Abstract
Background/Aim: The impact of clinical response to taxanes plus ramucirumab (RAM) on overall survival (OS) has not been clarified for advanced gastric cancer (AGC), although this type of therapy is already in use as second-line chemotherapy (CTx). This study aimed to investigate the prognostic impact of the clinical response to taxanes plus ramucirumab (RAM) for AGC patients. Patients and Methods: This study included AGC patients treated with paclitaxel (PTX) or nab-paclitaxel (nab-PTX) and RAM. A retrospective analysis of response and survival rates in consecutive medical records of patients was performed. Results: Forty-two patients were enrolled. Median progression-free survival and OS were 5.4 months [95% confidence interval (CI)=4.440-6.361] and 11.8 months (95% CI=8.648-15.019), respectively. In Cox-hazard multivariate analysis, peritoneal metastasis [hazard ratio (HR)=2.830; 95% CI=1.320-6.067; p=0.008], and disease control rate (HR=0.310; 95% CI=0.129-0.741; p=0.008) were independent factors. Conclusion: The response to taxanes plus RAM CTx had an impact on the survival of patients with AGC.
Gastric cancer was the fourth most common cause of new cancer cases in 2002 after lung, breast, and colorectal cancer, and the second most frequent cause of cancer-related death worldwide (1). In 2018, gastric cancer was estimated to have caused more than 1 million new cases and 780,000 deaths worldwide, particularly in East Asia, including Japan and South Korea, where the incidence rates were notably high at 32.1 men and 13.2 women per 100,000 people (2). Patients with advanced gastric cancer (AGC) can be treated with surgical resection, various chemotherapies (CTx), and radiation therapy; however, the 5-year overall survival (OS) rate for patients with stage IV disease is still 16.4% in Japan (3). To improve the prognosis of AGC patients, continuous CTx assessments and new treatments are required.
In a large trial, WJOG 4007, paclitaxel (PTX) as a taxane was shown to be beneficial as a reasonable second-line treatment after first-line CTx with fluoropyrimidine plus platinum (4). Ramucirumab (RAM) is a human IgG1 monoclonal antibody against vascular endothelial growth factor receptor-2 (5) that was shown to be beneficial for OS versus placebo in the REGARD trial (6). In addition, in the global RAINBOW study, CTx in combination with PTX plus RAM was shown to significantly improve progression-free survival (PFS) and OS in patients with AGC who had progressed on platinum- or fluoropyrimidine-based therapies (7). Another taxane, nanoparticle albumin-bound paclitaxel (nab-PTX), is a novel, solvent-free, albumin-bound, nanometre-sized 130 nm form of paclitaxel particles, and is free of polyoxyl castor oil and hydrated ethanol as solvents, reducing the risk of hypersensitivity reactions (8, 9). In patients with AGC, the efficacy of nab-PTX administered once every 3 weeks was demonstrated in a phase II trial conducted in Japan with an OS rate of 27.8% (10).
The rationale for the establishment of second-line CTx for AGC is based on two large clinical trials. In the RAINBOW trial, the combination of PTX with ramucirumab (RAM) was highly responsive compared with PTX alone (7). The ABSOLUTE trial showed that weekly nab-PTX was non-inferior to weekly PTX in efficacy (11). Recently, in the ABSOLUTE trial, quality of life (QOL) analysis was performed according to the response rate of second-line CTx, and it was reported that the antitumor effect was associated with QOL (12). In Japan, the J-0202 study showed that the combination of nab-PTX and RAM was highly responsive and well tolerated (13). Therefore, clinically, taxanes (PTX, nab-PTX) plus RAM are recommended as second-line CTx in the current Japanese gastric cancer treatment guidelines, with a few exceptions (14).
In the past, progression-free survival after first-line CTx for AGC has been reported to be correlated with survival (15, 16). However, it has also been reported that progression-free survival and disease control rate in second-line CTx are not correlated with OS (17). In other words, it is unclear whether the response rate of second-line CTx for patients with AGC has an impact on OS. This study aimed to investigate the prognostic impact of response to taxanes plus RAM as second-line CTx for patients with AGC.
Patients and Methods
Patient characteristics. We assessed the medical records of consecutive patients with AGC who were treated with CTx including taxanes plus RAM as a second-line setting according to treatment guidelines from July 2015 to December 2019 at Nippon Medical School (14). The study protocol of this retrospective analysis was approved by the Institutional review board of the Nippon Medical School Hospital. PTX or nab-PTX was applied at the discretion of the attending physician, that is, randomly. This study was performed in accordance with the Declaration of Helsinki. The protocol of this study was a retrospective registration and was approved by the Ethical Review Committee of Nippon Medical School on November 11, 2021. (Tokyo, Japan; approval number: B-2021-446). Informed consent was obtained by providing a means to opt out.
