Abstract
Background: Taxane-based chemotherapy is useful for peritoneal dissemination control in advanced/recurrent gastric cancer; however, insufficient relative dose intensity (RDI) may preclude disease control achievement. Nab-paclitaxel, with high tumour permeability, is a promising second- or later-line treatment. Patients and Methods: We retrospectively evaluated the clinical safety and efficacy of nab-paclitaxel for advanced/recurrent gastric cancer patients treated between April 2013 and December 2015. The response rate, RDI and survival outcomes were assessed. Results: Of 14 evaluated patients, 4 achieved partial response. Overall response and the disease control rates were 28.5% and 64.2%, respectively. Nine patients developed peritoneal metastasis; their overall response and disease control rate were 22.2% and 66.6%. Patients with high RDI (≥80%) showed longer progression-free and overall survival than those with low RDI (≤80%) (11.8 vs. 4.0 months, p=0.02; and 14.3 vs. 8.2 months, p=0.03, respectively). Conclusion: Nab-paclitaxel, at an RDI ≥80%, was safe and beneficial for these patients.
Although the prognosis of unresectable/recurrent gastric cancer is poor, chemotherapy with S-1 (tegafur plus gimeracil plus oteracil potassium) remarkably improves treatment outcomes (1, 2). In Japan, S-1 is also used for adjuvant therapy and recommended as first-line treatment of unresectable/recurrent gastric cancer (2, 3). Taxanes are mainly used for second- or later-line chemotherapy (4). Further, taxane-based chemotherapy has been shown to prolong patients' expected survival time (4-8). Many patients planned to undergo second-line chemotherapy have a poor Eastern Cooperative Oncology Group (ECOG) performance status (PS). Nevertheless, continued treatment and sustained relative dose intensity (RDI) may improve patient's prognosis (9, 10).
Nanoparticle albumin-bound (nab)-paclitaxel is paclitaxel linked to 130-nm albumin nanoparticles. It is a new class of anticancer agent that incorporates albumin particle technology. Nab-paclitaxel allows for a safe infusion of significantly higher doses of paclitaxel than with standard paclitaxel therapy. Additionally, nab-paclitaxel allows shorter infusion schedules without the need for premedication for hypersensitivity reactions as with standard paclitaxel. Furthermore, nab-paclitaxel shows an increased paclitaxel transport across endothelial cells and greater antitumor activity compared with standard paclitaxel in a preclinical study (11).
In a domestic phase II clinical trial, patients with treatment-refractory cancer who were treated with first-line chemotherapy containing S-1 showed a favourable response rate of 28%, progression-free survival (PFS) of 2.9 months and overall survival (OS) of 9.2 months after treatment with nab-paclitaxel (12). However, this phase II clinical trial is the only one to evaluate nab-paclitaxel treatment for patients with gastric cancer. Thus, the safety and survival benefits of nab-paclitaxel in clinical practice remain unclear. In this retrospective study, we evaluated the clinical safety and efficacy of nab-paclitaxel for unresectable/recurrent gastric cancer patients.
Patients and Methods
Patient selection. We included unresectable/recurrent gastric cancer patients treated at out Institute between April 2013 and December 2015. The inclusion criteria were as follows; (i) patients with unresectable/recurrent gastric cancer, (ii) aged between 20 and 85 years, (iii) with ECOG PS 0-2, (iv) with or without history of gastrectomy, and (v) adequate hematologic, liver and renal functions (i.e., neutrophils >1,500/ml; platelet count >100,000 /ml; estimated glomerular filtration rate (eGFR) >40 ml/min/1.73 m3; total bilirubin concentration ≤two times the upper limit of normal; and liver transaminase or alkaline phosphatase concentrations ≤three times the upper limit of normal). Exclusion criteria were as follows: (a) patients with active malignant disease, (b) with severe co-morbidity, (c) pregnant women.
Basic characteristics of the 14 patients.
