing evidence has suggested that the presence of an ongoing systemic inflammatory response (15, 29–37) and nutritional data (38, 39), ECOG performance status (15), and CA19-9 (15) can be used as predictors of poor outcomes in patients with cancer. However, such factors were not identified as predictors of therapeutic effect of GnP in our study. This might be connected with the early diagnosis of recurrence in our cohort, resulting in a relatively good condition.

Currently, the strongest regimens for patients with PCs include GnP and FOLFIRINOX (16–18), which have been recommended by international guidelines as first-line treatments for patients with metastatic PCs (40, 41). However, which treatment would perform better as first-line therapy remains controversial. Whether histological types or subtypes should be considered when tailoring treatment remains to be demonstrated (11). PC has been reported to have high heterogeneity within the primary and metastatic tumors, which could possibly be associated with drug resistance (11, 28, 42). In the future, circulating tumor cells and circulating tumor DNA may provide real-time and more accurate predictors for sensitivity and/or resistance to therapies (43–48).

Some limitations of the current study are to be represented. First, this was a retrospective, single-center study with a relatively small sample. Additionally, no histological diagnosis has been made for metastatic lesions. However, no reports have focused on predictors of the therapeutic efficacy of GnP in patients with recurrent PC after pancreatectomy. Accordingly, our finding showed that histological type can be useful for selecting anti-cancer agents in clinical practice.

We have revealed that histological type was an independent predictor of the therapeutic effect of GnP for patients with recurrent PC after radical surgery. This result might have significant implications for the treatment selection of GnP and FOLFIRINOX.

Ethics approval and consent to participate

This study was reviewed and approved by the ethics committee of the University of Yamanashi.

Informed consent statement

Patients were not required to provide informed consent given that the analysis used anonymous clinical data obtained after each patient agreed to treatment by written consent.

Data sharing statement: No additional data are available.

Clinical trial registration number: UMIN ID: 000031203

Acknowledgements

None

Funding

None.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author information

Hiromichi Kawaida contributed to this work.

Affiliations

First Department of Surgery, Faculty of Medicine, University of Yamanashi

Author contributions

All authors helped perform the research. Kawaida H was actively involved in this study, especially with the statistical design. The concept and clinical design were established by six surgeons (Kawaida H, Hosomura N, Amemiya H, Saito R, Kono H and Ichikawa D). Acquisition of data was performed by all physicians (Kawaida H, Hosomura N, Amemiya H, Saito R, Shoda K, Furuya S, Akaike H, Kawaguchi Y, Kono H, Itakura J, Fukasawa Y, Kawakami S, Shindo H, Takahashi E, Takano S, Fukasawa M, Simizu T, Enomoto N, Fujii H, Ichikawa D). Interpretation of data and drafting the article was performed by H. Kawaida. Finally, this article was revised and approved by all 20 investigators. Thus, all 20 authors actively participated in this study.

Corresponding author

Correspondence to Hitomichi Kawaida.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Human Research Ethics Committee of Faculty of Medicine, University of Yamanashi (No. H30232).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Predictors of the therapeutic effect of Nab-paclitaxel plus gemcitabine therapy for patients with recurrent pancreatic cancer after pancreatectomy

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Abstract

Figures

Introduction

Patients and Methods

Patients

Treatment

Evaluation factor

Study evaluations

Statistical analysis

Results

Patients’ characteristics and univariate analysis

Multivariate analysis

Relationship between the histological differentiation and overall survival after recurrence

Discussion

Conclusion

Declarations

References

Additional Declarations

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