Background
Approximately 40% of patients with gastric cancer are diagnosed with distant metastases (stage IV), with the liver, peritoneum, and lungs being the most common metastatic sites.1–3 For these patients, palliative systemic therapy is the cornerstone of treatment and has been shown to improve both survival and quality of life compared with best supportive care (BSC) alone.4
Despite this, international consensus on the optimal palliative systemic treatment regimen is lacking. Doublet therapy consisting of a platinum derivate and fluoropyrimidine is generally preferred as first-line treatment, with the addition of trastuzumab in the case of a HER2-positive tumor or, more recently, nivolumab in the case of sufficient PD-L1 expression.5–7 Triplet therapy has been suggested to improve treatment outcomes, but its survival benefit is under debate and triplets are associated with increased toxicity.8,9 Because no optimal combination regimen has been defined yet, substantial variation in clinical practice exists.10 A recent study confirmed this heterogeneity by determining 45 different first-line regimens in the Netherlands among 2,204 patients with metastatic esophagogastric adenocarcinoma.10
Randomized controlled trials (RCTs) have provided the primary evidence for treatment approaches.11–14 However, these trials frequently do not adequately reflect subgroups of patients. Patients with peritoneal metastases are particularly underrepresented because many trials require measurable disease for response evaluation, which is often not present in patients in whom the peritoneum is the only metastatic site. Also, the typical severe symptoms associated with peritoneal metastases usually require quick initiation of systemic therapy, precluding the more time-consuming process of trial enrollment. Consequently, subgroup analyses in patients with peritoneal metastases are often exploratory and underpowered.14,15
The efficacy of systemic treatment for peritoneal metastases is potentially hampered by the peritoneal–plasma barrier and the poor blood supply in the peritoneum.16,17 Moreover, common symptoms in peritoneal dissemination, such as intestinal obstruction and malignant ascites, often result in malnutrition and impaired performance status, limiting the possibilities for palliative systemic treatment. The aim of this study was to describe first-, second-, and third-line systemic treatment regimens in patients with synchronous peritoneal metastases of gastric and gastroesophageal junctional origin and to investigate the efficacy of different treatment regimens in a real-world setting.
Methods
Data Collection
Patients diagnosed with metastatic gastric adenocarcinoma in the Netherlands between 2015 and 2020 were identified in the Netherlands Cancer Registry (NCR). Gastric cancer was defined as C16.0 through C16.9 (which includes tumors of the gastroesophageal junction and cardia) according to ICD-O-3. The NCR is a population-based registry that includes all patients with newly diagnosed cancer via a direct linkage to the national pathologic archive and the Dutch Hospital Data. Trained registrars of the NCR collect patient, tumor, and treatment characteristics from the hospital’s medical records. The vital status of all patients is obtained through an annual linkage to the municipal administrative database.
For the current study, only patients with gastric peritoneal metastases at diagnosis (synchronous peritoneal metastases) were selected, defined as code C480, C481, C482, or C488 according to the ICD-O-3 for the metastatic location at diagnosis. This study was performed in accordance with the STROBE guidelines.18
Outcomes
The primary outcome of this study was to describe the differences in first-, second-, and third-line systemic treatment patterns. The secondary outcomes included overall survival (OS) and time-to-treatment failure (TTF), patient characteristics associated with receiving systemic treatment, and reasons for not receiving systemic treatment.
Systemic Treatment
In this study, we defined a systemic treatment line as either a single systemic agent or a combination of systemic agents administered concurrently until suspension, regardless of the reason for discontinuation. Our assumptions regarding the definition of a systemic treatment line were based on a previous study.10 For combination regimens, all systemic agents must have been started within 3 days of the first agent administered to be considered as a single treatment line. However, if trastuzumab was added to the regimen ≥3 days after the start of the other agent(s), but before the other agents were stopped, this was still considered part of the regimen, because the histopathologic determination of HER2 receptor status may have led to delay. If a patient restarted the same regimen after a therapy break, it was still considered part of the same treatment line regardless of the duration of the break. If one agent of a combination therapy was stopped but the other agent(s) continued, this was considered as continuation of the treatment line (eg, continuation of capecitabine after capecitabine/oxaliplatin). This also applied when one agent was switched to another agent of the same drug group (drugs with the same working mechanism; eg, fluorouracil and capecitabine). Treatment was considered a next line if a new agent of another drug group was started that had not been administered in the previous regimen. Data on second- and third-line treatment were only available in patients with complete follow-up. Follow-up registration for patients diagnosed after 2017 was not yet fully completed by the NCR (eg, data on sequential treatment lines), and therefore not included in analyses for second- and third-line treatment.