The eligibility criteria for patients were as follows: age 20 years or older; diagnosed with unresectable or recurrent AGC with histologically confirmed oesophagogastric junction (EGJ) or gastric adenocarcinoma; having a history of previous treatment with fluoropyrimidine-containing first-line CTx; and received concurrent treatment with PTX or nab-PTX plus RAM from July 2015 to December 2019. The exclusion criteria were as follows: histological types other than adenocarcinoma; and a previous history of CTx with taxanes.
CTx schedule and study procedures. In the PTX regimen, patients received intravenous paclitaxel 80 mg/m² on days 1, 8, and 15 of the 28-day cycle, followed by RAM 8 mg/kg (ImClone Systems, Branchburg, NJ, USA), which was administered intravenously on days 1 and 15. This regimen included 5 mg chlorpheniramine as a premedication. In the nab-PTX regimen, patients received paclitaxel 100 mg/m2 intravenously on days 1, 8, and 15 of the 28-day cycle, followed by ramucirumab 8 mg/kg intravenously on days 1 and 15. No premedication was required for this regimen. Dose modifications and treatment interruptions were determined by the respective investigators on the basis of the criteria reported in the clinical trials (7, 13). Taxanes plus RAM CTx were continued until disease progression, unacceptable toxicity, or withdrawal of consent. Especially for taxanes, which are cell-killing anticancer agents, the defined dose regimen was kept in consideration of adverse events. The dosages for each patient were totalled. Relative dose intensity (RDI) is the ratio of the actual prescription dose intensity (DI; mg) to the planned DI, using the following formula:
total RDI (%)=actual prescription DI/planned DI ×100 (18).
The following clinical characteristics were collected for each patient: age, sex, Eastern Cooperative Oncology Group performance status (ECOG-PS), primary site (EGJ or stomach), time to progressive disease on first-line CTx (> or <6 months), histology, and main metastatic site (peritoneal or other). In relation to second-line CTx, taxanes (PTX or nab-PTX) and the number of treatment courses were collected. For clinical response, disease control was divided into four categories: complete response (CR) partial response (PR), stable disease (SD), and progressive disease (PD).
Third-line therapies were administered at the discretion of each physician, with anti-programmed cell death-1/programmed cell death-1 ligand 1 (anti-PD-1/PD-L1) inhibitors, irinotecan, trifluridine, and tipiracil hydrochloride (FTD/TPI), or best supportive care (BSC) being the treatment of choice.
Clinical response to CTx. The survival benefit of second-line treatment was defined as the time from the start of treatment to disease progression or death from any cause for PFS and the time to death from any cause for OS, respectively. Clinical response to tumour control was assessed by each investigator according to the Response Evaluation Criteria for Solid Tumors Version 1.1 (19). The overall response rate (ORR) or disease control rate (DCR) was defined as the percentage of patients whose response to second-line CTx lasted at least 6 weeks from the start of treatment. ORR was the percentage of patients evaluated as having a CR or PR, and DCR was the percentage of patients rated as having a CR, a PR, or SD. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events version 4.03.
Statistical analysis. All statistical analyses were performed using Statistical Package for the Social Sciences version 22.0 (IBM Inc., Armonk, NY, USA). Continuous variables were expressed as medians and ranges, and the differences between each clinicopathological feature category were analysed using standard thresholds. Cox proportional hazard regression analysis was used to identify significant independent factors for OS. Survival curves were generated using Kaplan–Meier estimates. ORR, DCR, and safety analyses between treatment groups were performed using Fisher’s exact test. Factors that were significantly different at p<0.05 in the univariate analysis were assessed by multivariate analysis. In the univariate and multivariate analyses, hazards ratios (HR) with 95% confidence intervals (CI) were calculated.
Results
Patients and CTx dosage. A total of 52 patients with AGC after first-line CTx received taxanes plus RAM as second-line CTx from July 2015 to December 2019 at our Ιnstitution. Forty-two patients who could be followed-up for prognosis were enrolled in this study and analysed. Patients’ characteristics are shown in Table I. Twenty patients were administered PTX and 22 patients were administered nab-PTX. The main metastatic sites were divided into peritoneal or other as non-curative factors, and there were 17 and 25 cases, respectively. The non-peritoneal sites included distant lymph nodes, liver, lung, and bone metastases. All patients were treated with a range of 1 to 19 courses each, with a median of 4 courses. The median total RDI by taxanes was 66.2% in the PTX group and 69.5% in the nab-PTX group. The nab-PTX group was able to maintain a relatively higher RDI, but the difference was not significant (p=0.815, data not shown). However, the prescribed dose of RAM was administered as planned.
