Second-line Chemotherapy in Advanced Gastric Cancer: Taxanes versus 5-FU-Based Treatment

By Yakup Duzkopru, Ebru Cilbir, Goksen Inanc Imamoglu, Ozlem Dogan, Tulay Eren

Affiliations

1. Department of Medical Oncology, Health Sciences University Diskapi Yildirim Beyazit Training and Research Hospital, Medical Oncology, Ankara, Turkiye

doi: 10.29271/jcpsp.2023.07.770

ABSTRACT
Objective: To determine the comparative efficacy of taxane-based treatment and 5-FU-based treatment as second-line chemotherapy regimens in advanced gastric cancer patients, as measured by overall survival (OS) and progression-free survival (PFS).
Study Design: Observational study.
Place and Duration of the Study: Department of Medical Oncology, Health Science University Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkiye, from January 2008 and December 2020.
Methodology: Patients aged 18 years and older, diagnosed with gastric cancer, who received at least one line chemotherapy were included. Patients who received FOLFIRI, FOLFOX, and capecitabine in the second-line therapy were grouped as those who received 5-FU-based treatment, while those who received docetaxel and paclitaxel were grouped as those who received taxan-based treatment. The primary outcome measures, OS and PFS, were assessed and compared between the treatment groups using the Kaplan-Meier method.
Results: A total of 172 patients were included in this analysis, among whom 73 (42.4%) received second-line chemotherapy. Among the patients who received the second-line treatment, 50 (68.5%) were males. The median age of the cohort was 60 years (23-86), with 37 (50.7%) patients falling into the <60 age group. The overall response rates (ORR) were 8% (2/25) in the taxane group and 16.7% (8/48) in the 5-FU-based treatment group. The median overall survival (OS) for all patients receiving second-line therapy was 7.52 months (standard error: 0.97; 95% confidence interval [CI]: 5.62-9.43). Specifically, the median OS was 5.16 months (standard error: 1.07; 95% CI: 3.07-7.25) in the taxane group and 8.02 months (standard error: 1.40; 95% CI: 5.28-10.75) in the group receiving 5-FU-based therapy (p=0.11).
Conclusion: The superiority of chemotherapy regimens to each other could not be demonstrated. However, the second-line treatment demonstrated clear superiority over the best supportive care. Therefore, it is recommended that all patients with good performance status (PS) should be offered second-line treatment.

Key Words: Gastric cancer, Second-line chemotherapy, Taxanes, Treatment efficacy, 5-Fluorouracil.

INTRODUCTION

Gastric cancer is the fifth most common cancer worldwide with over 1 million new cases and it is the fourth most common cancer in cancer-related deaths.¹ Only one-third of patients have operable disease when they are diagnosed, with the majority of cases being in the locally advanced and metastatic stage.² Metastatic gastric cancers have a poor prognosis and a 5-year survival rate of 5.9%.³

The  primary  treatment  of  gastric  cancer  is  surgery  at  the  early stage. Combinations of fluoropyrimidines and platinum compounds are used in first-line treatment in metastatic cases, and combination of immunotherapy and chemotherapy (CT) has become the new standard treatment for eligible patients in recent years. Although most patients initially respond to treatment, and eventually progress.⁴ Median OS after the second-line therapy has been reported between 4 months and 5.9 months in different studies.^4,5 Second-line chemotherapy options are; paclitaxel, docetaxel, 5-fluorouracil (5-FU) and irinotecan, ramucirumab (an antiangiogenic agent) alone or in combination with paclitaxel, trastuzumab in human epidermal growth factor receptor 2 (HER2) positive patients and pembrolizumab in MSI high patients.^6-9

However, since PFS and OS are not at the desired level, the search for new treatment options continues. The objective of this study was to evaluate and compare second-line chemotherapy regimens used in the treatment of advanced gastric cancer.

METHODOLOGY

Patients who were followed up with the diagnosis of gastric cancer in the Department of Medical Oncology, Health Science University Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkiye, between 2008 and 2020 were retrospectively screened. Patients diagnosed with gastric cancer, aged 18 years and older, who received chemotherapy for at least 3 months in a metastatic setting were included in the study. Patient data were recorded from the hospital database and by examining the follow-up files. Patients with missing data or out of follow-up, patients with second cancer and who received herbal or additional treatment were excluded. The study protocol was approved by the Hospital’s ethical committee (date: 12.07.2021, No. 115/06).

The time from the start of the second-line chemotherapy until the date of radiological progression according to the RECIST criteria was accepted as PFS. The time from the start of treatment in the second-line to the date of the last control or the date of death was accepted as OS. Those who received FOLFIRI, FOLFOX, and capecitabine in the second-line therapy were grouped as those who received 5-FU-based treatment (n=48), while patients who received docetaxel and paclitaxel were grouped as those who received taxan-based treatment (n=25). Treatment groups are compared for OS and PFS. In this study, the median age was calculated as 60 and the patients were divided into 2 groups as <60 years and ≥60 years.

