Efficacy and safety of SOX chemotherapy with or without surgery in AFP-producing advanced gastric cancer
- Authors:
- Published online on: May 24, 2017 https://doi.org/10.3892/ol.2017.6240
- Pages: 579-586
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Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
α-fetoprotein (AFP)-producing gastric cancer (APGC) is a rare subtype of gastric cancer that accounts for between 1.3 and 15% of all gastric cancer (GC) (1). APGC is characterized by a significant increase in serum AFP and also AFP expression in tumor cells (2). The potential underlying molecular mechanism may be the common embryonic origin of the stomach and liver from the foregut (3). The genes responsible for expression of AFP are inhibited during fetal development and may be reactivated during tumorigenesis of gastric cells (4,5). APGC is associated with a poor prognosis in <90% of patients due to its high propensity for lymphatic and venous invasion, and synchronous, as well as metachronous, liver metastases. Similar to other types of advanced GC, occurrence of complications in patients with APGC also indicates incurability. The disease is typically diagnosed at an advanced stage and is therefore associated with a high recurrence rate (6). Although surgical resection or systemic chemotherapy is used to treat liver metastases, the benefit of a palliative gastrectomy in patients with advanced GC is debatable (7). Following palliative treatment, high incidences of postoperative morbidity, prolonged hospital stay and poor quality of life have been observed frequently in patients with APGC and a poor survival rate compared with patients with non-APGC (8).
Conventional chemotherapy is predominantly ineffective in APGC. However, a previous study has suggested that a SOX (S-1 and oxaliplatin) regimen may be an effective therapy to treat advanced GC (9). S-1 is an orally active derivative of 5-fluorouracil (5-FU), which is a fourth-generation oral fluoropyrimidine (10). The study indicated that S-1-based therapy is superior compared with 5-FU in terms of overall survival (OS), progression-free survival (PFS) and objective response rate (10). For the treatment of GC, oxaliplatin is typically administered with fluorouracil and leucovorin in a combination known as FOLFOX (11). Previous studies have reported higher response rates (between 53 and 59%) and lower toxicity with a SOX chemotherapy regimen in the treatment of advanced GC (9,10,12). Previous phase II trials have demonstrated the superior efficacy and safety profile of the SOX regimen as a first-line treatment for advanced GC in Korean (13) and Chinese (14) patients. APGC with liver metastasis that appears to be unresectable may become resectable following treatment with neo-adjuvant chemotherapy. However, it remains controversial to perform surgery following adjuvant chemotherapy in cases of advanced gastric cancer (15). Although the use of SOX chemotherapy in gastric cancer has been established, there are limited data reported in the literature for its use, safety and efficacy to treat APGC, possibly due to its rarity. The efficacy and safety of the SOX regimen with or without resection of the primary tumor was retrospectively evaluated for the treatment of APGC.
Materials and methods
Characteristics of enrolled patients
A total of 24 patients with APGC that satisfied the inclusion and exclusion criteria were identified from Liaocheng People's Hospital (Liaocheng People's Hospital) between January 2011 and December 2013. All medical data of the patients were reviewed retrospectively and only the outcomes were updated at the time of analysis. The inclusion criteria were: i) APGC diagnosed by pathology or cytology; ii) liver metastasis diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI) with >3 inoperable metastatic lesions; iii) performance status score 0–2 according to the Eastern Cooperative Oncology Group (16); iv) no contraindication for oral medication; and v) without obvious myelosuppression including having a whole blood count of ≥3×109 cells/l (normal, 4.0–10.0 cells/l), hemoglobin ≥8.0 g/dl (normal 11.0–15.0 cells/l), platelet count of ≥75×109 cells/l (normal, 100–300), adequate liver function (defined as total bilirubin ≤3-fold that of the upper limit and aspartate aminotransferase/alanine aminotransferase level of ≤3-fold that of the standard limit) and adequate renal function (serum creatinine ≤1.8 mg/dl). The exclusion criteria included the following: i) History of severe allergy to study drugs; ii) neurological disorders or physically unable to cooperate with the present study; iii) severe dysfunction of heart, lung, liver or kidney; and iv) extensive metastasis. The present study was approved by the Ethics Committee of Liaocheng People's Hospital. Written informed consent was obtained from all study participants.