Patient characteristics.
Of the 42 patients, 39 patients (92.6%) received subsequent third-line CTx, and 3 patients (7.1%) underwent BSC. The third-line CTx included anti-PD-1/PD-L1 inhibitors: irinotecan, 22 cases (52.4%); trifluridine, 12 cases (28.6%); and FTD/TPI, 4 cases (9.5%).
Survival and clinical response. The median PFS and OS were 5.4 months (95% CI=4.440-6.361) and 11.8 months (95% CI=8.648-15.019), respectively (Figure 1 and Figure 2). The results of univariate and multivariate Cox proportional hazards analyses for OS are shown in Table II and Table III, where peritoneal metastasis (HR=2.830; 95% CI=1.320-6.067, p=0.008) and clinical response (HR=0.310; 95% CI=0.129-0.741, p=0.008) were independent factors that impacted OS. In particular, regarding clinical response, which is an independent factor in OS, Kaplan–Meier survival curves and log-rank tests are shown for disease control (CR/PR/SD) and PD (Figure 2). The median OS was 6.3 months (95% CI=5.109-7.558) for PD (N=14) compared with 12.3 months (95% CI=10.224-15.509) for disease control (N=28) (p=0.026).
Progression-free survival and overall survival in all cases.
Kaplan–Mayer survival rate by clinical response to second-line treatment.
Univariate analysis by Cox proportional hazard analysis of overall survival.
Multivariate analysis by Cox proportional hazard analysis of overall survival.
In all 42 cases, measurable lesions were diagnosed; the clinical best overall response rates are shown in Table IV. The ORR and DCR for all patients were 19.0% and 66.7%, respectively. The DCR for taxanes was 55.0% and 77.2% for PTX plus RAM and nab-PTX plus RAM, respectively, which was not significantly different (p=0.126), but the clinical response for nab-PTX plus RAM included one CR (4.5%) (data not shown).
Clinical best overall response.
Safety. Treatment-related adverse events (AEs) of all patients are shown in Table V. There were six cases (14.3%) with grade ≥3 AEs, including duplications, of which four cases (9.5%) were neutropenia, but patients did not receive granulocyte colony-stimulating factor. Grade 2 or lower AEs included neutropenia in 20 patients (47.2%), sensory neuropathy in 10 patients (23.8%), anorexia in 6 patients (14.3%), and skin rash in 4 patients (9.5%) in patients treated with PTX only. The RAM-related AEs were proteinuria only in seven cases (16.7%). There were no noteworthy AEs related to the combination of therapies.
Treatment-related adverse events.
Discussion
In this study, we retrospectively investigated the efficacy of taxanes plus RAM CTx as second-line treatment for AGC. We showed that peritoneal metastasis and clinical response were prognostic factors in OS. To our knowledge, this is the first cohort study to investigate the prognostic impact of clinical response to second-line therapy for AGC. Furthermore, this study achieved PFS and OS of 5.4 months and 11.8 months, respectively, and these endpoints were comparable or better than those achieved in several large-number studies (7, 20).
In the previous large study, WJOG4007, the ORR and DCR for PTX monotherapy was 20.9% and 62.6% for PTX, respectively (4). In the RAINBOW study, PTX plus RAM was shown to be superior to PTX alone in CTx for patients with AGC, establishing it as second-line treatment (7). These rationales are the basis of treatment guidelines for AGC in Japan (14). In the ABSOLUTE trial, weekly nab-PTX was shown to be non-inferior to PTX in efficacy, and each of them has become a standard CTx. In this previous study, the clinical response of ORR and DCR for this taxane monotherapy was 24% and 72% for PTX, and 33% and 78% for nab-PTX, respectively (11). Furthermore, in the Japanese J-0202 study, the nab-PTX plus RAM combination showed a particularly high response, with an ORR and DCR of 54.8% and 92.9%, respectively (13). Shitra et al. reported that PFS after first-line CTx in patients with AGC, the performance status of patients, and the use of second-line CTx were independently associated with OS (15). In contrast, they reported that PFS and the anti-tumour response rate did not correlate well with OS as an endpoint with second-line CTx in AGC (17). Moreover, recent reports indicated that in patients with AGC, RAM as a salvage line resulted in less tumour shrinkage (21). Recently, taxanes and RAM CTx have been reported to have beneficial effects on QOL as well as early response in patients with AGC (12). This means that in practice, the prognostic impact of the response to taxanes plus RAM as second-line CTx for AGC is uncertain.
