Efficacy of Gemcitabine Plus Nab-paclitaxel in Second-line Treatment of Metastatic Pancreatic Cancer: a Multicenter Retrospective Study in Turkey

doi:10.21203/rs.3.rs-4800776/v1

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Efficacy of Gemcitabine Plus Nab-paclitaxel in Second-line Treatment of Metastatic Pancreatic Cancer: a Multicenter Retrospective Study in Turkey

https://doi.org/10.21203/rs.3.rs-4800776/v1

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Despite numerous studies on second-line therapies in metastatic pancreatic cancer, there is no randomized study evaluating the efficacy of gemcitabine plus nab-paclitaxel as a second-line treatment. This study aims to examine the efficacy of gemcitabine plus nab-paclitaxel in second-line therapy. In this retrospective study, a total of 218 patients from 23 centers were included and the median age of 60.2 years. The primary endpoint was progression-free survival (PFS), secondary endpoints included overall survival (OS), treatment efficacy based on ECOG performance status (PS), and tumor marker (CEA, CA 19 − 9) levels. In the second-line treatment with gemcitabine plus nab-paclitaxel, the median PFS was 5.1 months (95% CI, 5.6 to 7.1), and the median OS was 8.6 months (95% CI, 7.3 to 10.0). Median PFS was 6.6 months in patients with normal CEA levels compared to 4.4 months in patients with high CEA levels (P = 0.01). Median PFS was 6 months in patients with ECOG PS 0–1 compared to 3.8 months in patients with PS 2 (P < 0.01). This study demonstrates the contribution of gemcitabine plus nab-paclitaxel in both OS and PFS in second-line treatment of metastatic pancreatic cancer. We believe it is a good option, especially for younger patients with good ECOG PS.

Metastatic pancreatic cancer

Gemcitabine plus Nab-Paclitaxel

Progression-free survival

Overall survival

Pancreatic cancer is the 12th most common type of cancer worldwide, with 511,000 new cases annually, and its mortality rate is nearly equal to its incidence rate. This makes pancreatic cancer the sixth leading cause of cancer-related death. Unfortunately, the prognosis is quite poor, with a five-year survival rate of 13% for all stages, which drops below 5% at the metastatic stage.¹

Surgical resection is the only curative option for pancreatic cancer. However, 85% of patients are not eligible for resection at diagnosis.² In cases of pancreatic cancer not suitable for local treatment, multiple-agent cytotoxic chemotherapy drugs are generally used. Initially, median survival with single-agent gemcitabine or fluoropyrimidine drugs was around 6 months, but with multi-agent combinations, median OS can approach 1 year.^3,4 The selection of these agents depends on various factors, primarily performance status. International guidelines recommend FOLFIRINOX (a combination of folinic acid, 5-fluorouracil [5-FU], irinotecan, and oxaliplatin), gemcitabine plus nab-paclitaxel, or Liposomal irinotecan + 5-FU + leucovorin + oxaliplatin (NALIRIFOX) regimens for first-line treatment in patients with good performance status who can tolerate multi-agent chemotherapy.⁵ Although there is no randomized study comparing these combinations directly, both have been shown to be superior to single-agent gemcitabine in randomized trials.^3,4 Despite their superiority over gemcitabine, most patients with pancreatic cancer experience progression due to the aggressive nature of the disease. Post-progression treatment options are more limited, with single-agent gemcitabine or 5-FU-based drugs or combination therapies for patients with good performance status being used. In rare cases, targeted agents may be used for specific genetic alterations (RET, TRK fusion, MSI, BRCA, etc.).⁵

Although gemcitabine plus nab-paclitaxel has been proven more effective than gemcitabine monotherapy in first-line treatment, there is no randomized study evaluating its efficacy as a second-line treatment. Prospective single-arm studies with a limited number of patients have reported overall response rates (ORR) of 10–20% and OS ranging from 7.6 to 8.9 months with gemcitabine plus nab-paclitaxel in second-line treatment after FOLFIRINOX failure.^6,7 With single-agent gemcitabine in this stage, ORR is around 10%, and median OS is below 6 months.⁸ Although patient selection bias cannot be ignored, indirect comparisons suggest that gemcitabine plus nab-paclitaxel is numerically better.

