Abstract
Background/Aim: We compared patients with advanced gastric cancer [Union for International Cancer Control (UICC) III] versus patients with stage UICC IV and peritoneal carcinomatosis treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) versus patients with stage UICC IV treated without HIPEC to ascertain if CRS and HIPEC improve overall survival (OS). Patients and Methods: We retrospectively analysed thirty-seven advanced gastric cancer patients who had been treated at our department from 2012 to 2017. The endpoint was median OS. Results: Eighteen (49%) patients with UICC stage III showed a median OS of 37.4 months. Eight (21%) patients in the HIPEC group reached a median OS of 33.8 months. Median OS in the UICC IV group (11 patients, 30%) treated with a palliative concept was 6.2 months and therefore significantly worse (p=0.004). Conclusion: A systemic approach combined with CRS and HIPEC in selected stage IV gastric cancer patients improves the OS comparable to patients in UICC stage III.
Gastric cancer accounts for 8.8% of cancer-related deaths per year, thus it is the third leading cause of cancer-related deaths in the world (1). At diagnosis, 21-39% of the patients present in a synchronously metastatic stage (2, 3). In 14% (35% of patients with metastatic disease) diagnosis implicates synchronous peritoneal carcinomatosis, which is the sole site of metastasis in 24% of patients. Prognosis is rather poor. Median survival does not exceed 3-5 months, and the 5-year survival is 0% (3).
Chemotherapy alone plays a minor role in the treatment of gastric cancer with peritoneal carcinomatosis, yet the concept of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), which has been investigated for over three decades (4), presents a therapeutic option for selected patients.
Our aim was to compare the overall survival (OS) of patients with gastric cancer stage Union for International Cancer Control (UICC) IV and a low peritoneal carcinomatosis index (PCI) ≤12, who have been treated with radical surgery, CRS and HIPEC, to patients with advanced gastric cancer stage UICC III as well as to patients with stage UICC IV who have been treated with palliative surgery and/or chemotherapy.
Patients and Methods
Patients. We conducted a retrospective analysis of 109 consecutive patients with newly diagnosed advanced gastric cancer at the time of first diagnosis, staged as UICC ≥ III, who have been treated in our hospital between January 2012 and September 2017.
All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For HIPEC, additional ethical approval was obtained from the Ethical Committee of the hospital of Mercy Sisters Linz.
Every patient included in this study underwent computed tomography (CT), gastroscopy and endosonography. Patients with stage cT4 or suspicious peritoneal carcinomatosis at CT scan underwent staging laparoscopy to assess PCI. Treatment algorithms were specified in our interdisciplinary tumour board. UICC stage III was defined as cT3/cT4 cN+ and UICC stage IV as cT4b cN+ or any cT cM1. Perioperative chemotherapy was administered if cancer was histologically proven. Afterwards, surgery was conducted when patients showed response to neoadjuvant chemotherapy (NACT), defined as stable disease, partial or complete response in re-staging CT according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. In case of progressive disease, patients received either palliative treatment or best supportive care. Selection criteria for the study groups are shown in Figure 1.
Patient selection. pat.: Patients.
Surgical strategy. CRS and HIPEC were performed in patients with PCI ≤ 12 at time of surgery, Eastern Co-operative Oncology Group (ECOG) <2 and in absence of extraperitoneal metastases. After resection of the primary tumour, maximal cytoreduction with removal of all visible nodules plus partial peritonectomy was performed. The completeness of cancer resection (CCR) according to Sugarbaker's criteria was assessed by the surgeon at the end of the procedure. HIPEC was performed with the “closed abdomen” technique using 400 mg/m2 oxaliplatin at 42°C for 45 to 60 min.
Chemotherapeutical strategy. From 2012-2015, patients received either EOX (epirubicin/oxaliplatin/capecitabine) or ECF (epirubicin/cisplatin/5-fluorouracil) in accordance with the MAGIC trial (5); from 2015-2017, patients eligible for the OE 05 trial received cisplatin/5-FU (6). Patients not eligible for the above trials received either FLOT (5-fluorouracil/folinic acid/oxaliplatin/docetaxel) if her-2-neu negative (7) or ToGA (trastuzumab for gastric cancer) if her-2-neu positive (8). No chemotherapy at all was given in 5/19 (26%) patients due to age, co-morbidities, tumour bleeding or incompliance.
Demographic and clinical characteristics.
Statistical analysis. OS according to UICC subgroups after first diagnosis of gastric cancer represented the main objective of our research. Another goal of this study was to identify predictive factors for OS using Cox-regression analysis. Data analysis was performed using the statistic software SPSS, Version 23.0.
To compare the different groups regarding patient and tumour characteristics we used two-sided Fisher's Exact tests for nominal variables and Mann–Whitney-U-Tests for metric variables. Survival rates were calculated using the Kaplan–Meier method. Cox regression analysis was used to identify independent risk factors for OS. A p-value<0.05 was considered to be statistically significant.
Results
Demographics and clinical characteristics. A total of 37 patients were included in this study. The mean age in our population was 66.1±11.6 years. Patients in the UICC IV + HIPEC group were approximately 10 years younger compared to patients within the two other groups (p=0.19).
Kaplan–Meier analysis of overall survival.
In our cohort, patients with metastatic disease showed very poor response to neoadjuvant chemotherapy. We observed a response rate of 29% (2/8) in the UICC IV + HIPEC group and 0% (4/4) in the UICC IV (PER) without HIPEC group. On the contrary, 6/10 patients (60%) at stage UICC III showed either a visible response to NACT in the CT scan or decreasing tumour marker levels.