Treatment. Nab-paclitaxel was administered intravenously over 30 minutes at a dose of 260 mg/m2 on day 1 of 3-week cycles. In consideration of the PS, a one- or two-level dose reduction was employed during the initial treatment.
End-points and evaluation of clinical response. The primary end-point was safety in clinical practice. The secondary end-points were response rate, OS and PFS. Tumour response was assessed with computed tomography according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) (13). We calculated the RDI and adverse events were assessed using Common Terminology Criteria for Adverse Events ver 4.0.g
OS was defined as the time elapsed from the first visit to death. PFS was defined as the time elapsed from the day of nab-paclitaxel treatment start to the date of the first occurrence of disease progression or death by any cause. The follow-up period was closed on December 2016. Survival curves were constructed using the Kaplan-Meier method.
Results
Patients' characteristics. Fourteen patients were included in this study. Patients' characteristics are shown in Table I. Patients had a median age of 69 (range=63-78) years. Three patients had PS of 2; nine patients, 1; and two patients, 0. The histological type was differentiated in eight patients (57%) and undifferentiated in six. The metastatic site was the peritoneum in nine patients; liver, four; and lungs, one patient (including overlap). Peritoneal metastasis was the most common. S-1, cisplatin and CPT-11 were mainly used for first- or second-line chemotherapy before nab-paclitaxel treatment.
The initial dose of nab-paclitaxel was as follows: 260 mg/m2 for five patients; 220 mg/m2 for four patients; and 180 mg/m2 for five patients. The dose was decreased in nine patients (64.3%) and increased in three. The number of treatment courses, RDI and reasons for treatment discontinuation are shown in Table II. The median total number of treatment courses was 8 (2-16). The median RDI was 79.3% based on the dose given during each course for each patient and the specified dose of nab-paclitaxel (260 mg/m2). The reasons for treatment discontinuation were disease progression (57%, 8/14), adverse events (14%, 2/14) and patient preference (14%, 2/14). The treatment is ongoing in two patients.
Treatment status and reasons for discontinuation (n=14).
Adverse events.
Adverse events. The main adverse events of any grade were peripheral neuropathy (71.4%, n=10), anorexia (57%), neutropenia (29%) and alopecia (29%). Nine patients presented Grade 1 or Grade 2 peripheral neuropathy. Two patients discontinued because of adverse events: one patient with Grade 3 peripheral neuropathy and one patient with Grade 3 rash. No treatment-related death occurred (Table III).
Efficacy. Table IV shows the response to treatment of the 14 patients. Of all patients, 4 achieved partial response. The overall response rate was 28.5% and the disease control rate 64.2%. In a subset of nine patients with peritoneal metastasis, the overall response rate was 22.2% and the disease control rate 66.6%.
Clinical responses of patients.
Summary of results of trials using nab-paclitaxel or paclitaxel in patients with gastric cancer.
Figure 1 shows the Kaplan–Meier survival curves. Median OS was 10.5 (95% confidence interval (CI)=3.8-14.3) months and the median PFS 6.0 (95% CI=3.5-11.8) months. Based on the median RDI of 79.3%, 80% was set as the RDI cut-off and patients were divided into a ≥80% RDI group (high RDI) and ≤80% RDI group (low RDI). The PFS of patients in the high RDI group was better than that of patients in the low RDI group (11.8 vs. 4.0 months, p=0.02, Figure 2A). The OS of patients in the high RDI group was also better than that of the patients in the low RDI group (14.3 vs. 8.2 months, p=0.03, Figure 2).
Discussion
This study has demonstrated three important findings. First, nab-paclitaxel is safe for second- or later-line chemotherapy for advanced/recurrent gastric cancer patients in clinical practice. Second, the clinical outcomes achieved with nab-paclitaxel as a second- or later-line chemotherapy agent are acceptable. Third, a sufficient RDI is needed for patients treated with nab-paclitaxel to benefit from such clinical outcomes.
