The clinical effect of conversion surgery for advanced gastric cancer patients with peritoneal metastasis
Introduction
Gastric cancer (GC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide (1,2). In particular, GC patients with peritoneal metastasis (PM) are known to have a very short survival period.
Systemic chemotherapy is the standard treatment for unresectable GC (3). The prognosis of patients treated with systemic chemotherapy has steadily improved, but median survival time (MST) remains between 10 and 16 months (4,5). New approaches such as intraperitoneal (i.p.) chemotherapy are needed to improve the prognosis of these patients, especially with PM.
We have demonstrated the efficacy of paclitaxel (PTX) in i.p. chemotherapy for PM (6). Following this result, we designed a new regimen combining i.p. PTX and S-1 and intravenous (i.v.) PTX for GC patients with PM and demonstrated its feasibility in a preliminary study (7). However, no patients underwent surgery in our preliminary study, and the most common progression onset region was the primary tumor, not malignant ascites. These patients had obstructed stomachs owing to the increased size of the primary lesions (7). Based on these results, we considered that gastrectomy might improve the prognosis of the patients for whom our new regimen was effective. Therefore, in our next phase II trial, gastrectomy called conversion surgery (CS) (8), was performed in patients who responded to chemotherapy. The result showed a promising MST of 21.3 months for GC patients with PM (9).
Several retrospective studies have reported the long-term survival in selected patients after CS (10-12), but as yet, the role of CS is unclear. Because these previous studies have evaluated the significance of CS for the chemotherapy responder group compared with the chemotherapy non-responder group, it is difficult to identify whether these results are caused by the effect of chemotherapy or the effects of surgery.
Prospective randomized controlled trials are needed to verify the efficacy of CS in patients who respond to chemotherapy. However, undertaking such a randomized study to evaluate the efficacy of CS might be difficult in this patient population, and so we conducted a retrospective study making use of updated our preliminary and phase II trial data (7,9). We present the following article in accordance with the STROBE reporting checklist (13) (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-431/rc).
Methods
Patient population and treatment groups
This retrospective study included 50 GC patients with PM who underwent i.p. and systemic chemotherapy at Kindai University Hospital between May 2003 and October 2008. Patients were followed up in the outpatient or inpatient department or through telephone calls every 3 months for the first 2 years, every 6 months for 3–5 years, and annually thereafter by May 2020. In this study, the median follow-up time was 22.27 (4.40–160.2) months.
Inclusion criteria were diagnosis with histologically proven adenocarcinoma of the stomach; the presence of PM confirmed by staging laparoscopy; absence of non-curative factors except for PM. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The TNM categories were based on the Japanese Classification of Gastric Carcinoma (3rd English edition) (14).
This study was approved by the institutional review board of Kindai University Hospital (No. 31-085) and was conducted according to the principles of the Declaration of Helsinki (as revised in 2013). Informed consent or an alternative was obtained from all patients.
Patients were divided into two groups, chemotherapy alone (CTx) and conversion surgery intervention (CSI). In the CTx group (May 2003 to December 2004) (7), PTX was administered into the peritoneal cavity at the staging laparoscopy. One week after i.p. chemotherapy, S-1 was administered orally and PTX was administered i.v. as previously reported (15). The treatment course was repeated until unacceptable toxicity or disease progression was observed. In the case of disease progression, 2nd line chemotherapy was administered, if possible. Second line chemotherapy regimens varied, including irinotecan, docetaxel, S-1 and cisplatin with or without combination.
The CSI group (January 2005 to October 2008) (9) received the same combination chemotherapy as the CTx group. Systemic chemotherapy was repeated until either sufficient response for a macroscopically curative operation or unacceptable toxicity or disease progression was observed. In the case of disease progression, 2nd line chemotherapy was administered, if possible.
Disease assessment and indication for CS
Assessment of chemotherapy efficacy has already published (7,9). In patients with target lesions, the antitumor effect was assessed based on the RECIST guidelines (16). In contrast, in patients without target lesions, the antitumor effect was assessed based on the wall thickness of the primary tumor. More than 30% improvement in wall thickness was considered a responder (9). Pathological efficacy was assessed by pathologists based on the Japanese Classification of Gastric Carcinoma (3rd English edition) (14).
In the CSI group, second-look laparoscopy was performed if the response to chemotherapy was complete response, partial response or improvement in wall thickness of 30% or more. CS was performed if the results confirmed negative PM and negative peritoneal cytology findings and curative resection was deemed possible. Intraoperative and postoperative complications were reported according to the Clavien-Dindo classification (17). Complications were defined and recorded according to the National Cancer Institute Common Toxicity Criteria version 4.0 (18).