Median follow up time was 33.3 months. Most patients died within the first two years after diagnosis (23/37, 62%).
Table I demonstrates the demographic and clinical characteristics.
Survival. The median survival time after first diagnosis of gastric cancer was 37.4 months [95% confidence interval (CI)=7.15-67.69] in UICC III patients, 33.8 months (95%CI=4.11-63.47) in UICC IV + HIPEC patients compared to 6.2 months (95%CI=2.61-9.81) in the UICC IV (PER) without HIPEC group (Figure 2). The 1-year and 3-year OS rates were 72% and 54% in UICC III patients, 88% and 40% in UICC IV + HIPEC patients and 18% and 0% in the UICC IV (PER) without HIPEC group, respectively.
To evaluate the different clinical variables influencing OS we implemented a cox regression model. OS in the UICC III group compared to the UICC IV + HIPEC group was not significantly different in the univariate (p=0.955) cox regression analysis. Yet, the UICC IV + HIPEC group showed significantly better OS compared to the UICC IV (PER) without HIPEC patients in the univariate (p=0.004) cox regression analysis.
The only other variable showing statistical significance in the univariate analysis was R0 resection (R0 vs. R1: p=0.001) with an OS of 37.4 months (95%CI=13.2-61.7) for patients with R0 resection and 9.4 months (95%CI=2.3-16.4) in case of R1 resection. R1 resection was seen in three patients - one per group (Table II).
Discussion
As advanced gastric cancer is still associated with poor median OS, new treatment options have to be investigated. Chemotherapy alone showed a median OS of 13 months in the phase III SPIRITS trial for S-1 (tegafur/gimeracil/oteracil) plus cisplatin (9) or a median OS of 13.8 months in the ToGA trial for her-2-neu-positive gastric cancer (8). Yet, they didn't perform a subgroup analysis for patients suffering from peritoneal carcinomatosis.
There are contradictory data concerning the outcome of patients receiving gastrectomy plus chemotherapy vs. chemotherapy alone. According to Geng et al., gastrectomy plus chemotherapy leads to a median OS of 15 months compared to only 7 months in the chemotherapy alone group (10), whereas Fujitani et al. found that OS is better if patients receive chemotherapy alone (11). One option for improvement could be systemic therapy combined with radical surgery augmented by CRS and HIPEC in selected patients. As we observed in our cohort, this approach improved median OS in patients with limited peritoneal carcinomatosis in gastric cancer to 33.8 months. If treated according to this regimen, limited peritoneal carcinomatosis (PCI<8 within our cohort) in gastric cancer patients does not seem to worsen OS significantly compared to patients in UICC group III (p=0.96). In other words, CRS and HIPEC can potentially shift the formerly strict border between curative and palliative treatment intention represented by peritoneal carcinomatosis, towards a curative approach in selected patients with limited peritoneal carcinomatosis.
Another goal of this study was to identify predictive factors for OS. The only factor being statistically significant in univariate analysis turned out to be R0 resection. However, Chia et al. (12) showed that T and N stages only influence the outcome in univariate analysis whereas positive resection margins and inadequate lymph node dissection strongly increase the risk of recurrence. Our assumption is that R0 resection as well as adequate radical surgery including proper D2 lymph node dissection and achieving CCR 0, represent the most important factors influencing overall survival.
Univariate cox regression analysis of clinical variables influencing OS.
Despite the promising results of our patient cohort treated with CRS and HIPEC with oxaliplatin, we have to acknowledge the limitations of this study, including the small number of patients and its retrospective character. Nevertheless, we showed a significant survival benefit for patients who were treated with a multimodal concept of systemic chemotherapy, radical surgery and HIPEC in case of limited peritoneal carcinomatosis compared to patients treated with palliative strategies. Furthermore, these patients showed a median OS comparable to patients with non-metastatic stage UICC III. Although the study group is small, it is in line with other recently published studies, who report a median OS of 21.2 months (13) and 13 months (14) for patients treated with radical surgery and HIPEC. Hence, the findings of this study support further research in selected patients with low PCI, good performance status and young age.
Acknowledgements
The Authors thank Nikolaus Haselgruber and Sigrid Metz-Gercek for statistical analysis validation. The Authors would also like to thank all patients who participated in this study.
Footnotes
Authors' Contributions
Study conception and design: Wundsam HV, Braeuer F, Rohregger K, Pressl G; Acquisition of data: Braeuer F, Wundsam HV, Fischer I; Analysis and interpretation of data: Braeuer F, Wundsam HV, Rohregger K; Drafting of manuscript: Wundsam HV, Braeuer F, Brammen L; Critical revision of manuscript: Fuegger R, Brammen L.
Previous communication: Parts of the data have been presented at an oral presentation at the ÖCK (Austrian Congress of Surgery) and PCNC (Peritoneal Cancer Network Congress) 2018, Vienna, Austria, and as a poster at the 11th International Workshop on Peritoneal Surface Malignancy 2018, Paris, France.
Conflicts of Interest
Our study was undertaken without any financial assistance and there are no relationships that may pose any conflict of interest. All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For HIPEC additional Ethical approval was obtained from the Ethical Committee of the hospital of Mercy Sisters Linz.
- Received February 17, 2020.
- Revision received February 28, 2020.
- Accepted March 4, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