In East Asia, peritoneal dissemination is reported to be the most common site of metastasis even after the radical resection of gastric cancer (3, 22). Furthermore, the frequency of peritoneal metastases increases with the clinical course, especially after repeated CTx in patients with AGC. In a recent report of taxanes plus RAM, the amount of peritoneal dissemination in the main metastatic sites has been reported in detail (20). Uzgare et al. have shown that paclitaxel is an efficacious inducer of apoptosis in gastric cancer cell lines in vitro, suggesting the possibility of chemosaturation therapy with percutaneous hepatic perfusion. (23) In a mouse peritoneal dissemination model, PTX and nab-PTX were reported to reduce ascites and exert anti-proliferative effects and were associated with improved prognosis (24). Therefore, the control of peritoneal dissemination, especially in patients with AGC, is correlated with prognosis. Taxanes, especially nab-PTX, are effective in controlling peritoneal dissemination, which may correlate with prognosis (25). In other words, the response to taxane CTx in patients with peritoneal dissemination impacts prognosis. In this study, therefore, we investigated several non-curative factors of peritoneal dissemination or other factors.
The best response rates in this study were 19.0% for ORR and 66.7% for DCR, which were not as high as that of large-scale clinical trials but are realistic in actual clinical practice. Rather, the results are more favorable, with PFS and OS rates of 5.4 and 11.8 months, respectively. A particular feature of this study was that PFS prolongation was influenced by treatment continuity of four or more courses. Furthermore, the OS prolongation was impacted by the factor that the metastasis site was peritoneal and the response, especially CR, PR, and SD with taxane plus RAM. Previously, we reported that in nab-PTX monotherapy, adherence was related to dose intensity, which is correlated with prognosis (18). Thus, it can be strongly suggested that the taxane CTx continuity impacts the response, and furthermore, it impacts the prolongation of prognosis.
Twenty-two patients (52.4%) underwent subsequent anti-PD-1/PD-L1 therapy. There were no treatment-related AEs to note with these immunotherapies. Hagi et al. reported that nivolumab was not directly effective in patients with AGC with ascites, but many cases with severe ascites were included in this study (26). However, in lung cancer treatment, Nakahama et al. reported that the clinical response to CTx immediately before nivolumab treatment enhanced disease control thereafter (27). We performed multivariate analysis of patients’ characteristics in PFS similar to OS, and the results showed that peritoneal metastasis (HR=3.156; 95% CI=1.512-6.586, p=0.002) and clinical response as SD/PR/CR (HR=0.295; 95% CI=0.135-0.646; p=0.002) were independent factors. Additionally, an ECOG-PS of 0-1 (HR=2.824; 95% CI=1.145-6.961; p=0.024) and continuity of treatment course for more than four courses (HR=0.457; 95% CI=0.229-0.911; p=0.026) were independent factors. In other words, the results of taxanes plus RAM in this study suggest that the PS was relatively good, the peritoneum was the main metastatic site, and the continuity of four or more courses of CTx prolonged PFS. Therefore, a clinical response above SD impacts the prognosis. If a response is obtained with continuous CTx of taxanes plus RAM, further administration of nivolumab may impact the prognosis prolongation.
This study had several limitations. First, this was a non-randomized retrospective study performed at a single institution with a limited sample size. Second, in Japan, where the nab-PTX regimen was approved in 2017, the nab-PTX plus RAM group had a shorter survival observation period than the PTX plus RAM group and included patients who were still under follow-up.
In conclusion, this study showed that clinical response with second-line CTx for patients with AGC in clinical practice has an impact on prognosis. The continuity of taxane plus RAM and their clinical response had an impact on the prognosis of patients with AGC.
Acknowledgements
We thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
Y Masuda designed and performed the research and wrote the paper; Y Kanazawa designed the research and supervised the paper; K Matsuno, D Kakinuma, N Sakurazawa, F Ando, N Hagiwara, and T Nomura contributed to the analysis; S Kato and T Yoshiyuki provided clinical advice; and H Yoshida supervised the paper.
Conflicts of Interest
Yuka Masuda, Yoshikazu Kananazawa, Kunihiko Matsuno, Daisuke Kakinuma, Nobuyuki Sakurazawa, Fumihiko Ando, Nobutoshi Hagiwara, Tsutomu Nomura, Shunji Kato, Toshiro Yoshiyuki, and Hiroshi Yoshida declare that they have no conflicts of interest.
- Received December 31, 2021.
- Revision received January 23, 2022.
- Accepted January 31, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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