Post-operative adjuvant chemotherapy using with one course of weekly i.v. PTX (19) and S-1 monotherapy (20) was administered for at least 1 week after CS. Treatment after recurrence was at the discretion of the attending physician.
Statistical analysis
Differences between the two groups were analyzed by using Fisher’s exact, chi-square or Mann-Whitney U tests. The overall survival (OS) rates were estimated by the Kaplan-Meier method and compared the survival curves with the log-rank test. Prognostic factors were determined using by univariate and multivariable analyses (Cox proportional-hazards regression modeling).
A P value of less than 0.05 was considered statistically significant. All statistical analyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA).
Results
Patient characteristics and tumor response
Clinical outcomes of 50 GC patients with PM (32 men and 18 women) treated with chemotherapy (7,9) were analyzed and updated. Patients were classified into either CTx (n=15) (7) or CSI (n=35) groups (9). There were no significant differences in age, sex, ECOG performance status, histological subtype or chemo cycle between the two groups (Table 1). Regarding tumor response, in the CTx group, three patients with a measurable target lesion showed a partial response, and six patients without a measurable target lesion demonstrated a 30% decrease in wall thickness. Thus, in the assessment of antitumor efficacy, 9 of 15 patients (60%) were diagnosed as responders.
Table 1
| Characteristics | CTx group (n=15) | CSI group (n=35) | P value |
|---|---|---|---|
| Age (years), median [range] | 62 [22–75] | 64 [32–75] | 0.656 |
| Gender (men/women), n | 9/6 | 23/12 | 0.750 |
| ECOG performance status (0/1), n | 13/2 | 35/0 | 0.458 |
| Macroscopic type, n (%) | 0.652 | ||
| Type non-T4 | 5 (33%) | 13 (37%) | |
| Type 4 | 10 (67%) | 22 (63%) | |
| Histological subtype, n (%) | 0.633 | ||
| Intestinal | 3 (20%) | 10 (29%) | |
| Diffuse | 12 (80%) | 25 (71%) | |
| Chemo cycle, median [range] | 8 [2–20] | 8 [5–12] | 0.685 |
| Tumor response, n (%) | |||
| RECIST guideline | n=5 | n=13 | 0.805 |
| Complete response | 0 (0%) | 1 (8%) | |
| Partial response | 3 (60%) | 7 (54%) | |
| Stable disease | 1 (20%) | 3 (23%) | |
| Progressive disease | 1 (20%) | 2 (15%) | |
| Wall thickness | n=10 | n=22 | 0.714 |
| Over 30% decrease | 6 (60%) | 15 (68%) | |
| Increase | 4 (40%) | 7 (32%) |
ECOG, Eastern Cooperative Oncology Group; RECIST, Response Evaluation Criteria in Solid Tumours; CTx, chemotherapy alone; CSI, conversion surgery intervention.
Conversely, in the CSI group, there was one complete response and seven partial responses. And a further 15 patients showed a 30% decrease in wall thickness. Thus, 23 of 35 patients (65.7%) were diagnosed as responders (Table 1). Therefore, second-look laparoscopy was performed in the 23 patients in the CSI group. Unfortunately, however, one patient was found to have residual PM. Therefore, CS was performed in 22 patients with resolved PM (Figure 1).
Surgery and pathological findings
CS was performed 4–6 weeks (median, 5 weeks) after the last administration of S-1. All CS were performed by laparotomy. Curative total gastrectomy was performed in 19 patients, while curative distal gastrectomy and pancreaticoduodenectomy were performed in two and one patient, respectively. Four patients underwent splenectomy and one underwent transverse colon resection. Postoperative complications were observed in only two patients (9%), one with anastomotic leakage and one with pancreatic fistula. Both of these patients recovered with conservative treatment. Further details of surgical findings are presented in Table 2. The pathological effects of chemotherapy were grade 0 in 3 (13.6%) patients, grade 1a in 12 (54.5%), grade 1b in 2 (9.0%), grade 2 in 4 (18.2%), and grade 3 in 1 (4.5%) patients (Table 2).