Statistical analyses were performed using IBM SPSS Statistical Software (IBM SPSS Statistics version 22.0, IBM SPSS, USA). The clinical and demographic characteristics of the patients were analysed by descriptive analysis. Categorical and numerical variables were presented as numbers and percentages (n,%). Continuous data were expressed as means ± standard deviation when the data followed normal distribution; otherwise, they were expressed as median and range. PFS and OS were calculated by the Kaplan-Meier method. Hazard ratio (HR) and 95% confidence interval (CI) values were calculated by the Cox-regression model. Differences between groups were calculated with the log-rank test. A p-value <0.05 was considered statistically significant for all analyses.

RESULTS

Out of the 172 patients who underwent at least one-line of chemotherapy, 73 (42.4%) received second-line chemotherapy. Among those who received second-line chemotherapy, 50 were males (68.5%). The median age of the patients was 60 (23-86) years. Thirty-seven (50.7%) patients were in the <60 age group. Fifty-five (75.3%) of the patients were in the de novo metastatic group. Peritoneal metastasis was present in 22 (30.1%) of the patients. There were additional comorbid diseases in 32 (43.8%) of the patients.

As second-line treatment, 25 (34.2%) patients received taxanes and 48 (65.8%) received 5-FU-based treatment. Among those who received 5-FU-based treatment, 32 (43.8%) received FOLFIRI, 10 (13.7%) received FOLFOX, and 6 (8.2%) received single-agent capecitabine. Baseline characteristics are shown in Table I.

The overall response rates (ORR) were 8% (2/25) in the taxane group and 16.7% (8/48) in the 5-FU-based treatment group. In terms of ORR, there was no significant difference between the taxane and 5-FU-based treatment groups (p= 0.307). Considering the disease control rate, it was 32% (8/25) in the taxane group and 45.8% (22/48) in the 5-FU-based treatment group. There was no statistically significant difference between the groups (p=0.254).

Median OS was 7.52 (std. Error=0.98, 95% CI 5.60-9.45) months in all patients receiving second-line therapy. Median OS was 5.16 (std. error = 1.07 95% CI 3.07-7.25) months in the taxane group. The median OS was 8.83 (std. error = 1.35, 95% CI 6.18-11.50) months in the group receiving 5-FU based therapy. There was no statistically significant difference between the treatment groups in terms of OS (p=0.096). Median OS was 8.83 (std. error = 1.47 95% CI 5.96-11.72) months in the <60 age group, and median OS was 6.21 (std. error = 1.54 95% CI 3.19-9.23) months in the ≥60 age group. Although there was a numerical difference between the age groups in terms of OS, this difference was not statistically significant (p=0.10). In terms of OS and PFS, the results of the Cox regression multivariate analysis performed are presented in Table II.

Median PFS was 4.17 (std. error = 0.627, 95% CI 2.94-5.40) months in the whole patient population. Median PFS was 2.89 (std. error = 0.137, 95% CI 2.62-3.16) months in the taxane group and the median PFS was 5.45 (std. error = 1.017, 95% CI 3.46-7.45) months in the 5-FU-based treatment group. The difference between the groups was statistically significant (p:0.001). Median PFS was 5.75 (std. error = 0.71 95% CI 4.35-7.15) months in the <60 age group, and median PFS was 3.45 (std. error = 0.74 95% CI 2.00-4.90) months in the ≥60 age group. While the difference between age groups in terms of PFS was significant in univariate analysis (p:0.029), no significant difference was found in multivariate analysis (p=0.176, Table II).

Since all patients received platinum and fluoropyrimidine-based therapy in the first-line, patients receiving capecitabine and FOLFOX as second-line therapy were excluded. After this exclusion, only patients who received FOLFIRI (32 patients) and taxane (25 patients) as second-line therapy were compared. There was a statistically significant difference in terms of PFS between the groups that took taxanes and FOLFIRI, with a median PFS of 2.89 months and 4.3 months, respectively (p=0.013). There was no statistically significant difference between the groups in terms of ECOG Performance Status (p=0.537). There was no statistically significant difference between the groups in terms of OS; receiving taxanes and FOLFIRI with a median OS of 5.16 months and 8.84 months, respectively (p=0.130).

The incidence of any grade neutropenia was 44%, 56.3%, 16.7%, and 33.3% in the taxan, FOLFIRI, capecitabine, and FOLFOX groups, respectively. The incidence of grade 3-4 neutropenia was 28%, 31.3%, 16.7% and 33.3%, respectively.