This study primarily aims to investigate the efficacy of gemcitabine plus nab-paclitaxel in second-line treatment of metastatic pancreatic cancer following FOLFIRINOX progression. Secondarily, the tolerability, frequency of side effects, and which patient groups the treatment is more effective for will be investigated.

Between December 2014 and April 2023, a total of 218 patients were included in this study, of which 134 (61.5%) were male and 84 (38.5%) were female (male/female ratio: 1.6). The median follow-up period was 16.9 months (range, 5.1 to 62.6 months). The median age at diagnosis was 60.2 years (range, 33.8 to 76.6 years). At diagnosis, 171 patients (78.4%) were in the metastatic stage. By the cut-off date, 184 patients (84.4%) had died, and 34 (15.6%) were still alive. The general demographic characteristics of the patients during first-line treatment are provided in Table 1.

Table 1

General characteristics of patients during first-line treatment
		N = 218 (%)
Age (years)		60.2 (33.8–76.6)
Sex
	Male	134 (61.5)
	Female	84 (38.5)
Disease state at the time of diagnosis
	Non-metastatic	47 (21.6)
	Metastatic	171 (78.4)
ECOG at the time of diagnosis
	0–1	187 (85.7)
	2	31 (14.3)
PFS after first-line treatment (months)		6.8 (6.1–7.4)
OS after first-line treatment (months)		17.9 (16.2–19.6)
PFS: Progression-free survival, OS: Overall survival

In the metastatic stage, the median PFS with first-line treatment was 6.8 months (95% CI, 6.1 to 7.4), and the median OS was 17.9 months (95% CI, 16.2 to 19.6).

In the second-line treatment, patients received a median of 6 cycles (range, 1–36 cycles) of gemcitabine plus nab-paclitaxel. The general characteristics and treatment responses of patients during second-line therapy are shown in Table 2. The median PFS for patients receiving gemcitabine plus nab-paclitaxel was 5.1 months (95% CI, 5.6 to 7.1). In second-line treatment, 34 patients (15.6%) were still alive, with a median OS of 8.6 months (95% CI, 7.3 to 10.0). When comparing PFS based on response status at 3 months, patients with partial response had a median PFS of 9.7 months (95% CI, 8.3 to 10.1), and those with stable disease had a median PFS of 7.3 months (95% CI, 6.5 to 8.1), which was statistically significant (P:0.01) (Fig. 1).

Table 2

General characteristics of patients during gemcitabine plus nab paclitaxel treatment
		N = 218 (%)
Age (years)		61.7 (34.3–77.3)
Number of cycles given		3 (1–36)
Response status at 3 months (N = 218)
	Complete radiological response	3 (1.4)
	Partial response	49 (22.5)
	Stable disease	48 (22.0)
	Progressive disease	118 (54.1)
Response status at 6 months (N = 96)
	Complete radiological response	4 (4.1)
	Partial response	16 (16.6)
	Stable disease	27 (28.1)
	Progressive disease	49 (51.2)
ECOG
	0–1	149 (68.3)
	2	69 (31.7)
Carcinoembryonic antigen (CEA) level
	Normal	84 (38.5)
	High	117 (53.7)
	Missing	17 (7.8)
Carbohydrate antigen 19 − 9 (CA 19 − 9) level
	Normal	54 (24.8)
	High	146 (67.0)
	Missing	18 (8.3)
PFS after first-line treatment (months)		5.1 (4.3-6.0)
OS after first-line treatment (months)		8.6 (7.3–10.3)
ECOG:Eastern Cooperative Oncology Group, PFS: Progression-free survival, OS: Overall survival

The relationship between tumor marker levels (CEA and CA 19 − 9) and survival was analyzed by comparing high and normal levels before the first cycle of gemcitabine plus nab-paclitaxel. Patients with normal CEA levels (< 5 ng/ml) had a median PFS of 6.6 months (95% CI, 5.3 to 7.9), while those with elevated CEA levels (≥ 5 ng/ml) had a median PFS of 4.4 months (95% CI, 3.9 to 4.8), which was statistically significant (P: 0.01)(Fig. 2). For OS, patients with normal CEA levels had a median OS of 12.1 months (95% CI, 9 to 15.2), compared to 7.9 months (95% CI, 6.8 to 9) for those with elevated CEA levels, which was statistically significant (P < 0.001) (Fig. 3). There were no significant differences in PFS and OS between patients with normal and elevated CA 19 − 9 levels.