Table 2
| Finding | Number (n=22) |
|---|---|
| Peritoneal lavage cytology | |
| CY0/CY1 | 22/0 |
| PM | |
| Negative/positive | 22/0 |
| Type of surgery | |
| Total gastrectomy | 19 |
| Distal gastrectomy | 2 |
| Pancreaticoduodenectomy | 1 |
| Combined resection | |
| Spleen | 4 |
| Colon | 1 |
| Surgical approach | |
| Open/laparoscopic | 22/0 |
| Lymph node dissection | |
| D1/D1+/D2 | 0/0/20 |
| Residual tumor | |
| R0/R1/R2 | 22/0/0 |
| Operative time (min) | |
| Median [range] | 333 [230–600] |
| Intraoperative bleeding (mL) | |
| Median [range] | 731 [195–1,987] |
| Postoperative hospital stay (days) | |
| Median [range] | 13 [10–28] |
| Postoperative complications | |
| Anastomotic leakage | 1 (Gr. 2) |
| Pancreatic fistula | 1 (Gr. 2) |
| Depth of tumor invasion | |
| ypT0/T1a/T1b/T2/T3/T4a/T4b | 1/1/2/1/16/1/0 |
| Lymph node metastasis | |
| ypN0/N1/N2/N3a/N3b | 10/2/5/1/4 |
| JCGA-histological response (primary tumor) | |
| Grade 0/1a/1b/2/3 | 3/12/2/4/1 |
CS, conversion surgery; CY0, peritoneal cytology negative for carcinoma cells; CY1, peritoneal cytology positive for carcinoma cells; PM, peritoneal metastasis; JCGA, Japanese Classification of Gastric Carcinoma (3rd English edition); Gr., toxicity grade according to the Clavien-Dindo classification.
Adjuvant chemotherapy
Adjuvant chemotherapy was initiated in all 22 CS patients. And there were no treatment-related deaths during the treatment period.
Survival
The OS of both groups is shown in Figure 2. In the CTx group, the MST reached 15.8 months, with 1-, 2-, and 5-year OS rates of 66.7%, 26.7% and 6.7%, respectively, whereas the MST was 21.3 months and the 1-, 2-, and 5-year OS rates were 68.6%, 45.7% and 13.7%, respectively, in the CSI group. There was no significant difference in survival between the two groups [P=0.14; 95% confidence interval (CI), 0.3016–1.197].
OS rates were analyzed in the two groups, taking into account differences in chemotherapy efficacy and surgery. In the CTx group who have responded to chemotherapy, the 1-, 2-, and 5-year OS rates were 77.7%, 22.2% and 11.1%, respectively, and the MST was 15.8 months. In the CSI group who underwent surgery, the 1-, 2-, and 5-year OS rates were 77.2%, 59.1% and 21.8%, respectively, and the MST was 29.8 months. In chemotherapy-responders, there was no significant difference in OS between the two groups (P=0.059; 95% CI, 0.1473–1.039) (Figure 3). However, four patients in the CSI group survived for more than 5 years. In addition, at the time of analysis (May 2020), two patients are still alive for more than 12 years after CS.
The MST for chemotherapy non-responders in the CTx group was 15.4 months, with 1- and 2-year OS rates of 50.0% and 33.3%, respectively. The 1- and 2-year OS rates for chemotherapy non-responders in the CSI group who did not undergo surgery were 53.8% and 15.3%, respectively, with an MST of 14.7 months; there was no significant differences in OS between the two groups of chemotherapy non-responders (P=0.957; 95% CI, 0.383–2.758) (Figure 4).
Survival differences about histological response and failure patterns
The survival rates did not differ significantly between grade 1b over response group (n=7) and grade 0 or grade 1a response group (n=15) among those who have undergone CS in the CSI group, (log-rank test, P=0.653) (Figure 5).
Recurrence was observed in 16 of the 22 patients who underwent CS. The site of recurrence was the peritoneum in 9 cases and other sites in 7 cases. The site of metastasis other than peritoneal were bone in 4 cases and liver in 3 cases.
Prognostic analysis in the responder group
Multivariable analysis indicated lymph node metastasis (P=0.0317) and CS (P=0.0380) as independent prognostic factors (Table 3).
Table 3
| Independent factors | Univariate analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value | ||
| Age | 0.4499 | ||||||
| <60 years | 1.000 | Reference | |||||
| >60 years | 1.258 | 0.693–2.285 | |||||
| Macroscopic type | 0.5694 | ||||||
| Type non-T4 | 1.000 | Reference | |||||
| Type 4 | 1.210 | 0.627–2.335 | |||||
| Lymph node metastasis | 0.0109 | 0.0317 | |||||
| cN0–1 | 1.000 | Reference | 1.000 | Reference | |||
| cN2 | 2.432 | 1.226–4.823 | 2.892 | 1.148–7.285 | |||
| Histological type | 0.4208 | ||||||
| Differentiated type | 1.000 | Reference | |||||
| Undifferentiated type | 0.760 | 0.390–1.481 | |||||
| CS | 0.0020 | 0.0380 | |||||
| Absence | 1.000 | Reference | 1.000 | Reference | |||
| Presence | 0.369 | 0.197–0.694 | 0.331 | 0.118–0.925 | |||
CTx, chemotherapy alone; CSI, conversion surgery intervention; CS, conversion surgery; CI, confidence interval.
