Role of cytoreduction and hyperthermic intraperitoneal chemotherapy for metastatic gastroesophageal junction adenocarcinoma?

Abstract

Introduction

Gastric cancer (GC) stands as the fifth most prevalent cancer worldwide and the third leading cause of cancer-related mortality across both genders, contributing to ~8.8% of all annual cancer deaths. [1] Notably, peritoneal carcinomatosis (PC) can develop in patients with a primary gastric tumor in a substantial proportion of GC patients, with estimates ranging from 14% to 43%, making it accountable for ~35% of all synchronous metastases [2, 3]. Intriguingly, in 9% of GC cases, PC may manifest as the sole site of synchronous metastasis [2].

Out of all gastric cancers, the incidence of esophagogastric junction adenocarcinoma (AEG) is on the rise, aligning with the epidemiological trends in distal esophageal adenocarcinoma and gastric cardial tumors (AEG type III) [4–7]. Unfortunately, in many AEG patients, symptoms tend to surface when lymph nodal or visceral metastases are already well-established, which regrettably results in a generally bleak overall survival rate [8].

Intraperitoneal chemotherapy, combined with hyperthermia (HIPEC), provides regional dose intensification within the peritoneal cavity, effectively targeting peritoneal carcinomatosis with minimal systemic exposure [9]. Administered ideally during or immediately after surgery, it leverages its cytotoxic effects to destroy cancer cells within postoperative fibrin, while delayed administration faces challenges due to scar tissue and adhesions, leading to non-uniform drug distribution [10]. Hyperthermia enhances HIPEC by impairing deoxyribonucleic acid (DNA) repair, protein denaturation, and increasing drug penetration and sensitivity in tumor cells. HIPEC is the standardized nomenclature for this technique as per international consensus [11].

We report a case of gastroesophageal junction adenocarcinoma with peritoneal metastasis successfully treated with innovative techniques of cytoreductive surgery (CRS) and HIPEC, and later on surgery and systemic chemotherapy, highlighting HIPEC as one of the viable options and the importance of a multimodal approach for the treatment of this case.

Case presentation

A 46-year-old female with history of gastric-esophageal reflux disease (GERD), hyperlipidemia, and hypothyroidism presented to the gastroenterology clinic with difficulty swallowing and mid-epigastric pain for over a year. Family history was significant stomach cancer in maternal grandfather. The patient had quit alcohol intake (two glasses of wine per week) 1 month prior to presentation and was a former smoker (five pack-years). Review of systems was significant for weight loss, fatigue, and back pain. Physical exam showed normal vital signs and systemic exams.

The patient underwent an esophagogastroduodenoscoy (EGD) that revealed stenosis of the gastric-esophageal (GE) junction and friable area into the cardia. Biopsies revealed a poorly differentiated carcinoma with features of adenocarcinoma and focal squamous cell carcinoma. The invasive adenocarcinoma had mucinous features and intestinal metaplasia.

The biopsy was negative for Helicobacter pylori, CMV, HSV 1/2, and fungi. There was low probability of microsatellite instability. The duodenum was negative for dysplasia and malignancy. Computed tomography (CT) of the abdomen and pelvis was unremarkable except for gallstones. CT of the chest showed no lymphadenopathy or evidence of extramural extension.

The patient then underwent an endoscopic ultrasound (EUS). It revealed a malignant-appearing ulcerated GE junction lesion and regional lymph nodes concerning malignant infiltration. A biopsy of the lesion revealed a moderately to poorly differentiated and ulcerated carcinoma involving the lamina propria of cardia-type gastric mucosa. The mass was HER-2 negative. The foveolar gastric epithelium was unremarkable, and no squamous esophageal mucosa was present. PET/CT showed no distant metastatic disease.

The patient then underwent a port-a-cath placement for chemotherapy and diagnostic laparoscopy to identify any peritoneal disease. Biopsies of the peritoneum revealed adenocarcinoma infiltrating fibroconnective tissue. A biopsy of the right diaphragm was also positive for malignancy in two sites. Based on biopsy, a T3N1 adenocarcinoma of the GE junction was staged.

The patient started radiation therapy and weekly carboplatin-taxol chemotherapy regimen. A repeat PET/CT 4 months later revealed no evidence of metastatic lymphadenopathy. Staging laparoscopy 2 months after the PET/CT showed no gross peritoneal disease. Cytologic washing of the right upper quadrant, left upper quadrant, and pelvis also revealed no evidence of malignancy. Her resting peritoneal cancer index (PCI) score was 0.

