Sintilimab combined neoadjuvant intraperitoneal and systemic chemotherapy in gastric cancer with peritoneal metastasis
Abstract
Intraperitoneal chemotherapy combined with systemic chemotherapy is one of the therapeutic modalities currently used for the treatment of gastric cancer patients with peritoneal metastasis. This study was designed to evaluate the efficacy and safety of sintilimab plus S-1 combined intraperitoneal and intravenous paclitaxel. This is an open-label, single-center, phase II study including 36 gastric adenocarcinoma patients with peritoneal metastases diagnosed by laparoscopy. All enrolled patients received sintilimab, intraperitoneal and intravenous paclitaxel plus oral S-1 every 3 weeks. Conversion operation should be considered when a patient responds to the regimen and the peritoneal metastasis disappears. After gastrectomy, the protocol treatment is repeated until disease progression, unacceptable toxicity, investigator decision or patient withdrawal. The primary end point is the 1-year survival rate.
Clinical Trial Registration:NCT05204173 (ClinicalTrials.gov)
Gastric cancer remains the fifth most commonly diagnosed cancer and is the fourth most common reason for cancer death [1]. Morbidity and mortality rates for gastric cancer have decreased gradually in China, owing to effective therapy against Helicobacter pylori [2]. Intra-abdominal spread is the predominant cause of treatment failure after curative-intent gastrectomy [3]. About 90% of cancer recurrences were local and/or retroperitoneal lymph node metastasis, peritoneal dissemination and liver metastasis [4]. Meanwhile, peritoneal carcinomatosis was present in about 14% of gastric cancer patients at the time of initial diagnosis. The prognosis of gastric cancer with peritoneal seeding is poor, with a median survival of 4 months [5].
Systemic chemotherapy remains the backbone of therapy for metastatic gastric cancer. Nevertheless, the response of peritoneal carcinomatosis to systemic chemotherapy is poor, mainly owing to the presence of the plasma-peritoneal barrier, which isolates the peritoneal cavity from the efficacy of intravenous (iv.) chemotherapy [6]. The main therapeutic modalities for the treatment of peritoneal surface malignancies include systemic chemotherapy, cytoreductive surgery with or without hyperthermic intraperitoneal (ip.) chemotherapy (HIPEC), catheter-based ip. chemotherapy and pressurized ip. aerosol chemotherapy [3]. HIPEC is widely used for patients with peritoneal dissemination. Although some evidence exists on its effects on selected disease entities, it has not yet been the standard of care, owing to a lack of randomized controlled trials.
Paclitaxel (PTX; ip. and iv.) plus oral S-1 with or without gastrectomy is offered at some centers, although this approach remains controversial. Neoadjuvant ip. and systemic chemotherapy (NIPS) is a long-course combination treatment of ip. chemotherapy using implanted catheter access ports. NIPS or ip. chemotherapy using docetaxel or PTX seems to further reduce peritoneal progression and improve survival. The PHOENIX-GC trial failed to display the statistical superiority of ip. and iv. PTX plus S-1 in gastric cancer patients with peritoneal dissemination. However, the randomized phase III trial indicated the clinical benefits of ip. PTX for patients with a moderate number of ascites [7].
The current authors performed a phase II trial of ip. and iv. PTX plus S-1 and confirmed its efficacy and safety. Based on the phase II study, a phase III multicenter randomized controlled trial was further designed to compare ip. and iv. PTX plus S-1 versus iv. PTX plus S-1 in gastric cancer patients with peritoneal dissemination [8]. On the basis of the preliminary results, NIPS might be superior to S-1 plus iv. PTX as standard therapy.
In addition, the CheckMate 649 trial assessed first-line nivolumab plus fluoropyrimidine and oxaliplatin for advanced gastric, gastroesophageal junction and esophageal adenocarcinoma. This study met dual primary end points of overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 Combined Positive Score (CPS) ≥5, as well as the secondary end points of OS in those with PD-L1 CPS ≥1 and OS in all randomly assigned patients [9]. Meanwhile, based on the ORIENT-16 study, sintilimab plus leucovorin, fluorouracil and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (XELOX) was regarded as first-line therapy for PD-L1 CPS ≥5 advanced gastric cancer patients. It is reasonable to speculate that gastric cancer patients with peritoneal dissemination could gain the most benefits from immunotherapy plus chemotherapy [10].
In this study, sintilimab, PTX and S-1 were combined to treat gastric cancer patients with peritoneal dissemination. The work was designed to estimate the efficacy and safety of sintilimab plus ip. and systemic chemotherapy. If this phase II trial is able to show the superiority of sintilimab plus S-1 combined with ip. and iv. PTX, a phase III trial will be performed for further study.
