Efficacy and safety of gemcitabine plus nab-paclitaxel combination chemotherapy in patients with advanced pancreatic cancer refractory to gemcitabine monotherapy

doi:10.21203/rs.3.rs-3221445/v1

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Efficacy and safety of gemcitabine plus nab-paclitaxel combination chemotherapy in patients with advanced pancreatic cancer refractory to gemcitabine monotherapy

https://doi.org/10.21203/rs.3.rs-3221445/v1

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Background: This study aimed to investigate the efficacy and safety of gemcitabine (GEM) plus nab-paclitaxel (nab-PTX): (GnP), which remain unknown, in patients with advanced pancreatic cancer (PC) who showed good tolerance to GEM monotherapy prior to being refractory to it.

Methods:We retrospectively analyzed the data ofpatients with locally advanced or metastatic PC who received GEM followed by GnP between December 2014 and March 2019, regardless of the treatment line.

Results:A total of 14 patients who received GnP after becoming refractory to GEM were included in this study. Eight patients were included in the nab-PTX naïve group: seven of whom were treated with GEM monotherapy as first-line chemotherapy and one was refractory to GEM monotherapy after modified FOLFIRINOX treatment. The other six patients were included in the nab-PTX reintroduction group. In this group, all patients received GnP followed by GEM maintenance therapy to prevent adverse events, such as peripheral neuropathy and fatigue. The nab-PTX naïve and reintroduction groups showed partial response in 2 and 0 patients, with a median progression-free survival of 7.6 and 1.4 months and median overall survival of 9.4 and 6.2 months, respectively. In the safety analysis, grade 3 peripheral neuropathy was observed in one patient in the nab-PTX reintroduction group, while other observed adverse events were grade 1 or 2.

Conclusion: This study suggests that GnP is safe and effective even after GEM-refractory PC, and GEM treatment followed by GnP may be a potentially effective treatment option for patients with nab-PTX-naïve PC.

Pancreatic cancer

Gemcitabine

Nab-paclitaxel

FOLFIRINOX

Peripheral neuropathy

Pancreatic cancer (PC) is associated with a very poor prognosis, having an estimated 5-year survival rate of 11% [1]. Surgical resection remains the only curative option for PC. However, approximately only 20% of PC cases are resectable at the time of diagnosis [2]. Even after radical resection, most patients experience disease recurrence, highlighting the role of palliative chemotherapy in the treatment of PC. Two standard chemotherapeutic regimens for patients with metastatic PC have emerged from the MPACT and PRODIGE 4/ACCORD 11 trials: gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) and 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) [3, 4]. In addition, a modified FOLFIRINOX regimen, which omits the bolus 5-fluorouracil and reduces irinotecan, is widely used in Japan, as shown in a single-arm prospective study [5].

While GEM plus nab-PTX (GnP) and FOLFIRINOX are commonly used as first-line chemotherapies for advanced PC, GEM monotherapy remains a viable option for patients with old age, poor Eastern Cooperative Oncology Group performance status (PS), and severe complications [6]. In clinical practice, physicians may switch to GnP even after starting GEM monotherapy as the first-line chemotherapy, with the expectation of tumor shrinkage. However, the use of GnP or FOLFIRINOX is often associated with the development of peripheral neuropathy [3–5, 7]. This adverse event (AE) can significantly deteriorate the quality of life, as peripheral neuropathy is often difficult to manage. Therefore, GEM maintenance therapy remains necessary in patients with persistent GnP efficacy. In some cases, due to AEs, treatment may need to be changed from GnP to GEM monotherapy in clinical practice. Additionally, some patients refractory to FOLFIRINOX may be treated with GEM monotherapy and not with GnP as second-line chemotherapy to avoid the associated AE of peripheral neuropathy linked to oxaliplatin.