Given the nature of this patient’s metastatic gastric cancer and optimal response to systemic chemotherapy, complete cytoreduction with intraperitoneal perfusion using heated mitomycin was recommended. A total of 9 months after the initial EGD, she underwent a subtotal gastrectomy, feeding jejunostomy tube placement, and distal esophagectomy. A biopsy of the distal esophagus and proximal stomach revealed residual moderately differentiated adenocarcinoma of 3.5 cm, staged yT2N0. CT 1 month later revealed no evidence of recurrent and metastatic disease. She was maintained on nivolumab immunotherapy and ramucirumab-taxol.

Discussion

In gastric cancer, the development of peritoneal carcinomatosis (GCPC) often arises from intraperitoneal free cancer cells (IFCC), which can originate through spontaneous shedding from the primary tumor or inadvertently during surgical procedures [12, 13]. IFCC prevalence is higher in advanced GC stages, particularly those affecting the stomach’s serosal surface. Surgical procedures for GC can release cancer cells from various sources, including lymphatic channels, resection margins, and tumor-contaminated blood within the surgical field, facilitating their spread within the peritoneal cavity [14, 15]. Once within this cavity, cancer cells are aided by factors such as gravity, intestinal peristalsis, and diaphragmatic contractions. The “tumor cell entrapment hypothesis” suggests that these IFCC quickly adhere to surgical raw areas and become trapped in a hypoxic environment, making them resistant to systemic chemotherapy. Intraperitoneal chemotherapy (IPC) is specifically designed to eliminate these persistent IFCC following curative resection [16].

Now we look at the rationale for Hyperthermic Intraperitoneal Chemotherapy (HIPEC). It offers localized drug concentration in the peritoneum, maintaining lower systemic levels through the plasma-peritoneal barrier [9]. A unique advantage lies in the absorption of drugs in the peritoneal cavity into the liver via the portal vein, potentially impacting liver micrometastases. Ideally, IPC is administered during or immediately following surgery, where its cytotoxic effect targets cancer cells within fibrin generated during the wound healing process. Delayed IPC leads to fibrin converting to scars, trapping intraperitoneal free cancer cells (IFCC), causing poor drug penetration and non-uniform distribution due to adhesions [10]. Hyperthermia enhances IPC by directly impairing DNA repair, denaturing proteins, and inhibiting oxidative mechanisms, while indirectly increasing drug penetration, uptake, and the sensitivity of neoplastic cells. This approach is internationally known as HIPEC, the standardized nomenclature for this combined therapy [11].

The success of HIPEC for gastric cancer with peritoneal carcinomatosis (GCPC) is influenced by several factors. The extent of peritoneal carcinomatosis, as assessed by scoring systems like the Peritoneal Carcinomatosis Index (PCI), is a critical prognostic factor [17]. Lower PCI scores are associated with a higher likelihood of complete cytoreduction and better survival. Preoperative ascites is a poor prognostic factor, significantly reducing patient survival [18]. The experience of the medical institution in performing CRS and HIPEC independently affects both patient survival and postoperative complications, highlighting the importance of a learning curve for better outcomes [19]. Response to neoadjuvant chemotherapy, the presence of synchronous PC, completion of more than six cycles of systemic chemotherapy with no serious adverse events, and the absence of signet ring cell histology have been identified as independent predictors for improved survival after CRS and HIPEC [20, 21].

The ideal candidate for CRS and HIPEC in GCPC is typically a young patient with a good performance status, a low PCI score, a resectable primary tumor, no ascites, a positive response to neoadjuvant chemotherapy, and the potential for complete cytoreduction [18, 19, 22]. Our case report underscores the importance of not only CRS and HIPEC treatment for GCPC but also a multimodal approach including surgery and systemic chemotherapy.

Author contributions

Syed M.H. Zaidi, Kimberly Ho, and Amir H. Sohail wrote the initial draft and performed a literature review. Jennifer Whittington supervised the project and made critical revisions.

Conflict of interest statement

None declared.

Funding

None declared.

Data availability

Since this is a case report all relevant data were included. However, if further information is required, it can be provided upon request.

References