Methods
Study aim
This is an open-label, single-center, phase II trial that assesses the efficacy and safety of combined PD-1 blockade (sintilimab) and chemotherapy (ip. and iv. PTX plus oral S-1) as neoadjuvant treatment in 36 gastric cancer patients with peritoneal metastasis. Conversion surgery (radical resection of R0, D2 lymph node dissection or palliative resection, D0–D2 lymph node dissection) was conducted according to the results of the second laparoscopic exploration. The primary outcome is the 1-year survival rate. The secondary outcomes are the number of participants experiencing clinical and laboratory adverse events (AEs), R0 resection rate, 3-year OS and 3-year PFS. The exploratory end point was serial monitoring of ctDNA in gastric cancer patients with peritoneal metastasis.
Study design
This is an open-label, single-center, single-arm phase II trial (ClinicalTrials.gov identifier: NCT05204173) for gastric cancer patients with peritoneal metastasis (Figure 1). Gastric adenocarcinoma was confirmed by histology and peritoneal metastasis was definitively diagnosed by laparoscopy. The peritoneal access port was implanted and Peritoneal Cancer Index (PCI) was confirmed in the first laparoscopic exploration. Gastric cancer patients with peritoneal metastasis enrolled in this phase II study received sintilimab (200 mg iv. infusion on day 1), PTX (50 mg/m2 iv. and 20 mg/m2 ip. infusion on days 1 and 8) plus oral S-1 (80 mg/m2 for 14 consecutive days with 1 week rest) every 3 weeks. PTX was diluted in 1 l normal saline and administered through a port over 1 h concurrently with iv. infusion of PTX. Patients will be assessed for tumor status every 3 cycles through CT scans based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Radical operation should be considered when the peritoneal metastasis disappears. After 18 weeks (6 cycles) of treatment, patients with stable disease/complete or partial response but unresectable disease will continue the same treatment. Patients will receive the protocol regimen again within 3–4 weeks after conversion surgery until disease progression, unacceptable toxicity, investigator decision or patient withdrawn.
IP: Intraperitoneal; iv.: Intravenous; PTX: Paclitaxel.
All patients signed written informed consent. This study protocol was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.
Characteristics of participants
Adult patients (18 years and older) with histologically proven gastric adenocarcinoma with peritoneal dissemination are eligible for participation. HER2-positive patients [11], including immunohistochemistry (IHC) 2+ and FISH-positive or IHC 3+, were excluded. Patients were treated with sintilimab combined ip. and iv. PTX plus oral S-1.
Inclusion criteria
| 1. | Histologically confirmed gastric adenocarcinoma; | ||||
| 2. | Peritoneal metastases from gastric cancer requiring definitive diagnosis by laparoscopy and without gastric outflow tract obstruction and intestinal obstruction; | ||||
| 3. | Written (signed) informed consent; | ||||
| 4. | Age ≥18 years at registration; | ||||
| 5. | Eastern Cooperative Oncology Group (ECOG) score ≤2; | ||||
| 6. | Expected life expectancy >3 months; | ||||
| 7. | Adequate bone marrow, liver and renal functions: absolute leucocyte count of ≥3.0 × 109/l; absolute neutrophil count of ≥1.5 × 109/l; platelet count of ≥100 × 109/l; hemoglobin ≥90 g/l; bilirubin of <1.5 × upper limit of normal (ULN); alanine aminotransferase and aspartate aminotransferase of <2.5 × ULN; serum creatinine of ≤1.5 × ULN; creatinine clearance of >50 ml/min; TSH ≤1 × ULN (if abnormal, T3 and T4 levels should be inspected at the same time; if T3 and T4 levels are normal, they can be included in the group); APTT ≤1.5 × ULN and INR ≤1.5 × ULN; myocardial enzymogram ≤1 × ULN. | ||||
Exclusion criteria
| 1. | Confirmed evidence of distant metastasis other than peritoneal metastasis (e.g., liver metastasis, lung metastasis, para-aortic lymph node metastasis, etc.); | ||||
| 2. | HER2-positive tumors (defined as IHC 2+ and FISH-positive or IHC 3+); | ||||
| 3. | History of chemotherapy, radiotherapy or immunotherapy for primary gastric cancer with peritoneal metastasis; | ||||
| 4. | During pregnancy, within 28 days of post parturition or during lactation; | ||||
| 5. | Synchronous or metachronous (within 5 years) malignancies; | ||||
| 6. | Severe mental disease, uncontrolled epilepsy or CNS disease; | ||||
| 7. | Clinically severe (i.e., active) heart disease, such as symptomatic coronary heart disease, New York Heart Association (NYHA) class II or more severe congestive heart failure or arrhythmia requiring drug intervention or a history of myocardial infarction in the last 12 months; | ||||