Physicians often consider three patterns of administration of GnP after GEM monotherapy. The first pattern involves administering GEM monotherapy, initially due to safety concerns, in patients with old age, poor PS, and severe complications, followed by GnP in the case of patients becoming refractory to GEM. The second pattern has been observed in patients treated with GEM monotherapy after FOLFIRINOX, with GnP being introduced after patients become refractory to GEM. The third pattern has been reported in patients intolerant to GnP and receiving GEM monotherapy; after progression on GEM monotherapy, GnP was reintroduced, even though patients were reluctant to receive it. However, the efficacy and safety of GnP remain unknown in patients with advanced PC who become refractory to GEM but show good tolerance to GEM monotherapy. Therefore, this study aimed to evaluate the efficacy and safety of GnP in patients with advanced pancreatic cancer refractory to GEM monotherapy.

Study design and participants

This single-center retrospective study focused on patients with histologically or cytologically confirmed locally advanced or metastatic PC who received treatment with GnP and/or GEM monotherapy at Kyorin University Hospital, Japan, between December 2014 and March 2019. Regardless of the treatment line, patients who received GEM followed by GnP were eventually included in this study and were further categorized into the nab-PTX-naïve and nab-PTX reintroduction groups. This study was approved by the Ethics Committee of the Kyorin University Faculty of Medicine (IRB approval number: 1368) and conducted according to the principles outlined in the Declaration of Helsinki.

Assessment of response and AEs

The response rate (RR) was evaluated using computed tomography (CT) following the Response Evaluation Criteria in Solid Tumors guidelines, version 1.1. CT was performed every 2–3 months, and AEs were assessed using the Common Terminology Criteria for Adverse Events, version 4.0.

Statistical analysis

Several parameters were evaluated, including GnP treatment duration, tumor response, AEs, RR, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RR was defined as the proportion of patients who achieved complete response (CR) or partial response (PR). DCR was defined as the proportion of patients with CR, PR, or stable disease (SD). PFS was measured as the time from the initiation of GnP treatment after GEM-refractory to the date of disease progression, death from any cause, or whichever occurred earlier. OS was defined as the time from the initiation of GnP treatment after GEM-refractory to the date of death from any cause. PFS and OS were estimated using the Kaplan–Meier method. Statistical analyses were performed using the SAS Release version 9.4 statistical software suite (SAS Institute, Cary, NC, USA).

Patient characteristics

A total of 285 patients with advanced PC received GnP or GEM monotherapy between December 2014 and March 2019. Of these patients, 14 who received GnP for GEM-refractory disease were eventually included in this study. The median age of patients was 72 years, with a PS of 0 in six patients and 1 in eight patients at the initiation of GnP after GEM-refractory. Regarding the primary tumor sites, three patients had tumors located in the pancreatic head and 11 patients had tumors in the pancreatic body and tail. Among these patients, three had locally advanced disease, and 11 had metastases (Table 1).

Table 1

Patient characteristics (n = 14)
Age, years [range]	72 [38–79]
Sex Male Female	7 (50.0%) 7 (50.0%)
ECOG performance status 0 1	6 (42.9%) 8 (57.1%)
Primary tumor site Head Body and tail	3 (21.4%) 11 (78.6%)
Extent of disease Locally advanced Metastatic	3 (21.4%) 11 (78.6%)
Site of metastasis Liver Peritoneum Lymph node Lung	10 (71.4%) 4 (28.6%) 2 (14.3%) 1 (7.1%)
Surgical resection Unresectable Recurrent	11 (78.6%) 3 (21.4%)
Pathologic type Adenocarcinoma Adenosquamous carcinoma	11 (78.6%) 3 (21.4%)
Previous lines of chemotherapy 0 1	7 (50.0%) 7 (50.0%)
Previous chemotherapy GnP Modified FOLFIRINOX	6 (42.9%) 1 (7.1%)
Median CA19-9, U/mL [range]	2,909 [< 2.0–120,000]
Abbreviations: ECOG, Eastern Cooperative Oncology Group; GnP, gemcitabine plus nab-paclitaxel; CA19-9, Carbohydrate antigen 19 − 9.