First-line systemic therapy strategies were classified into the following treatment regimens: monotherapy, doublets with a fluoropyrimidine derivate and oxaliplatin, other doublets, triplets containing docetaxel, triplets containing anthracyclines, other triplets, and trastuzumab-containing regimens.
OS and TTF
OS was defined as the interval between start of treatment until the end of follow-up or death, and was updated until February 1, 2022. In patients who received BSC only, OS was calculated from the date of diagnosis. TTF was used as a proxy for progression-free survival because these data were not available in the NCR database. TTF was calculated as the interval between start of treatment and the first progression that resulted in termination of the treatment, death, or end of follow-up, as described previously.10 TTF was only available in patients with complete data registration (patients primarily diagnosed in 2015–2017).
Statistical Analysis
Baseline characteristics were described using medians with IQRs for continuous variables, and absolute numbers and percentages for categorical variables. Differences between patients treated with and without systemic treatment were analyzed using the chi-square test (for categorical variables), the chi-square test for trends (for ordinal variables), and the Mann-Whitney U test (for continuous variables). Kaplan-Meier survival curves were generated for the different treatment regimens and compared using the log-rank test. Multivariable Cox regression analyses were used to test for associations between systemic treatment regimens and OS and TTF, with adjustments for sex, age, comorbidities, performance status, tumor location, Lauren classification, and the presence of metastases outside of the peritoneum. A P value <.05 was considered statistically significant. Analyses were performed using SPSS Statistics, version 28 (IBM Corp) and R Statistical Software (v4.1.2; R Core Team 2021).
Results
Patient Characteristics
This study included a total of 1,972 patients with gastric cancer and synchronous peritoneal metastases (Figure 1). Patients were excluded if they received chemotherapy outside the Netherlands (n=6), they received chemoradiotherapy (n=3), or the chemotherapy regimen was not specified (n=1). The included patients were predominantly male (59%) with a median age of 70 years (IQR, 60–78 years) (Table 1). Half of the patients had no comorbidities (50%) and the WHO performance status (PS) was 0 or 1 in 44%. In terms of tumor characteristics, most patients (52%) had a diffuse tumor type and the location of the primary gastric tumor was evenly distributed. Almost half of the patients (45%) had distant metastases in other organs in addition to the peritoneal metastases.
Study flow diagram.
Abbreviations: NCR, Netherlands Cancer Registry; PMGC, peritoneal metastatic gastric carcinoma; PS, performance status.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.7013
Baseline Patient Characteristics
Of all patients, 842 (43%) were treated with palliative systemic therapy (Figure 1). These patients were significantly younger, had fewer comorbidities, and had a better PS than patients who were not treated with systemic therapy (Table 1). The presence of metastases at other locations than the peritoneum did not differ between the 2 groups. Patients with peritoneal metastases exhibited a higher prevalence of primary tumors located at the antrum/pylorus and a more frequent occurrence of the diffuse tumor type compared with patients with metastases in other locations besides the peritoneum (Table S1 in the supplementary materials, available online with this article). Reasons for not receiving palliative systemic therapy were patient preference (26%), comorbidities/PS (21%), and disease progression (18%) (Figure 1). Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was performed on a very limited scale in only 25 patients as part of the PERISCOPE-I trial.19
First-, Second-, and Third-Line Systemic Therapy Regimens
In total, 35 different first-line systemic therapy regimens were administered (Figure 2A, Supplementary Table S2). Capecitabine + oxaliplatin (CAPOX) was most commonly administered (44%), followed by fluorouracil/leucovorin/oxaliplatin (FOLFOX; 19%), epirubicin + capecitabine + oxaliplatin (EOX; 8%), and capecitabine as monotherapy (5%). Most patients were treated with a doublet consisting of a fluoropyrimidine derivate and oxaliplatin (n=529; 63%), followed by anthracycline-containing triplet (n=99; 12%), docetaxel-containing triplet (n=75; 9%), trastuzumab-containing regimen (n=62; 7%), monotherapy (n=51; 6%), and other doublets (n=22; 3%).