Immunohistochemistry (IHC) analysis
All of the specimens were obtained from endoscopic biopsy and surgical resection of gastric cancer tissues. The sections were treated with 3% hydrogen peroxide (H2O2) and heated in microwave for antigen retrieval. Following blocking with 10% mouse serum (catalog no. M1025100, Wolcavi Biotech Co., Ltd., Beijing, China), the sections were incubated with a mouse anti-human primary antibody against AFP (1:1,000; catalog no. MAB-0013; Fuzhou Maixin Biotech Co., Ltd., Fuzhou, China) overnight at 4°C. The sections were washed with phosphate-buffered saline (PBS, Na2HPO4 8.1 mmol/l, KH2PO41.5 mmol/l, NaCl 137 mmol/l, 2.7 mmol/l; PH 7.4) and then further incubated with secondary antibody (1:500, catalog no. KIT-5002; MaxVision™ HRP-Polymer anti-mouse IHC kit; Fuzhou Maixin Biotech, China). The reaction was visualized using 3,3′-diaminobenzidine (Fuzhou Maixin Biotech, China) and counterstained with Mayer's hematoxylin. A known AFP-positive slide was set as a positive control, and a slide incubated with PBS instead of primary antibody was used for a negative control. Immunostaining of AFP was mainly located in cytoplasm or membrane, presented as yellow or brown particles. Immunostaining of AFP was scored on the scale of semiquantitative assessment by combining evaluation of the intensity and percentage of positive cells. Percentage scores were assigned as follows: 0, 0%; 1, 1–10%; 2, 11–50%; 3, 51–80%; and 4, 81–100%. The intensity of AFP staining was scored as 0 (none), 1 (yellow), 2 (light brown) and 3 (deep brown). The scores of percentage and intensity were added to give a final score from 0 to 7: 0–1, negative; 2–3, weak positive; 4–5, positive; and above 5, strong positive. All the slides were inspected blindly by two independent pathologists, who solved all discordant cases by discussion, or a mean value of the two scores was used.
Treatment regimen
Patients in the SOX group received only chemotherapy, whereas those in the SOX plus surgery group were treated with palliative surgical resection of the primary lesion supplemented with pre- and post-operative SOX chemotherapy. The specific regimen consisted of oxaliplatin intravenously on the first day and S-1 twice daily for 14 consecutive days. The dosage was calculated according to body surface area (BSA): BSA <1.25 m2, 80 mg/day; 1.25 m2 ≤BSA <1.5 m2, 100 mg/day; BSA >1.5 m2, 120 mg/day. This chemotherapy regime was repeated every 3 weeks with a total of ≥4 cycles in the two treatment groups. Antiemetic and supportive treatments were administered according to the standard clinical practice during chemotherapy.
PFS was defined as the duration between initiation of treatment and disease progression or date of mortality or loss to follow-up. OS was defined as the duration between initiation of treatment and date of mortality or loss to follow-up. Patient status was monitored using enhanced CT, MRI, serum AFP levels and gastroscopy. The treatment efficacy following two cycles of chemotherapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (17) following every two treatment cycles. Tumor lesions were measured 1 week before and 2 months after therapy. Gastroscopy was performed following chemotherapy if required. All adverse events were recorded and followed up according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE4.0; version 4.03; http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5×7.pdf.
Statistical analysis
Statistical analyses were performed using SPSS (version 21.0; IBM SPSS, Armonk, NY, USA). The differences in clinicopathological characteristics of patients in the SOX and SOX plus surgery groups were analyzed using the χ2 test. PFS and OS were compared using Kaplan-Meier estimator analysis. The differences in prognoses between the two groups were analyzed using a log-rank test. Quantitative data were analyzed using Fisher's exact test. P<0.05 was considered to indicate a statistically significant difference.