Patient groups

Patients were divided into two groups: the nab-PTX-naïve group (n = 8) and the nab-PTX reintroduction group (n = 6), based on their treatments (Fig. 1). Among the nab-PTX-naïve group, seven patients were treated with GEM monotherapy as first-line chemotherapy. Among these seven patients, four were aged > 75 years, two had severe complications (one with multiple lifestyle-related diseases such as hypertension, diabetes, and dyslipidemia, and the other with a history of cardiac disease), and the remaining patient requested GEM monotherapy despite being eligible for GnP. Additionally, one patient in the nab-PTX-naïve group initially received modified FOLFIRINOX as first-line chemotherapy but had to switch to GEM monotherapy for second-line chemotherapy due to grade 3 peripheral neuropathy. These eight patients constituted the nab-PTX-naïve group.

On the other hand, the nab-PTX reintroduction group comprised six patients treated with GnP as first-line chemotherapy. However, due to AEs such as grade 3 peripheral neuropathy (n = 1), grade 2 peripheral neuropathy (n = 4), and grade 2 fatigue (n = 1), GEM maintenance therapy was initiated, without evidence of tumor progression as peripheral neuropathy.

Efficacy

The median treatment duration for GEM monotherapy or maintenance was 5.4 months in the nab-PTX-naïve group and 2.3 months in the nab-PTX reintroduction group. In contrast, the median treatment duration for GnP after GEM-refractory was 7.6 months in the nab-PTX-naïve group and 1.2 months in the nab-PTX reintroduction group. Regarding the overall response, in the nab-PTX-naïve group, two patients achieved PR and five had SD, resulting in an RR of 25% and DCR of 88%. In the nab-PTX reintroduction group, two patients had SD, with an RR of 0% and DCR of 33% (Table 2). The median PFS was 7.6 months in the nab-PTX-naïve group and 1.4 months in the nab-PTX reintroduction group (Fig. 2). The median OS was 9.4 months in the nab-PTX-naïve group and 6.2 months in the nab-PTX reintroduction group (Fig. 3).

Table 2

Evaluation of parameters related to GEM plus nab-PTX treatment after GEM-refractory in the nab-PTX-naïve and nab-PTX reintroduction groups
First-line chemotherapy	nab-PTX-naïve group (n = 8)	nab-PTX reintroduction group (n = 6)
Treatment duration of GEM monotherapy, months [range]	5.5 [1.3–9.6]	2.3 [0.6–4.7]
Treatment duration of GEM plus nab-PTX after GEM-refractory, months [range]	7.6 [0.5–20.8]	1.2 [0.5–2.6]
Overall response (PR/SD/PD), n PR SD PD	2 5 1	0 2 4
RR (%)	25.0 (95% CI: 3.2–60.1)	0 (95% CI: 0–45.9)
DCR (%)	87.5 (95% CI: 47.3–99.7)	33.3 (95% CI: 4.3–77.7)
Abbreviations: GEM, gemcitabine; nab-PTX, nab-paclitaxel; PR, partial response; SD, stable disease; PD, progressive disease; RR, response rate; DCR, disease control rate; CI, confidence interval

Safety

Table 3 presents the detailed occurrence of AEs. Only two patients experienced grade 3 peripheral neuropathy, and there were no instances of grade 4 AEs or treatment-related deaths. Grade 1 or 2 peripheral neuropathy, fatigue, and anorexia were frequently observed AEs.

Table 3

Adverse events associated with GEM plus nab-PTX after GEM-refractory
	nab-PTX naïve group (n = 8)			nab-PTX reintroduction group (n = 6)
Select adverse events	Grade 1	Grade 2	Grade 3	Grade 1	Grade 2	Grade 3
Peripheral sensory neuropathy	4	3	0	1	3	2
Fatigue	5	1	0	0	1	0
Anorexia	2	2	0	1	0	0
Nausea	3	0	0	1	0	0
Dysgeusia	0	0	0	2	0	0
Abbreviations: GEM, gemcitabine; nab-PTX, nab-paclitaxel.