At the start of gemcitabine plus nab-paclitaxel treatment, 68.3% of patients (n = 149) had ECOG PS 0 or 1, while 31.7% (n = 69) had ECOG PS 2. In the survival analysis, patients with better ECOG PS (0 or 1) had a median PFS of 6 months (95% CI, 5.1 to 7), compared to 3.8 months (95% CI, 3 to 4.6) for those with ECOG PS 2, which was statistically significant (P < 0.01) (Fig. 4). For OS, patients with ECOG PS 0–1 had a median OS of 10.2 months (95% CI, 8.1 to 12.4), compared to 6.8 months (95% CI, 7.3 to 8.2) for those with ECOG PS 2, which was statistically significant (P < 0.01) (Fig. 5).

Univariate analysis showed better OS in patients with low CEA levels compared to those with high CEA levels (HR = 0.65 [95% CI: 0.48–0.89]; P: 0.007). Similarly, there was a significant survival advantage for patients with ECOG PS 0–1 compared to PS 2, with details of univariate and multivariate analyses provided in Table 3.

Table 3

Univariate - multivariate overall survival analysis in patients receiving gemcitabine plus nab paclitaxel
Variable	Overall survival
	Univariate			Multivariate
	HR	%95 Cl	P value	HR	%95 Cl	P value
CEA level (Low vs. high)	0.65	0.48–0.89	< 0.01	0.76	0.55–0.96	0.03
CA 19 − 9 level (Low vs. high)	1.2	0.85–1.6	0.2
ECOG (0–1 vs. 2)	0.59	0.43–0.80	0.01	0.51	0.37–0.72	< 0.001
Metastasis status at the time of diagnosis (Non metastatic versus metastatic)	1.34	0.95–1.9	0.05
CEA: Carcinoembryonic antigen, CA 19 − 9: Carbohydrate antigen 19 − 9, ECOG:Eastern Cooperative Oncology Group

In patients receiving gemcitabine plus nab-paclitaxel, grade 3 or higher toxicity was observed in 28.9% (n = 63) of patients with neutropenia, 19.7% (n = 43) with anemia, and 20.1% (n = 44) with thrombocytopenia. Dose reduction due to toxicity was performed in 63 patients (28.9%), and treatment was discontinued in 20 patients (9.2%) due to toxicity. There were no deaths related to gemcitabine plus nab-paclitaxel treatment. The frequency of treatment-related adverse events is shown in Table 4. During treatment, granulocyte colony-stimulating factor (G-CSF) support was provided to 38.1% of patients (n = 83).

Table 4

Treatment-related adverse events
Event	Any grade, n (%)	Grade 3–4, n (%)
Aneemia	186 (85.8)	43 (19.7)
Neutropeenia	157 (72)	63 (28.9)
Thrombositopeni	133 (61.5)	44 (20.1)
Liver toxicity	7 (3.2)	1 (0.5)
Cardiac toxicity	2 (0.9)	0
Respiratory toxicity	1 (0.5)	0
Noropathy	30 (13.8)	12 (5.5)
Others	14(6.4)	2 (0.9)

According to the results of this retrospective multicenter observational study, which analyzed the data of 218 patients who used gemcitabine plus nab-paclitaxel as second-line treatment following FOLFIRINOX progression, the objective response rate (ORR) was 23.9%, PFS was 5.1 months, and OS was 8.6 months. Despite the limited treatment options for this disease and the lack of optimal sequential data, our findings support the use of gemcitabine plus nab-paclitaxel in second-line treatment for patients who progressed on FOLFIRINOX and have good performance status.

Although second-line treatments such as liposomal irinotecan and FOLFOX have been studied and shown to improve survival, there is still no clear guideline recommendation for second-line treatment of metastatic pancreatic cancer.^10,11 The combination of gemcitabine plus nab-paclitaxel as a second-line treatment has not yet been approved or included in guidelines. The lack of consensus on second-line treatment recommendations and the unmet needs of many patients prompted this study. We aimed to evaluate the efficacy and tolerability of gemcitabine plus nab-paclitaxel in second-line treatment for patients who progressed on first-line therapy.