Results
Patient characteristics
A total of 46 patients with APGC admitted to Liaocheng People's Hospital between January 2011 and December 2013 were identified and 24 patients (15 males, 9 females; average age, 59 years, range, 32–81 years; Table I) among them met the inclusion and exclusion criteria and were enrolled in the present retrospective study. A total of 10 patients were assigned to the SOX group as they were resistant to docetaxel, cisplatin and/or 5-FU. In total, 14 patients were assigned to the SOX plus surgery group and underwent SOX chemotherapy prior to and following palliative resection of the primary lesion. All patients exhibited typical histopathological characteristics, including poorly differentiated adenocarcinoma and signet ring cells (Fig. 1). AFP was detected using immunohistochemical staining (stained in brown; Fig. 2A and B); carcinoembryonic antigen and cancer antigen 125 were also positive (Fig. 2C and D). Typical characteristics of GC were observed upon gastroscopy. However, the lesions of certain patients were comparatively small and were frequently less ulcerated (Fig. 3). All patients exhibited significantly elevated AFP levels. Patients with metastatic lesions of >5 cm in diameter exhibited AFP levels >3,000 µg/l.
Efficacy evaluation
All patients were monitored using CT during and following treatment, including alterations in the largest horizontal diameter of the tumor multiplied by the largest vertical diameter, the number of tumors and any newly diagnosed tumors (Figs. 4–6). In the SOX group, 4 (40%) cases exhibited a partial response; in 3 (30%) cases, the patient's condition was evaluated as stable and 3 (30%) cases demonstrated evidence of disease progression. In the SOX plus surgery group, 6 (42.8%) cases exhibited a partial response, 4 (28.6%) cases remained stable and 4 (28.6%) cases demonstrated evidence of disease progression. The disease control rate was 70.0 and 71.4% in the SOX and SOX plus surgery group, respectively. However, no statistically significant difference was identified (P=0.208; Table II).
The dynamics of the plasma AFP levels were monitored in patients during and following treatment. AFP detection in plasma was identified as a sensitive indicator of APCG treatment efficacy (Fig. 7).
The PFS in the two groups was 6.5 [95% confidence interval (CI), 4.6–8.4] and 7 (95% CI, 5.7–8.3) months, respectively. The observed difference between groups was not significant (P=0.703; Table II; Fig. 8A). The OS of the two groups was 13.5 (95% CI, 8.1–18.9) and 14 (95% CI, 11.0–17.1) months, respectively. No statistically significant difference between groups was identified (P=0.710; Table II; Fig. 8B).
Safety profile
Adverse events in the study population are summarized in Table III. Level 3 to 4 adverse effects included leucopenia, granulocytopenia, anemia and diarrhea with no significant difference identified between the two groups (P>0.05). In the SOX plus surgery group, 1 case of each surgery-associated event (gastroplegia, pancreatic fistula, pulmonary infection and refractory ascites) was reported. However, all patients improved with expectant treatment with no treatment-associated mortality.
Discussion
GC is the fourth most frequent cancer globally (18). In total, ~84% of patients with GC develop advanced disease, with a median survival without chemotherapy of between 3 and 4 months. For advanced-stage GC, chemotherapy is the preferred treatment option (19). Samaratunga et al have suggested that neoadjuvant chemotherapy with at least two cycles of the SOX regimen may induce a relatively high number of pathologically complete responses without increasing morbidity and mortality (20). Consequently, the SOX regimen is considered to be one of the most effective chemotherapy treatments for GC, particularly in China and Japan (it is not available in the majority of other countries) (9–12). The SOX regimen is now considered as a chemotherapeutic option for the treatment of GC. However, its efficacy in patients with APGC has not been conclusively demonstrated.
Elevated serum AFP levels are frequently observed in patients with hepatocellular carcinoma and yolk sac tumors (21). According to certain studies, AFP may be produced by gastrointestinal tract organs, rectal carcinoma, gallbladder carcinoma and lung carcinoma (22). Bourreille et al (21) reported the first case of APGC with liver metastasis in 1970. Liu et al (1,23) reported >100 cases of patients with APGC since 1970. APGC is established to be an aggressive tumor with a higher propensity for liver metastasis. APGC is associated with immunosuppression due to increased levels of AFP expression and a poorer prognosis as compared with other subtypes of GC (24). Key factors affecting the prognosis of APGC include primary lesion progression, histopathological characteristics of cancer cells and immune status of the patient (21).