Subsequent treatment

Regarding subsequent treatment, one patient participated in a phase I clinical study, three patients received S-1 as the next-line therapy, and the remaining patients were transferred to palliative care.

In the present study, we retrospectively evaluated the therapeutic efficacy and safety of GnP in patients with GEM-refractory advanced PC. The results showed GnP exhibited high efficacy in nab-PTX-naïve patients with GEM-refractory advanced PC, with an RR of 25%, a median PFS of 7.6 months, and a median OS of 9.4 months. However, the efficacy of GnP in patients who underwent nab-PTX reintroduction was limited, with an RR of 0%, a median PFS of 1.4 months, and a median OS of 6.2 months. Furthermore, GnP demonstrated acceptable safety levels in patients with GEM-refractory disease.

5-fluorouracil-based therapy has been the mainstay of second-line chemotherapy in patients with GEM-refractory advanced PC. Recently, nanoliposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) has been established as a standard chemotherapy option for GEM-refractory advanced PC based on the NAPOLI-1 study [8]. This study showed an RR of 16.2%, a median PFS of 3.1 months, and a median OS of 6.1 months for nal-IRI plus 5-FU/LV. Similarly, in a Japanese validation study, nal-IRI plus 5-FU/LV showed an RR of 7%, a median PFS of 1.7 months, and a median OS of 6.3 months [9]. Moreover, S-1, an oral fluoropyrimidine, has been used as a sequential treatment for GEM-refractory advanced PC; its two single-arm prospective trials showed an RR of 15% and 9.5%, a median PFS of 2.0 and 4.1 months, and a median OS of 4.5 and 6.3 months, respectively [10, 11]. Although cross-trial comparisons are difficult, the efficacy of GnP, with an RR of 25%, a median PFS of 7.6 months, and a median OS of 9.4 months, in the nab-PTX-naïve group in this study, appears to be comparable to or even better than the results observed in clinical trials of patients with GEM-refractory advanced PC. Therefore, we believe that nab-PTX can be used in patients who are nab-PTX-naïve or non-resistant.

Furthermore, the MPCAT trial results highlighted the synergistic effects of GEM and nab-PTX [3, 12, 13]. An analysis of a mouse xenograft model of GEM-refractory PC indicated that nab-PTX can disrupt the cancer stroma, leading to reactive angiogenesis, increased perfusion, and delivery of GEM to cancer cells [12]. GEM is rapidly metabolized to the inactive form of uracil by cytidine deaminase (CDA) for renal excretion, but nab-PTX has been found to decrease CDA concentration in animal models, thus maintaining the concentration of the active form of GEM [13]. In a mouse model of PC, the concentration of GEM in the cancer stroma was 2.8 times higher with GnP than with GEM monotherapy [12]. Therefore, GnP is expected to exert antitumor effects even in patients experiencing GEM failure.

Although GnP and FOLFIRINOX are the standard first-line chemotherapies due to their superior effectiveness over GEM monotherapy in randomized phase III trials, they are associated with higher incidences of AEs [3, 4]. Therefore, these regimens should be administered to patients with a good PS. On the other hand, some patients with advanced PC, such as the elderly or those with poor PS and/or several complications, are better suited for GEM monotherapy [14]. In addition, the guidelines from the Japan Pancreas Society recommend GEM monotherapy as first-line therapy for such patients [6]. Based on our findings, it may be possible to consider adding nab-PTX as a treatment option after GEM-refractory disease if these patients show good tolerance to GEM monotherapy. Nevertheless, our study demonstrated that the efficacy of GnP was limited in the nab-PTX reintroduction group, possibly because of the shorter duration of GEM maintenance therapy in this group than in the nab-PTX-naïve group. The duration of GEM maintenance therapy was short because of tumor progression. Therefore, we consider that the patients in the nab-PTX reintroduction group might be refractory to GEM and nab-PTX (initial GnP treatment) already, upon nab-PTX reintroduction.