In the PRODIGE 4 study, which evaluated the efficacy of FOLFIRINOX in first-line treatment, the median PFS was 6.4 months, and OS was 11.1 months.⁴ In our study, patients who received FOLFIRINOX in first-line treatment had a median PFS of 6.8 months and a median OS of 17.9 months. According to a meta-analysis by Nichetti et al., NALIRIFOX, FOLFIRINOX, Gemcitabine plus Nab-Paclitaxel studies were examined in first-line treatment.¹² According to this meta-analysis, overall survival was 10.4–11.7 months. In our study, we found that PFS value was compatible with the literature and OS value was longer than the literature. The possible reasons for the longer OS data are that our patients had better ECOG PS, our patients were younger compared to previous studies, our patients received an effective combination such as gemcitabine plus nab-paclitaxel in the second line after FOLFIRINOX treatment in the first line and almost half of the patients received a third line treatment.

The primary objective of this study was to evaluate the efficacy of gemcitabine plus nab-paclitaxel in second-line treatment, where we found a median PFS of 5.1 months. In the largest randomized study of gemcitabine plus nab-paclitaxel in first-line treatment of metastatic pancreatic cancer, the MPACT study, the PFS was 5.5 months, and OS was 8.5 months. ³ Despite being a second-line treatment in our study, the PFS was 5.1 months and OS was 8.6 months, comparable to the MPACT study Other studies on gemcitabine plus nab-paclitaxel in both first- and second-line treatments reported PFS ranging from 3.5 to 5.7 months and OS from 7.1 to 18 months.^6,12–14 Our study aligns with the literature regarding both PFS and OS.

Although there is no randomized study on gemcitabine plus nab-paclitaxel in second-line treatment, several small studies have shown this combination to be more effective than gemcitabine monotherapy, providing a partial survival benefit.^8,13,15–17 In a literature review, we found qualitative similarities between our study and the one conducted by Zaibet et al., which compared the efficacy of gemcitabine plus nab-paclitaxel with gemcitabine monotherapy in patients who progressed on FOLFIRINOX. Their analysis indicated that the combination therapy was superior to monotherapy in terms of both overall and progression-free survival.¹³ Our study reported a higher ORR of 23.9%, compared to 12% in the Zaibet et al. study.

Numerous studies have shown that patients with good ECOG PS have better overall and progression-free survival than those with poor PS.^1,17,18 In our study, Cox regression analysis indicated that patients with ECOG PS 0–1 had significantly longer PFS and OS than those with PS 2, consistent with the literature.

Patients with high levels of CEA and CA 19 − 9 at the start of gemcitabine plus nab-paclitaxel treatment had worse PFS and OS. The MPACT study also found that patients with high, non-decreasing CA 19 − 9 levels had worse survival.^3,13 Other studies have similarly linked high CA 19 − 9 levels with poor prognosis. ^13,19 Our study also showed that high tumor marker levels were associated with poor survival, supporting these studies. In this respect, we believe that high tumor marker levels are associated with poor survival and have prognostic importance.

When our study was analyzed in terms of side effects and safety, neutropenia was the most common side effect observed in 28.9% patients with grade 3 and above. When previous studies were analyzed, neutropenia rates were found to be between 13–38% and our study was similar to the literature. ^3,19,20 The frequencies of grade 3–4 anemia and thrombocytopenia were also similar to those reported in the literature.^3,13

Neuropathy was a major concern since all patients had received FOLFIRINOX in first-line treatment. Neuropathy rates of 4% for taxane regimens and 0-7.5% for oxaliplatin are known.^{11,17,21–23} In our study, 13.8% of patients experienced grade 2–3 neuropathy, likely due to the sequential administration of oxaliplatin and taxane.

Despite being retrospective, our study is valuable due to its multicenter design and real-world data. A literature review revealed no other large-scale studies on the combination of gemcitabine plus nab-paclitaxel in second-line treatment of metastatic pancreatic cancer. Therefore, we believe our study, which demonstrated contributions to both PFS and OS in 218 patients from 23 centers, will contribute to the literature.

It is possible to mention some limitations of this study. The primary limitations of our study include the lack of randomization due to its retrospective nature and the absence of a control group receiving an alternative treatment. Additionally, patients who were deceased or had a poor performance status (PS) following first-line treatment were not included, and the metastasis sites and number of metastases were not specified.

In this study evaluating the efficacy of the gemcitabine plus nab-paclitaxel combination in second-line treatment for metastatic pancreatic cancer following FOLFIRINOX progression, we obtained a PFS of 5.1 months and an OS of 8.6 months. The majority of observed side effects were manageable. We found that the gemcitabine plus nab-paclitaxel combination is effective and tolerable, making it a good option, especially for younger patients with good ECOG PS. We believe that this study should be supported by prospective studies.