(A) First-line and (B) second-line treatment strategies in patients with synchronous peritoneal metastatic gastric carcinoma.
Only first-line treatment strategies administered in >5 patients and second-line strategies administered in >3 patients are shown.
Abbreviations: CAPOX, capecitabine/oxaliplatin; DOC, docetaxel/oxaliplatin/capecitabine; ECC, epirubicin/capecitabine/cisplatin; EOF, fluorouracil/oxaliplatin/epirubicin; EOX, epirubicin/oxaliplatin/capecitabine; FLOT, fluorouracil/leucovorin/oxaliplatin/docetaxel; FOLFOX, fluorouracil/leucovorin/oxaliplatin; RP, ramucirumab/paclitaxel; TPF, fluorouracil/cisplatin/docetaxel.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.7013
Of the 222 patients receiving first-line therapy with complete follow-up, 99 (45%) underwent second-line systemic treatment (Figure 2B, Supplementary Table S3). Ramucirumab and paclitaxel (RP) was most frequently applied as second-line treatment (63%), followed by paclitaxel (3%) and FOLFOX (2%). Third-line treatment was given to 10 (5%) of the patients treated with systemic therapy (Supplementary Table S4). Among these patients, monotherapy irinotecan was used most often (30%), followed by FOLFOX (20%).
Survival
Median OS (n=842) and median TTF (n=222) for patients receiving first-line systemic chemotherapy were 8.1 months (95% CI, 7.4–8.7 months) and 4.8 months (95% CI, 4.2–5.4 months), respectively. Patient baseline characteristics per treatment regimen are presented in Supplementary Table S5. The log-rank test showed a statistically significant difference in OS between the different treatment regimens (Figure 3). Patients treated with triplets containing docetaxel had better OS compared with patients treated with doublets containing a fluoropyrimidine derivate and oxaliplatin, both in univariable and multivariable analyses (Table 2; adjusted HR, 0.69; 95% CI, 0.52–0.91). Trastuzumab-containing regimens were associated with longer OS as well (adjusted HR, 0.68; 95% CI, 0.51–0.91). The OS of triplets with anthracyclines did not differ significantly from fluoropyrimidine/oxaliplatin doublets (Table 2). After adjusting for confounders, treatment with monotherapy was associated with significantly shorter OS (adjusted HR, 2.08; 95% CI, 1.53–2.83). A sensitivity analysis excluding patients who received CRS-HIPEC did not influence the results (data not shown). The TTF for trastuzumab-containing regimens was significantly longer than for other systemic treatment regimens in univariable and multivariable analyses (Supplementary Table S6 and Supplementary Figure S1). The TTF of other regimens did not differ significantly from the TTF of fluoropyrimidine/oxaliplatin doublets. The presence of distant metastases alongside peritoneal metastases was associated with a significantly shorter OS (adjusted HR, 1.33; 95% CI, 1.14–1.55; Supplementary Figure S2) compared with patients with peritoneal metastases only.
Kaplan-Meier curves displaying overall survival for different treatment strategies in patients with synchronous peritoneal metastases of gastric cancer.
The “other doublets” (n=3) and “other triplets” (n=23) treatment groups are not shown because of small patient numbers.
Abbreviation: FU, fluorouracil.
aP<.0001 corresponds to the result of the log-rank test comparing the different treatment groups.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.7013
Cox Regression Analyses for Overall Survival per First-Line Treatment Regimen
In patients with complete follow-up who received second-line systemic treatment (n=99), median OS from start of second-line treatment was 7.5 months (95% CI, 6.7–8.2 months). Numbers were too small to compare different second-line treatment regimens.
Median OS for patients who received BSC only (n=1,130) was 1.9 months (95% CI, 1.7–2.0 months) calculated from date of diagnosis. This was significantly shorter than for patients who received monotherapy (n=52; median OS, 6.2 months [95% CI, 5.0–7.4 months]; adjusted HR, 1.81 [95% CI, 1.34–2.44]; data not shown).