| 8. | Upper gastrointestinal obstruction or abnormal physiological function or malabsorption syndrome may affect S-1 absorbers; | ||||
| 9. | Known peripheral neuropathy > Common Terminology Criteria for Adverse Events (CTCAE) grade 1. However, patients with only the disappearance of deep tendon reflex (DTR) need not be excluded; | ||||
| 10. | Patients on steroid or immunosuppressant treatment after organ transplant; | ||||
| 11. | Patients with severe uncontrolled recurrent infections or other severe uncontrolled concomitant disease; | ||||
| 12. | Moderate or severe renal damage (creatinine clearance ≤50 ml/min) or serum creatinine > ULN, 115 μmol/l; | ||||
| 13. | Known dihydropyrimidine dehydrogenase (DPD) deficiency; | ||||
| 14. | Anaphylaxis to PTX or any research drug ingredient; | ||||
| 15. | Active autoimmune disease or history of refractory autoimmune disease; subjects with hypothyroidism requiring only hormone replacement therapy and skin diseases without systemic treatment (e.g., vitiligo, psoriasis or alopecia) can be selected; | ||||
| 16. | HIV antibody positive, active hepatitis B or C (hepatitis B: HBsAg positive and HBV DNA ≥10 copies/ml; hepatitis C: HCV antibody and HCV-RNA positive, requiring antiviral treatment at the same time); | ||||
| 17. | Steroid or other systemic immunosuppressive therapy was used 14 days before admission, excluding local or physiological doses of systemic glucocorticoids (e.g., no more than 10 mg/day of prednisone or other glucocorticoids of equivalent dose) by nasal spray, inhalation or other routes, or hormones used to prevent allergy of contrast agents; | ||||
| 18. | Uncontrolled arrhythmia and myocardial infarction within 12 months before admission or active tuberculosis. | ||||
Study arm
The intervention in this study was sintilimab, PTX and S-1. All enrolled participants received sintilimab (200 mg iv. infusion on day 1), PTX (50 mg/m2 iv. and 20 mg/m2 ip. infusion on days 1 and 8) plus oral S-1 (80 mg/m2 for 14 consecutive days with 1 week rest) every 3 weeks.
Conversion gastrectomy
The indications for conversion surgery were as follows: the disappearance of peritoneal metastases by second laparoscopy; negative peritoneal cytology; no other distant metastases by radiographic findings; downstaging the primary tumor to resectable by radiographic findings; and improvement of patient's general condition.
Measures of outcomes & assessments
The primary outcome is the 1-year survival rate. The secondary outcomes are the number of participants experiencing clinical and laboratory AEs, R0 resection rate, 3-year OS and 3-year PFS. Clinical response was evaluated by the investigators based on RECIST v1.1. AEs were monitored and graded according to the CTCAE v5.0. Outcomes were assessed at baseline and every three cycles after recruitment.
Sample size calculation
This phase II trial was a single-arm study and aimed to assess the efficacy and safety of PD-1 blockade (sintilimab) combined with chemotherapy (ip. and iv. PTX plus oral S-1). The 1-year survival rate was expected to increase from 50% to 75% with a statistical test efficiency (1-β) of 90% and a one-side test (α) at 0.05 significance level. The expected study subjects will be enrolled for over 1 year and followed up for 1 year. Using PASS software (version 15.0, NCSS, LLC, UT, USA) for sample size estimation, the log-rank test revealed a sample size of 36, with a dropout rate of 10%. A total of 36 patients will be recruited.
Statistical analysis
Study outcome parameters will be analyzed using descriptive statistical methods. OS will be measured from the date of enrollment to the date of any cause of death. PFS will be measured from the date of enrollment to the date of disease progression or any cause of death. Survival analyses will be performed by the Kaplan–Meier method. The log-rank test will be applied for the comparison of survival curves. AEs will be monitored and graded in accordance with CTCAE v5.0. p < 0.05 is considered statistically significant.
Translational analysis
This study is conducted to investigate the efficacy and safety of PD-1 inhibitor sintilimab plus chemotherapy in gastric cancer patients with peritoneal metastasis. In addition to selecting potential beneficiaries, the trial also incorporates translational analysis. Archival tissue biopsy samples will be collected at baseline and used for further studies. Blood samples will be sequentially collected at baseline and every three cycles (9 weeks) during therapy together with CT imaging. Both plasma samples and tumor specimens will be used for biomarker exploration analysis, which focuses on both discovery/hypothesis generation and validation objectives. All patients have signed the written informed consent for serial tumor genomic profiling.