Table I: Baseline characteristics.

	All patients n (%)	Taxan n (%)	5-FU based regimen n (%)
Gender    Female    Male	23 (31.5%)	6 (24%)	17 (35.4%)
	50 (68.5%)	19 (76%)	31 (64.6%)
Age     <60     ≥60	37 (50.7%)	9 (36%)	28 (58.3%)
	36 (49.3%)	16 (64%)	20 (41.7%)
ECOG PS      0      1      2	19 (26%) 39 (53.4%) 15 (20.5%)	6 (24%) 15 (60%) 4 (16%)	13 (27.1%) 24 (50%) 11 (22.9%)
Comorbid disease      Yes      No	32 (43.8%)	14 (56%)	18 (37.5%)
	41 (56.2%)	11 (44%)	30 (62.5%)
Location of primer tumour      Cardia, fundus      Corpus      Antrum, pylor	17 (23.3%) 28 (38.4%) 28 (38.4%)	6 (24%) 11 (44%) 8 (32%)	11 (22.9%) 17 (35.4%) 20 (41.7%)
De novo metastasis      Yes      No	55 (75,3%)	19 (76%)	36 (75%)
	18 (24.7%)	6 (24%)	12 (25%)
Peritoneal metastasis      Yes      No	22 (30.1%) 51 (69.9%)	6 (24%) 19 (76%)	16 (33.3%) 32 (66.7%)
Number of metastatic sites     One     Two or more	55 (75.3%) 18 (24.7%)	19 (76%)  6 (24%)	36 (75%) 12 (25%)
Second-line CT type     FOLFİRİ     FOLFOX     Capecitabine     Paclitaxel     Docetaxel	32 (43.8%) 10 (13.7%) 6 (8.2%) 16 (21.9%) 9 (12. %3)	25 (34.2%)	48 (65.8%)
ECOG PS: Eastern cooperative oncology group performance status.

Table II: OS and PFS Cox regression multivariate analysis.

	OS		PFS
	HR (95% CI)	p-value	HR (95% CI)	p-value
Age
<60	1(reference)	0.169	1(reference)	0.176
≥60	1.47(0.85-2.53)		1.43 (0.85-2.42)
Comorbidity
No	1(reference)	0.479	1(reference)	0.652
Yes	0.81(0.45-1.45)		1.13 (0.66-1.93)
Chemotherapy groups
Taxane	1(reference)	0.167	1(reference)	0.013
5-FU based therapy	0.66(0.37-1.19)		0.499(0.29-0.87)
PFS: Progression-free survival, OS: Overall survival.

DISCUSSION

In spite of the existence of many phase 3 studies carried out for the efficacy of the second-line treatment in locally advanced and metastatic gastric cancers, the superiority of chemotherapy regimens to each other could not be demonstrated. In this study, it was aimed to present real-life data as a retrospective, single-centre experience.

In the COUGAR-02 study, comparing docetaxel every 3 weeks and active symptom control, the median OS was 5.2 months in the docetaxel group and 3.6 months in the active symptom control group. PFS data were not presented in this study. Considering the response evaluation, the ORR was 7% in the docetaxel group, while the rate of stable disease was 46%.⁶ In the REGARD study comparing ramucirumab and BSC, Ramucirumab showed superiority over BSC in terms of median OS and PFS. Median OS was 5.2 months in the ramucirumab arm and 3.8 months in the BSC arm. Median PFS was 2.1 months in the ramucirumab arm and 1.3 months in the BSC arm. The ORR was 3% in the ramucirumab arm, while the stable disease rate was 45%.⁸ Similarly, in phase 3 studies conducted in Germany and Korea, it was shown that the second-line chemotherapy is superior to BSC.^10,11 In a phase 3 study (WJOG 4007) comparing weekly paclitaxel and biweekly irinotecan in advanced metastatic gastric cancer previously treated with platinum and fluoropyrimidine, median OS was 9.5 months in the paclitaxel group, and 8.4 months in the irinotecan group. Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group.⁹ In a phase 3 study comparing pembrolizumab and paclitaxel, KEYNOTE-061, median OS was 9.1 months in the pembrolizumab arm and 8.3 months in the paclitaxel arm. Median PFS was 1.5 months in the pembrolizumab arm and 4.1 months in the paclitaxel arm in this study. When the response assessment was made, the ORR was 16% vs. 14% in the pembrolizumab and paclitaxel arms, respectively.⁷ In this study, a total of 73 patients between the ages of 23 and 86 were included and the male/female rate was 68.5/31.5%. Thirty-seven patients were under 60 years of age. The median OS was 5.16 months in the taxan group and 8.83 months in the 5-FU-based treatment group. With these values, median OS was similar to the phase 3 study conducted by Ford et al. in which taxanes were used in the second-line (5.2 months)⁶ and also with the retrospective study conducted by Arai et al. (5.1 months).¹² The median OS in the current study was found to be similar to the phase 2 study of Kim et al. (7.6 months) in which irinotecan and 5-FU were used in the second-line.¹³