Discussion
This population-based study included 1,972 patients with gastric cancer and synchronous peritoneal metastases, of whom 842 (43%) were treated with palliative systemic chemotherapy. The most frequently applied systemic therapy was a doublet containing a fluoropyrimidine derivate and oxaliplatin, which is in line with international guidelines for metastatic gastric cancer, such as the ESMO or NCCN Guidelines.5,7 In this retrospective analysis, patients treated with a triplet containing docetaxel had longer survival than those treated with a doublet.
We observed substantial heterogeneity in the first-line systemic treatment choice in our study population, because 35 different treatment regimens were used. A total of 70% of the patients who had systemic treatment received first-line treatment consisting of a fluoropyrimidine-platinum doublet or a trastuzumab-containing regimen in case of HER2 expression. This heterogeneity aligns with another Dutch study involving patients with esophagogastric cancer and metastases at various locations, which also showed a significant degree of heterogeneity.10 Thus, the observed heterogeneity cannot be entirely attributed to the presence of peritoneal metastases. An explanation for the heterogeneity could be that (palliative) treatment of metastatic gastric cancer is not centralized in the Netherlands as opposed to curative treatment.20,21 Differences in local treatment protocols and changes in guidelines over time could therefore contribute to the observed heterogeneity.
Only 43% of the patients in this study were treated with first-line systemic therapy. This is in line with another study in patients with metastatic gastric cancer (37%), but substantially less than in other tumor types with synchronous peritoneal metastases, such as colorectal cancer (of whom 77% received first-line systemic treatment in a real-world study) or ovarian cancer.22,23 The most commonly documented reason for not receiving systemic treatment was patient preference. Unfortunately, in-depth analyses on the reasoning for not receiving systemic treatment were not possible with the available data. Shared decision-making plays an important role in deciding on systemic treatment in the palliative setting, but could be influenced by preferences and beliefs of the treating oncologist.24,25 Given that 29% of the patients who did not receive systemic treatment had a PS of 0 to 1, and therefore were theoretically eligible for systemic treatment, it would be valuable to better understand the rationale behind the choices made in these certain cases.
Treatment of peritoneal metastases of gastric origin has historically been associated with an unfavorable outcome. A recent study in this patient population found an increased use of systemic chemotherapy over the last 20 years, but this was not associated with improved survival.26 This limited effectiveness could be explained by the plasma–peritoneal barrier resulting in a low peritoneal concentration of the systemically administered agents.16,17 Moreover, studies in colorectal cancer suggest that peritoneal cancer cells inhibit different molecular characteristics than, for example, liver metastasis, making them less sensitive to chemotherapy.27,28 It should be noted that the observed OS in our study was similar to that reported in a different study involving patients with synchronous metastatic esophagogastric cancer (OS, 7.5 months).10 However, it is important to acknowledge that making a direct comparison between these studies is challenging due to differences in baseline characteristics and the absence of a multivariable comparison.
In the present study, patients treated with docetaxel-containing triplets had a longer survival compared with patients treated with doublet therapy. Trials investigating the added value of triplet therapy in metastatic gastric cancer are inconclusive. One phase III trial in patients with metastatic esophagogastric cancer showed no survival benefit, but reported an increased incidence of adverse events when adding docetaxel to FOLFOX treatment.12 However, in a randomized phase II trial in patients with metastatic or locally recurrent gastric adenocarcinoma, FLOT resulted in significantly increased OS, PFS, and response rate compared with doublet therapy.29 It could be hypothesized that docetaxel has a more effective transferability through the peritoneal–plasma barrier, thus resulting in an increased exposure of the peritoneal metastases. This is supported by 2 pharmacokinetic studies showing that intravenous administration of docetaxel results in rapid uptake in ascites.30,31 In both studies, concentrations of docetaxel in ascites were lower than in plasma (area under the curve (AUC) ascites/AUC blood ranging between 20% and 36%), but substantially higher than the 50% inhibitory concentration (ie, the concentration of a drug needed to inhibit the growth of cancer cells by 50%) of docetaxel, suggesting therapeutic intraperitoneal concentrations. It is important to note that due to the retrospective design, the absence of data on toxicity and the potential bias by indication, definitive conclusions regarding the added value of docetaxel-triplets cannot be drawn yet. However, due to the lack of phase III trials in patients with peritoneal metastases, these real-world data provide valuable information on the efficacy of different treatment regimens in daily-clinical practice and could provide a preliminary basis for prospective studies in this subgroup of patients.