Discussion
We aim to assess the efficacy and safety of combined PD-1 blockade and chemotherapy (neoadjuvant ip. and systemic chemotherapy) for gastric cancer patients with peritoneal metastasis in this phase II study. Meanwhile, we will explore the genomic profiling of ctDNA associated with the curative effect of NIPS plus immunotherapy.
Gastric cancer is a genomically heterogeneous disease, including intratumor and intertumor heterogeneity and spatial and temporal heterogeneity [12]. Peritoneal carcinomatosis is the most common reason for distant metastasis and disease recurrence in gastric cancer. The 5-year survival rate of stage IV gastric cancer is still around 9.4%. Gastric cancer with peritoneal dissemination may represent a systemic disease, hence, surgical resection or chemotherapy as a local treatment alone cannot achieve sufficient disease control. Previous studies have demonstrated that selected patients with advanced gastric cancer can have survival benefits with chemotherapy followed by curative surgery if all residual gross disease is potentially resectable. There is a clear association between radical resection and long-term survival. Therefore, multidisciplinary treatment is crucial for patients with resectable advanced gastric cancer.
Neoadjuvant therapy, also known as induction therapy, has the advantages of eliminating the micrometastases much earlier, reducing tumor burden and increasing operability [13]. Compared with postoperative adjuvant chemotherapy, neoadjuvant treatment can achieve better tolerance for patients. According to a comprehensive literature review, cisplatin, mitomycin C and PTX were the commonly prescribed chemotherapy agents in ip. delivery [14]. Due to the plasma-peritoneal barrier, ip. chemotherapy could increase the concentration of chemotherapeutic agents delivered to tumor cells compared with systemic chemotherapy [15]. The efficacy of neoadjuvant ip. and systemic chemotherapy for gastric cancer patients with peritoneal metastasis was assessed in a prospective phase II study. The median survival time of 25 treatment-naive patients with peritoneal cytology positive for carcinoma cells or peritoneal metastasis was 16.7 months [16]. The exploratory analyses of the PHOENIX-GC trial suggested potential clinical benefits of ip. PTX for gastric cancer with a moderate number of ascites [7]. In our previous study, oxaliplatin plus S-1 with ip. PTX (SOX + ip. PTX) was effective in Chinese advanced gastric cancer patients with peritoneal dissemination [17].
Conclusion
The present study will provide data on survival, efficacy and toxicity in gastric cancer patients with peritoneal metastasis. The ultimate goal is to search for effective therapeutic strategies for advanced gastric cancer patients.
Gastric cancer with peritoneal metastasis
Peritoneal dissemination is the most common reason for distant metastasis and disease recurrence in gastric cancer. The prognosis of gastric cancer with peritoneal seeding is poor, with a median survival of only 4 months.
DRAGON-09 trial (NCT05204173)
This is an open-label, single-center, single-arm phase II trial that assesses the efficacy and safety of combined PD-1 blockade (sintilimab) and chemotherapy (ip. and iv. paclitaxel plus oral S-1) as neoadjuvant treatment in 36 gastric cancer patients with peritoneal metastasis. Conversion surgery (radical resection of R0, D2 lymph node dissection or palliative resection, D0–D2 lymph node dissection) was conducted according to the results of the second laparoscopic exploration.
Objectives & end points
The primary end point is 1-year survival rate.
The secondary end points are the number of participants experiencing clinical and laboratory adverse events, R0 resection rate, 3-year overall survival and 3-year progression-free survival.
Exploratory objective includes biomarker exploration analysis.
Conclusion
The ongoing DRAGON-09 study will provide data on survival, efficacy and toxicity in gastric cancer patients with peritoneal metastasis.
Author contributions
Study conception and design: C Yan and Z Zhu; acquisition of data: H Yuan, S Lu, M Shi, Z Yang, W Liu, Z Ni, X Yao, Z Hua, R Feng, Y Zheng, Z Wang, BK Sah, M Chen, Z Zhu, C He, C Li and M Yan; analysis and interpretation of data: H Yuan, S Lu, M Shi, Z Yang and C Yan; writing and revising the manuscript: H Yuan, M Shi, Z Yang and C Yan; study supervision: C Yan, J Zhang, M Yan and Z Zhu. All authors read and approved the final manuscript.
Acknowledgments
The authors would like to thank the patients and their families as well as the investigators for their kind assistance in this research.
Financial & competing interests disclosure
This study was supported by the Multicenter Clinical Research Project of Shanghai Jiao Tong University School of Medicine (DLY201602) to Z Zhu, National Natural Science Foundation of China (82102760) to H Yuan, and Shanghai Rising-Star Program (20QA1406200) to M Shi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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