A study conducted on colorectal cancer has demonstrated the effectiveness of the “stop and go” approach for reducing the neurotoxicity of oxaliplatin [15, 16]. However, there are only a few reports on the use of the “stop and go” strategy of nab-PTX in advanced PC. Previously, the “stop-and-go” approach for managing nab-PTX neurotoxicity was referred to as the “OPTINAB” strategy [17]. A small retrospective study (n = 6) was conducted to evaluate the efficacy and safety of this strategy. In this study, patients received GnP until they developed grade 3 peripheral neuropathy, after which GEM monotherapy was continued as maintenance therapy. After disease progression, nab-PTX was reintroduced if the peripheral neuropathy grade decreased to 1 or lower. Although the reintroduction of nab-PTX was feasible, its efficacy was limited, with a mean PFS of 2.2 months, and the mean treatment duration for GEM maintenance was 2.8 months. These findings were similar to those of the nab-PTX reintroduction group in the present study, with a median PFS of 1.4 months and a median GEM maintenance duration of 2.3 months. Therefore, based on these results, patients with tumor progression during GEM maintenance after GnP may be preferably treated with 5-fluorouracil-based therapy rather than the “OPTINAB” strategy.

This study has some limitations. First, this was a single-center, retrospective study with a small number of patients. Nevertheless, to the best of our knowledge, this was the first study to evaluate patients in the nab-PTX-naïve and reintroduction groups. Our findings revealed the promising efficacy of GnP in patients with GEM-refractory advanced PC who were nab-PTX-naïve. Second, at the time of the planning of this study, nal-IRI plus 5-FU/LV was not approved in Japan, which limited the treatment options for patients with advanced GEM-refractory PC to S-1 monotherapy or FOLFIRINOX. Therefore, the results should be interpreted with caution to avoid selection bias. Third, the starting dose and dose modifications of GnP after GEM-refractory treatment were at the physician’s discretion.

In conclusion, GnP is a safe and potentially effective treatment option for nab-PTX-naïve patients with GEM-refractory advanced PC. However, whether GnP should be administered before or after 5-FU-based chemotherapy, particularly nal-IRI plus 5-FU/LV, remains unknown. Nevertheless, the information provided in this study on the use of GnP in this patient population will be valuable for future investigations.

Conflict of Interest Disclosure Statement:

FN has received research funding from Ono Pharmaceutical. JF has received honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Eisai, Eli Lilly, Astra Zeneca, Yakult, Incyte Biosciences, Fuji film, and research funding from Astellas, Astra Zeneca, Incyte Biosciences Japan, Eisai, MSD, Ono Pharmaceutical, Sanofy, J-Pharma, Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, Delta-Fly-Pharma, Chugai Pharmaceutical. The other authors declare no potential conflicts of interest.

Data availability statement

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

Author contributions

Conception/design: MN, NO, JF. Provision of study material or patients: MN, NO, MH, FN, JF. Collection and/or assembly of data: MN, NO. Data analysis and interpretation: MN, NO, WM, TI, TM, JF. Manuscript writing: MN, NO, JF. Final approval of manuscript: all authors.

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Efficacy and safety of gemcitabine plus nab-paclitaxel combination chemotherapy in patients with advanced pancreatic cancer refractory to gemcitabine monotherapy

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Version 1

Abstract

Figures

Introduction

Patients and Methods

Study design and participants

Assessment of response and AEs

Statistical analysis

Results

Patient characteristics

Patient groups

Efficacy

Safety

Subsequent treatment

Discussion

Declarations

References

Status:

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