In this study, monotherapy resulted in a significantly longer OS, measured from diagnosis, compared with BSC. However, being a retrospective analysis, it is crucial to interpret this observed difference within the context of potential inherent biases and potentially unmeasured confounding variables. A randomized phase III trial compared capecitabine monotherapy versus CAPOX in patients aged ≥70 years with metastatic gastric cancer found an OS (6.3 months) similar to our study and a survival benefit of platinum-based combination therapy.32 However, a more recent study showed that a reduced-intensity chemotherapy (doses 0.6 times standard capecitabine/oxaliplatin) was noninferior for frail patients, but improved quality of life.33 The use of monotherapy as first-line treatment for metastatic gastric cancer is currently not incorporated in the EMSO and NCCN Guidelines.5,7 For frail patients not eligible for doublet therapy, the survival data described in this study could play a role in the decision-making process between BSC and monotherapy, also taking into account the side effects and hospital visits associated with monotherapy. However, strong conclusions based on these data should not be made due to potential selection bias.
In recent years, studies have focused on exploring methods to deliver chemotherapy intraperitoneally to improve treatment of patients with peritoneal metastases. In this way, higher intraperitoneal concentrations of chemotherapy can be achieved compared with intravenous administration.34 Different methods exist for administering intraperitoneal chemotherapy.35 The combination of CRS and HIPEC showed promising results in several clinical studies, but evidence is still limited and its use is not yet standard of care.36,37 This is currently under investigation in the PERISCOPE II trial for patients with limited peritoneal dissemination (ie, peritoneal cancer index <7) and/or tumor positive peritoneal cytology.38 In the present study population, CRS-HIPEC was only applied on a very limited scale and did not influence the differences found between the systemic treatment regimens. Other methods for administering chemotherapy intraperitoneally include catheter-based intraperitoneal chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC).35 Both methods could provide an advantage in exposure to peritoneal metastases over systemic therapy, but its efficacy remains to be proven in ongoing and future clinical trials.39–41
To the best of our knowledge, this is the largest study in patients with synchronous peritoneal metastases of gastric origin describing the different systemic treatment regimens in a real-world setting. However, our study has some limitations. First, the NCR does not register detailed information about the extensiveness of the peritoneal metastases, such as the peritoneal cancer index. Therefore, it was not possible to include this in the multivariable analysis. Additionally, the mismatch repair status was not available within the dataset, impeding the possibility of incorporating this molecular marker into the analysis. Despite the multivariable analysis, selection bias remains possible due to the retrospective nature of this study. Furthermore, it is important to underscore that residual confounding due to unobserved variables likely affects the retrospective analyses. Moreover, nivolumab was only registered in the Netherlands for PD-L1–positive metastatic gastric cancer since 2022 based on the results of the CheckMate 649 study.13 Consequently, treatment with nivolumab was not yet implemented in our patient population. Finally, we did not have data on follow-up for TTF and second- and third-line treatment of all patients, which resulted in a smaller sample size and reduced power for the analyses of these outcomes.
Conclusions
This nationwide, real-world study showed a substantial heterogeneity in systemic treatment choices in patients with gastric cancer with peritoneal metastases in the Netherlands. Although the results are potentially influenced by selection bias, patients treated with triplets containing docetaxel and trastuzumab-containing regimens had a longer survival compared with patients treated with doublet therapy. It is important to note that median OS of all treatment groups is <1 year. Therefore, the survival benefit of chemotherapy should be weighed against the side effects and hospital visits. Furthermore, this underscores the urgent need for exploring alternative treatment approaches, including immunotherapy, CRS-HIPEC, catheter-based intraperitoneal chemotherapy, and PIPAC treatment, to improve outcomes.
Acknowledgments
The authors thank the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the collection of data for the Netherlands Cancer Registry as well as IKNL staff for scientific advice.
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