Discussion
Recently, CS for GC patients has attracted considerable attention as a novel treatment strategy (12). However, evidence on whether CS provides a considerable survival benefit for GC patients with PM is lacking. Therefore, in the present study, we attempted to clarify the significance of CS for GC patients with only PM. The OS rate of chemotherapy-responsive patients in the CSI group was not significantly different to responders in the CTx group (P=0.059; 95% CI, 0.1473–1.039). However, in the multivariable analysis indicated lymph node metastasis and CS as independent prognostic factors. Furthermore, only in the CSI group, four patients were alive for more than 5 years. Additionally, two patients were alive for more than 12 years after CS. We thus concluded that the advantage of CS was evident in some patients in the chemotherapy-responder group.
In contrast, only one patient in the CTx group survived for more than 5 years. Based on this case, we might need a better way to distinguish the chemotherapeutic response. Therefore, the development of chemosensitivity and biological maker is awaited in clinical practice.
Chemotherapy regimens for advanced GC with PM are also an interesting issue. Nakamura et al. reported a negative conversion rate of only 15.2% (5 of 33 patients) in PM using S-1 based regimens (21). Furthermore, Chan et al. reported a negative conversion rate of only 18.2% (4 of 22 patients) in PM treated with i.p. PTX and systemic capecitabine and oxaliplatin (22). On the other hand, our combination regimen showed a high conversion rate (62.8%) compared with other reports. As in our previous report, we considered that the direct effect on i.p. cancer-free cells by i.p. PTX and better translation of i.v. PTX to the peritoneal cavity induced the high negative conversion rate (23). In brief, we concluded that the i.p. PTX and systemic S-1/PTX regimen might be a promising alternative therapy in advanced GC with PM.
In this study, most of the resected primary gastric tumors were classified as histological grade 1a. This suggests that the chemotherapy performed at our institution had little effect on the primary tumor. Kurokawa et al. reported that histological response seemed to be a better surrogate endpoint of OS (24). While, our subclass analysis indicates the histological response did not affect the OS of CS patients, four patients who have survived for more than 5 years were ypN0 cases and one patient obtained pathological CR in the primary tumor.
Furthermore, in unresectable metastatic GC, some reports indicate that R0 provides long-term survival and that microscopic residual tumor (R1) and macroscopic residual tumor (R2) are strong prognostic factors for surgery (25,26). Therefore, CS should be performed for R0 resection to achieve long-term survival if the disappearance of PM is observed.
There were no surgical-related deaths in the present study. Our operative time, blood loss and operative morbidity were acceptable compared with previous studies (27,28). These results indicated that CS after our combination chemotherapy was safe and well tolerated.
The low number of surgical complications allowed the resumption of adjuvant chemotherapy early in the postoperative period. This may have contributed to the better prognosis of patients who underwent CS (29).
In conclusion, CS is safe and may prolong the survival of GC patients with PM. CS may be a promising treatment strategy for some GC patients with PM responding well to chemotherapy.
There are still some limitations to our study. First, this was a retrospective single-arm study. Second, the number of cases is relatively small. Third, the 2nd line chemotherapy regimens for chemotherapy non-responders were different and novel modalities (such as trastuzumab) were not used in this study period. These limitations might have affected the tumor-response to chemotherapy, negative conversion rate of PM and eventually the OS of the patients. Therefore, our conclusions need to be verified by more clinical trials.
Acknowledgments
We thank Gillian Campbell, PhD, from Edanz Group (https://www.edanzediting.com/ac) for editing a draft of this manuscript.
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned by the Guest Editors (Paul H. Sugarbaker and Kurt Van der Speeten) for the series “Intraperitoneal Chemotherapy for Peritoneal Metastases: HIPEC, EPIC, NIPEC, PIPAC and More” published in Journal of Gastrointestinal Oncology. This article has undergone external peer review.
Reporting Checklist: The authors have completed the STOBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-431/rc
Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-431/dss
Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-431/prf
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-431/coif). The series was sponsored by the Peritoneal Surface Oncology Group International (PSOGI). The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring the questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the institutional review board of Kindai University Hospital (No. 31-085) and was conducted according to the principles of the Declaration of Helsinki (as revised in 2013). Informed consent or an alternative was obtained from all patients.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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