As the precise underlying mechanism of APGC remains to be elucidated, the optimal treatment approach requires further consideration. Patients with APGC and liver metastasis may be eligible for resection of the primary if neo-adjuvant chemotherapy is administered. Studies have suggested that obstruction, perforation or bleeding may be eliminated when the primary tumor is resected in patients with advanced APGC and multiple organ metastases (25–27). It may also decrease tumor burden and the energy demand of patients. Studies have also demonstrated a decrease in cytokine levels and significant immunosuppression in these patients (24). Patients with APGC and liver metastasis exhibit an average survival time of ≤14 months despite treatment with adjuvant therapy (14). It has been suggested that percutaneous ethanol injection may be an effective treatment for liver metastasis and is associated with an average survival time of 18 months, which is longer than that associated with other treatment modalities, including partial hepatic resection and systemic chemotherapy (the latter having a survival time of ≤7 months) (8). Another previous study initially proposed that patients with a solitary liver metastatic lesion should be treated with surgical resection, whereas patients with multiple liver metastases should undergo a partial hepatectomy followed by transarterial continuous-infusion chemotherapy as the preferred therapeutic approach (28). Notably, all patients in this study did not survive for >8 months, demonstrating that hepatic resection should be considered carefully (24). In the present study, the efficacy and safety profile of SOX chemotherapy alone was retrospectively compared with the combined approach of SOX plus surgical resection in patients with APGC.
The efficacy of the SOX regimen to treat APGC was positive in the present study compared with previous studies involving patients with other types of GC, and those treatments had a significantly lower efficacy (9–11). The majority of metastatic lesions were decreased to half of their original size following one cycle of chemotherapy (Figs. 4–6). The plasma AFP level also decreased, but the same response was not observed in the primary tumor in the stomach using gastroscopy. The present study investigated whether unresectable primary tumors may become resectable through the administration of neo-adjuvant chemotherapy. The surgery was performed following between 2 and 3 cycles of chemotherapy, or following significant reduction in metastatic lesions and decreased AFP levels. Serious complications were more frequently observed in the SOX plus surgery group, including fever of unknown origin, pulmonary infection, pancreatic fistula and refractory ascites. The complications were associated with decreased tolerability of further chemotherapy, which in the majority of cases was delayed by >3 months after surgery. This delay resulted in disease progression in certain cases and was possibly responsible for increased drug resistance in these patients. The patients who exhibited resistance to drugs typically did not survive due to complications within 1 year of surgery. The results of the present study suggest that the advantage that may be gained by palliative resection of the primary tumor may be offset by the disadvantage from chemotherapy interruption. The palliative surgery may be performed following the administration of planned chemotherapy cycles or following the attainment of plateau response to chemotherapy.
In the SOX group, 4 patients demonstrated a partial response to treatment, 3 cases remained in a stable condition and 3 cases exhibited evidence of disease progression. In the SOX plus surgery group, 6 cases demonstrated a partial response, 4 cases remained stable and in 4 cases there was evidence of disease progression. The disease control rate was 70.0 and 71.4% in SOX and SOX plus surgery group, respectively, with no significant difference identified between the two groups (P=0.208), which suggested that resection of the primary lesion may not lower the tumor burden or affect metastatic lesions. The PFS in the SOX and SOX plus surgery groups was 6.5 (95% CI, 4.6–8.4) and 7 (95% CI, 5.7–8.3) months, respectively. The corresponding OS was 13.5 (95% CI, 8.1–18.9) and 14 (95% CI, 11.0–17.1) months, respectively. No significant difference in OS was identified between the two groups (P=0.710). These results suggested that there is no additional benefit from surgery to the PFS or OS rate. Additionally, primary lesion surgery did not appear to confer any prognostic advantage on patients with APGC and liver metastasis. The results of the present study differ from those of certain earlier studies (29,30), possibly as all subjects in the present study were patients with APGC.
The adverse events rates in the two groups were comparable. However, only patients in the SOX plus surgery group experienced severe adverse events, including gastroplegia, pancreatic fistula, pulmonary infection and refractory ascites. Although adjuvant chemotherapy prior to surgery aided in the surgical resection of the primary lesion, the post-surgical complications affected the continuity of chemotherapy leading to tumor resistance to chemotherapy. This phenomenon may contribute to the decreased efficacy of surgery observed in the present study. A robust evaluation of the SOX plus surgery regimen in patients with APGC is required.
In conclusion, the results of the present single-center retrospective study demonstrates the specific efficacy of SOX regimen in patients with APGC and provide evidence that irregular chemotherapy with SOX may lead to the development of tumor resistance. Future randomized, double-blind, large-scale clinical trials are required to conclusively establish the role of the SOX regimen in patients with APGC.
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