Kaplan-Meier curves of overall and progression-free survival of the 14 patients. OS, Overall survival; PFS, progression-free survival; M, months; CI, confidence interval.
Overall survival (OS) and progression-free survival (PFS) with a relative dose intensity (RDI) cut-off of 80%.
Nab-paclitaxel has been found to be a safe second- or later-line treatment for advanced gastric cancer, although patients undergoing second-line chemotherapy are generally in poor condition and, thus, at higher risk of developing severe adverse events. In this study, in which 29% of patients were undergoing third-line treatment, only two patients (14%) discontinued treatment for adverse effects.
When comparing the present results with those from the WJOG 4007 trial with weekly paclitaxel (4) and the domestic phase II trial of nab-paclitaxel (12), the response rates, PFS, as well as OS, were comparable among studies and nab-paclitaxel was found to be useful for second-line chemotherapy in clinical practice (Table V). However, further prospective studies are needed to validate the benefits of second-line nab-paclitaxel for advanced gastric cancer. In the WJOG 4007 trial, which included 91 patients treated with weekly paclitaxel, the response rate was 20.9%; the disease control rate, 64.2%; PFS, 3.6 months; and OS, 9.5 months (4). In the domestic phase II trial, which included 54 patients treated with tri-weekly nab-paclitaxel, the response rate was 27.8%; disease control rate, 59.3%; PFS, 2.9 months; and OS, 9.2 months (12). Notably, although our study included patients undergoing third-line treatment, we showed that these patients achieved acceptable and comparable response rates (28.5%), disease control rate (64.23%), PFS (6.0 months) and OS (10.5 months).
In order for patients to obtain the clinical benefits from nab-paclitaxel treatment, the RDI must be sufficiently high and maintained throughout the treatment. Although dose reductions are inevitable in second- or later-lines of chemotherapy, such dose reductions may also lead to decreased antitumor effects. For other malignancies, including breast and haematological cancers, a higher RDI has been demonstrated to contribute to survival (9, 10). In the present study, the median RDI was 79.3%; thus, an RDI of 80% was considered as the cut-off value. Patients with an RDI of ≥80% had significantly better PFS and OS. Further, this indicates that dose reductions of ≥20% should be considered carefully and that providing supportive care to maintain the patient's physical condition may be important.
Recently, improvements in survival outcomes have been observed in patients with advanced gastric cancer who received combination treatment with ramucirumab and paclitaxel in the RAINBOW and REGARD trials; however, treatment complications, including oncologic emergencies, such as perforation, were reported. Therefore, such combination treatments should be administered with care (14, 15). Conversely, in the ABSOLUTE trial, weekly nab-paclitaxel therapy was demonstrated to be non-inferior to 3-weekly nab-paclitaxel with a high response rate and a favourable rate of ascites decrease (16). These results indicate that further survival benefits can be expected from weekly nab-paclitaxel therapy in the future, as well as with the addition of ramucirumab to the second-line therapy with nab-paclitaxel for advanced gastric cancer.
This retrospective study has several limitations. First, it included only a small number of patients. Second, this study included patients undergoing not only second-line but also third-line treatment. Third, the criteria for dose reduction are not standardized. To evaluate the safety and benefits of nab-paclitaxel as second-line chemotherapy in clinical practice, large prospective studies, including only patients planned to undergo second-line treatment, are needed.
Nab-paclitaxel, as second- or later-line chemotherapy agent, is safe and beneficial for patients with unresectable/recurrent gastric cancer. Maintaining the RDI ≥80% is important to achieve the clinical benefits of nab-paclitaxel.
Acknowledgements
This works supported in part by the Medical staff of Nippon Medical School Hospital (data management).
Footnotes
Conflicts of Interest
None declared.
- Received March 6, 2017.
- Revision received March 19, 2017.
- Accepted March 20, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