This study is a retrospective analysis involving 23 cancer diagnosis and treatment centers from different provinces in Türkiye. In this multicenter study, patients with histologically confirmed pancreatic adenocarcinoma, diagnosed between December 2014 and April 2023, were screened. Following screening, a total of 218 patients who received gemcitabine plus nab-paclitaxel as second-line therapy after progression on FOLFIRINOX during the metastatic phase were included in the study. Patients over the age of 18 with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2 were included. Patients with a secondary malignancy, ECOG PS 3–4, or those who received nab-paclitaxel in treatments other than second-line were excluded from the study.

Chemotherapy regimens; For the Gem-Nab group, treatment consisted of a 60-min infusion of Nab-paclitaxel at a dose of 125 mg/m² followed by a 30-min infusion of Gem at a dose of 1000 mg/m² on days 1, 8 and 15 every 4 weeks, as previously reported.³ Treatment was delivered until either disease progression or unacceptable treatment toxicity was reached.

Metastasis confirmation was done via computed tomography (CT) or positron emission tomography (PET-CT). Response evaluation was performed every 8–12 weeks based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.⁹ Progression-free survival (PFS) was calculated from the start of chemotherapy to radiological progression, clinical progression, or death from any cause. Overall survival (OS) was calculated from the start of chemotherapy to death.

Hemogram and biochemical blood tests were examined before each treatment cycle. Chemotherapy-related toxicities were evaluated in line with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) V4.03 and managed by dose reduction of one or both drugs at the discretion of the physician.

In the study, tumor marker levels were measured before starting gemcitabine plus nab-paclitaxel, and survival relationships were analyzed in patients with high and normal levels. The upper limit for carcinoembryonic antigen (CEA) was 5 ng/ml, and for carbohydrate antigen 19 − 9 (CA 19 − 9) was 37 U/ml. The relationship between OS and PFS was examined in patients with good versus poor ECOG PS (ECOG PS 0–1 vs. PS 2).

Statistical Analysis

All analyses were conducted using IBM SPSS Statistics 25.0 The normality of the numerical data was assessed using the Kolmogorov-Smirnov test. Median values with minimum and maximum values were given for non-normally distributed data. Kaplan–Meier calculations with the log-rank test were used for the analysis of OS and PFS. Univariate and multivariate analyses were performed using a Cox proportional-hazard model. Hazard ratios (HR) and 95% confidence intervals (CI) were reported. Overall, p-values ≤ 0.05 were considered statistically significant.

Ethics declarations and informed consent

The study protocol was approved by The Van Regional Training and Research Hospital (IRB No. 2023 / 19/ 04 -13.09.2023 ), and was performed in accordance with the ethical guidelines of the World Medical Association’s Declaration of Helsinki. Informed consent was waived from the IRB due to the retrospective design.

Conference presentation

This study has been accepted as a poster at European Society for Medical Oncology 2024 (ESMO 2024) congress and will be presented with the number FPN 1523.

Data availability

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

Acknowledgements

The authors thank all of the patients and their families

Author contributions

YS, OK, MNA, MÜ, ZU, AUK, ME, YG and HY contributed to the study conception and design. Data acquisition was performed by YS, AAS, MG, MY, MEK, MÖA, SU,NA,İG, MS, MNB, MBA, MÖ, AA, MA, TA, BME,HA, HA, MS,BUK,EÖ, SA, SY, HY, SG, NM, İA, AB, Sİ, ST, . Quality control of data, data analysis and interpretation were performed by YS, YG, ZU, OK, and MNA. Statistical analysis was performed by YS, OK, MNA and MÜ. The frst draf of the manuscript was written by YS, OK, YG, MÜ, MNA and HY. The manuscript was critically reviewed by all authors. All the authors have read and approved submission of this fnal manuscript. Te requirement for consent for publication was obtained using the opt-in/opt-out approach according to each participating institution’s policy.

Competing interests

The authors declare no competing interests

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No competing interests reported.

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Efficacy of Gemcitabine Plus Nab-paclitaxel in Second-line Treatment of Metastatic Pancreatic Cancer: a Multicenter Retrospective Study in Turkey

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