Although the median OS was numerically longer in the group under 60 years of age compared to the group over 60 years of age, this difference did not reach statistical significance. In the current study, the median PFS was 2.89 months in the taxan group and 5.45 months in the group that received 5-FU-based treatment, and the difference between the groups was statistically significant (p=0.001). PFS in the taxane group was found to be similar to that of Arai et al.'s study (2.8 months),¹² which is also a retrospective study, comparing paclitaxel and irinotecan. In the current study, the ORR was found to be 8% in the taxane group and 14.9% in the group that received 5-FU-based treatment. Stable disease rates were 24% in the taxane group and 28.8% in the group that received 5-FU base treatment.

Since all patients received platinum and fluoropyrimidine based therapy in the first line, when the second-line use of capecitabine and folfox was excluded from the analysis. When the patients who received FOLFIRI (32 patients) and taxanes (25 patients) as the second-line therapy were compared; the median PFS was significantly longer in the FOLFIRI arm compared to taxane arm (p=0.130). The median PFS was 4.3 months and 2.89 months in the FOLFIRI and taxane groups, respectively. In terms of OS, there was no statistically significant difference between the groups receiving FOLFIRI and taxane, with a median OS of 8.84 months and 5.16 months, respectively (p: 0.130). This numerical difference did not give a statistically significant result. It was thought that this was due to the small number of patients.

The most common grade 3-4 side effects in paclitaxel and irinotecan treatments were neutropenia, which gastrointestinal side effects were noteworthy in the irinotecan arm. The most common side effects of ramucirumab treatment were fatigue, bleeding, and hypertension. In pembrolizumab treatment, the most common grade 3-4 side effects were fatigue and anaemia, and immune-related side effects were seen in less than 1%.^6-9 In this study, the most common grade 3-4 side effect was neutropenia in both the taxan group and the group receiving 5-FU-based treatment, with a similar rate (28% and 31.3%) in both groups.

When the second-line treatment options are compared, it is understood that they do not generally have significant advantages over one another. However, the adoption of targeted therapies has introduced new treatment options. Trastuzumab and trastuzumab deruxtecan are potential options for patients with HER2 overexpression. Additionally, immunotherapy agents such as pembrolizumab and nivolumab may be considered for patients with microsatellite instability (MSI) high-status patients.^14-16 However, since immunotherapy is not within the scope of reimbursement in gastric cancer in Turkiye, the authors could only present the patients who received CT.

The current study has some limitations. The retrospective single-centre study design and its susceptibility to bias were one of the most important limitations. Another limitation was that the number of patients in the treatment groups was small and unequal due to the low number of patients who could receive second-line treatment in advanced gastric cancer. Moreover, patients with incomplete records were excluded from analyses, which may have biased the results. This research should be supported by prospective studies with larger samples to confirm these findings.

Although the biology of advanced gastric cancer is under better and the availability of new treatments is increased, survivals are still not at the desired level.¹⁷ However, since the superiority of the second-line treatments over BSC has been shown, all patients with good PS should be offered the second-line treatment.⁵

One of the most important points in the selection of the second-line treatment is which treatment the patient received in the first-line. The best approach would be to make a decision by considering the patient's clinic, laboratory and comorbidities when choosing a second-line treatment.

CONCLUSION

The superiority of chemotherapy regimens to each other could not be demonstrated. However, the second-line treatment demonstrated clear superiority over the best supportive care. Therefore, it is recommended that all patients with good performance status (PS) should be offered second-line treatment.

DATA AVAILABILITY STATEMENT:
The raw data supporting the conclusions of this article will be made available by authors, without undue reservation.

ETHICAL APPROVAL:
The writers are responsible for all aspects of the writing, including ensuring that any concerns about the work’s quality or credibility are thoroughly investigated and resolved. The Health Sciences University Diskapi Yildirim Beyazit Training and Research Hospital (Ankara, Turkiye) Ethics Committee (Date: 12.07.2021, No. 115/06) approved the study, and all individual participants provided written informed consent.

PATIENTS’ CONSENT:
This is a retrospective study, so patients’ consent is not required.

COMPETING INTEREST:
The authors have no affiliation with any organisation with a direct or indirect financial interest in the subject matter discussed in the manuscript. The authors have reported that no funding was received for this study.

AUTHORS’ CONTRIBUTION:
YD: Had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, particularly with regard to any adverse effects.
GII, EC, OD, TE: Contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript.
All the authors have approved the final version of the manuscript to be published.

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