Combination versus single-agent as palliative chemotherapy for gastric cancer

Gastric cancer (GC) is the most common malignancy in Korea and the second leading cause of cancer-related death worldwide [1, 2]. For patients with recurrent or primary metastatic GC (RPMGC), palliative chemotherapy is the standard of care. In terms of chemotherapy regimen, combination chemotherapy (CC) is generally recommended in clinical practice [3‐7]. Two meta-analyses demonstrated a small but statistically significant survival benefit of CC compared to single-agent chemotherapy (SC) [6, 7]. However, individual randomized trials comparing CC and SC gave conflicting results [4, 6‐10]. Moreover, most randomized trials excluded patients who were elderly or who had poor performance status (PS) [3‐5, 8‐11]. Therefore, it is an important clinical issue to determine clearly whether CC is more beneficial than SC and to identify patient subgroups who may benefit from SC rather than CC.

There is increasing evidence that inflammation plays a critical role in the development and progression of cancers [12‐14]. Many inflammation-based prognostic markers have been suggested as potential prognostic factors in various types of cancers [12‐14]. Recently, as convenient and cost-effective blood-derived markers, the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), which may reflect the inflammatory response, immune response, and coagulation status, have been widely investigated as useful prognostic factors in many solid tumors including GC [12‐16].

In this study, we compared the overall survival (OS) between CC and SC in RPMGC patients, while analyzing the clinicopathological characteristics affecting outcome including NLR and PLR.

In the present study, patients with old age or poor PS patients underwent SC more frequently despite the significantly higher proportion of RPMGC patients with CC. On the other hand, CC was more commonly used in patients with peritoneal metastases. The most likely explanation for these findings is that oncologists judged that CC was too toxic for elderly patients and those with poor PS, whereas patients with peritoneal metastases required aggressive treatment, given its association with poor outcome. Although CC demonstrated an OS benefit in univariate analysis, it was not associated with favorable outcome in several subgroups such as elderly patients, and had no prognostic significance in multivariate analysis.

Large phase III trials to compare CC and SC incorporating third generation agents, such as S-1, docetaxel and irinotecan, have been conducted in Japan and have shown conflicting results [4, 8‐10]. In two trials, adding cisplatin or docetaxel to S-1 showed an OS benefit over S-1 alone [9, 10]. However, no significant difference in OS was observed between CC and S-1 monotherapy in two other trials [4, 8]. A recent meta-analysis of chemotherapy in advanced gastric cancer indicated that survival was significantly but slightly improved (about 1 month) with CC compared to SC [7]. Only a few retrospective studies have compared the outcomes between CC and SC. Two large retrospective studies demonstrated that CC was superior to SC in terms of OS [20, 21]. However, unlike the present study, neither retrospective study investigated the relationship between chemotherapy regimen and important clinical characteristics such as age, PS, and palliative resection [20, 21]. Moreover, because most randomized trials have included relatively young patients and patients with good PS, it is difficult to define the best chemotherapy strategy for elderly patients or those with poor PS [3‐5, 8‐11].

In the present study, no difference in OS between CC and SC was observed in patients with old age, ECOG PS 2 or 3, signet ring cell and combined/other histology, palliative surgical resection, and high PLR. Despite a lack of significant interaction between ECOG PS and type of regimen probably due to the small number of patients with PS 2 or 3, SC showed similar OS compared to CC. Given the relatively high risk of chemotherapy-related toxicities in CC, SC could be recommended in clinical practice for patients with poor PS. In patients with palliative surgical resection before first-line chemotherapy, there was no significant difference in OS between the CC and SC groups. Low tumor burden after palliative resection may be related to this result. However, routine use of SC in patients with palliative resection before chemotherapy cannot be recommended on the basis of these findings, given the retrospective nature of the present study, without significant interaction between surgical resection and chemotherapy regimen.

Limited data are available regarding chemotherapy regimens for elderly patients with RPMGC, because such patients are underrepresented in clinical trials [3‐5, 8‐11]. Two small retrospective studies comparing S-1 with S-1 and cisplatin (SP) for RPMGC patients older than 70 gave conflicting results, with both studies showing more severe toxicities in the SP group [11, 22]. Two larger retrospective studies from Korea and Japan for elderly patients demonstrated no difference in OS between CC and SC [3, 5]. In one of these studies, there was no significant difference in OS between the S-1 and SP groups, even after propensity score matching [3]. Furthermore, in a small phase III trial from Korea, comparing capecitabine with capecitabine and oxaliplatin in 50 elderly (≥70 years) RPMGC patients, there was no significant difference in OS, with higher incidence of some toxicities in CC arm [23]. In the current study cohort of elderly patients (≥ 70 years), only 3.8% of the CC group were in PS 2, while 25% of the SC group were in PS 2 (p = 0.001). Despite a significantly higher proportion of patients with good PS in the CC group, there was no difference in OS between the two groups in elderly patients. This finding and the significant interaction between regimen (CC vs. SC) and age suggest that CC may not be beneficial compared to SC in elderly patients with RPMGC, especially those aged 70 years or more. Given the results of the present study and previous investigations, SC can be recommended as a reasonable option for elderly patients, especially those with poor PS or comorbidity, although randomized trials are essential to define the standard chemotherapy regimen.

Considering imbalance in age and PS, well-established prognostic factors, between CC and SC groups, in the present cohort, PSM analysis was performed by adjusting patient characteristics before the initiation of chemotherapy as covariates. After PSM, there was no difference in OS between CC and SC groups. Increased proportion of patients with old age and ECOG PS 2 or 3 (10.2 to 31.4% and 5.0 to 18.6%, respectively) in CC group after PSM may be attributable to this result. In addition, no difference in OS between CC and SC was observed in old age and poor PS patients after PSM. These findings also suggest that SC could be useful option with less toxicity in elderly and poor PS patients.

Inflammation plays a critical role in the development and progression of various cancers [12‐14]. Of the various inflammatory markers, NLR and PLR have been suggested as potential prognostic markers in various cancers [12‐16]. A high NLR reflects a decrease in the number of lymphocytes and/or an elevated number of neutrophils. Neutrophils may play an important role in the development and progression of cancer by offering a suitable microenvironment for their growth [14, 24, 25]. Circulating neutrophils may secrete vascular endothelial growth factor (VEGF), interleukin-18, and matrix metalloproteinase, which are closely associated with tumorigenesis, progression and metastasis [14, 15, 24, 25]. Furthermore, the antitumor immune responses of activated T cells and natural killer cells may be inhibited by an elevated number of neutrophils surrounding tumor tissues [14, 24, 25]. Therefore, an elevated neutrophil count may have a negative effect on cancer patients, leading to poor outcome. In addition, because lymphocyte plays a crucial role in cellular adaptive immunity against cancer by attacking tumor cells at the outset of tumorigenesis, lymphopenia may reflect suppressed cell-mediated immunity against cancer [13‐16].

An elevated level of PLR also represents an increased number of platelets and/or a decreased number of lymphocytes. Elevated platelet counts may promote the metastatic potential of tumor cells in various biological pathways [13, 16, 24]. Platelets may secrete cellular growth factors such as platelet-derived growth factor, VEGF, transforming growth factor beta, and platelet factor 4, thereby stimulating tumor angiogenesis and growth [13, 16, 24]. In addition, platelets can activate the invasiveness of tumor cells by enhancing the formation of tumor stroma and supporting the adhesion of tumor cells to the endothelium [13, 16]. Furthermore, in the bloodstream, interactions between tumor cells and platelets could facilitate tumor cell metastasis by impeding the clearance of tumor cells by immune cells [13, 16].

In RPMGC, several studies have reported a significant association between high NLR or PLR and poor OS in patients treated with palliative chemotherapy [12, 14, 15, 24‐26]. In the present study, both NLR and PLR were independently associated with poor OS in RPMGC patients who received palliative chemotherapy. NLR correlated significantly with PS and palliative resection, well-established prognostic factors in RPMGC, but there was no significant association between PLR and the same factors.

One interesting finding in the current study is that there was no significant difference in OS between CC and SC in the high PLR group, despite the lack of interaction between PLR and regimen. A possible explanation for similar OS between CC and SC in the high PLR group is that high platelet counts reflect aggressive behavior of tumors that are refractory even to CC. Alternatively, CC may decrease lymphocyte count more than SC, leading to greatly suppressed cell-mediated immunity against cancer cells. Chemotherapy-induced lymphopenia is commonly observed event, especially in dose-dense regimens [27, 28]. Moreover, a few studies showed significant association between lymphopenia after chemotherapy with or without radiotherapy and poor outcome in several solid tumors [27, 29].

Having analyzed a relatively large number of patients, the present study reported comparable OS between CC and SC in certain subgroups of RPMGC patients, which might provide useful information for clinical decision-making. However, the current study has several limitations. First, it is a retrospective analysis from a single institution. Second, a variety of chemotherapy regimens were used in several therapy lines. Third, because the data were not prospectively collected, we did not analyze chemotherapy-related toxicities. Fourth, a very small number of patients were treated with first-line trastuzumab containing regimen, owing to the approval time of trastuzumab in Korea. Finally, because the optimal cut-off values of NLR and PLR have not yet been determined, application of the data from the present study to clinical practice requires further validation [14, 16]. Nonetheless, because the present study analyzed all patients who underwent palliative chemotherapy during the defined period with mature follow-up (minimum follow-up duration of survivors: 43 months), the results may reflect treatment outcomes in real-world clinical practice.

Although CC is the standard of care in RPMGC, SC can be considered a reasonable option in certain subgroups, such as elderly patients.