Prophylactic hyperthermic intraperitoneal chemotherapy in gastric cancer

Gastric cancer is an aggressive malignancy with poor overall survival rates as a result, in part, of its predilection for peritoneal dissemination. Peritoneal metastasis (PM) is found in up to 55 to 60 percent of patients at the time of diagnosis by imaging or staging laparoscopy.^1,2 In addition, despite multimodality therapy, peritoneal recurrence occurs in up to one-third of patients after curative-intent operations.^2,3 Hence, improved treatment of the peritoneal cavity may be a significant unmet need in gastric cancer. The surgeon may be in a unique position to apply high concentrations of chemotherapy directly to the peritoneal lining to alter outcomes. Although prophylactic use of hyperthermic intraperitoneal chemotherapy (HIPEC) remains investigational, early reports are promising, and patients should be encouraged to participate in clinical trials.

Gastric cancer is still a problem

The incidence of gastric cancer has declined in the past several decades, likely secondary to successful public health initiatives, such as smoking cessation, improved processing of food, and the treatment of Helicobacter pylori. Nonetheless, several risk factors remain, such as obesity and gastroesophageal reflux disease (GERD). Therefore, gastric cancer remains a significant health problem in the U.S. with more than 27,000 new cases diagnosed this year. In the U.S., the five-year overall survival rate for gastric cancer is 30.4 percent and decreases to 5 percent for advanced stage disease.⁴ Accurate baseline staging is essential to determine the appropriate treatment regimen. Clinical staging of gastric cancer has improved with endoscopic ultrasonography (EUS), positron emission tomography (PET), and computed tomography (CT). Despite advances in imaging, one of the most important staging modalities remains within the hands of the surgeon. Diagnostic laparoscopy identifies radiographically occult PM in up to 30 percent of patients and thus leads to treatment decision changes and avoids nontherapeutic laparotomies.

In a surgeon’s hands

However, the yield of staging laparoscopy depends on the thoroughness of the surgeon to evaluate as much as possible of the parietal and visceral peritoneal surfaces. Cytologic examination of peritoneal fluid obtained during staging laparoscopy can further increase the yield of staging laparoscopy but has limited sensitivity for detection of PM.⁵

Furthermore, intraperitoneal recurrence has been observed even in patients with negative cytology.⁶ Immunocytochemistry and molecular analysis of peritoneal lavage fluid improve prediction of PM with a sensitivity of 77 percent and specificity of 89 percent and should be considered in peritoneal staging, if available.^7,8 Despite the utility of staging laparoscopy, it is unfortunately underused in the U.S. According to one study of the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) Linked Database, only 8 percent of patients older than age 65 with gastric cancer underwent a diagnostic laparoscopy.⁹

After curative-intent surgical resection, the peritoneum remains the most common site of failure, as up to one-third of patients relapse in the peritoneum. Unfortunately, PM is associated with five-year survival rates of approximately 2 to 5 percent.^2,3 In addition to affecting survival, PM leads to poorer quality of life because of abdominal pain, bloating, ascites, and malignant bowel obstruction. Therefore, surgeons and patients are interested in preventing this process.

Oncologists are looking to immunotherapy through, for instance, the recent CheckMate-649 (Efficacy Study of Nivolumab Plus Ipilimumab or Nivolumab Plus Chemotherapy Against Chemotherapy in Stomach Cancer or Stomach/Esophagus Junction Cancer) and ATTRACTION-4 (Randomized, multicenter, phase 2/3 study of nivolumab plus chemotherapy in patients with previously untreated advanced or recurrent gastric or gastroesophageal junction cancer) trials, which demonstrated improvement in progression-free and overall survival in patients with the addition of a checkpoint inhibitor to standard systemic chemotherapy. Other answers may lie in targeted therapy, such as trastuzumab for HER2 (human epidermal growth factor receptor 2)-positive patients, investigated in the completed ToGA (Trastuzumab for Gastric Cancer) trial and ongoing INNOVATION trial (Effect of chemotherapy alone versus chemotherapy plus trastuzumab versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate).

However, the role of loco-regional therapy for the prevention of peritoneal disease recurrence using intraperitoneal chemotherapy has not yet been well established. It has been demonstrated that intraperitoneal administration of chemotherapy results in higher intraperitoneal concentration of the cytotoxic medications and minimal systemic exposure compared with intravenous administration. In turn, intraperitoneal chemotherapy may increase the efficacy of the chemotherapeutic agents while also allowing for substantial reduction in systemic toxicity. To date, prophylactic or adjuvant use of HIPEC in patients with gastric cancer has been evaluated to try to reduce the risk of PM. The hypotheses regarding how HIPEC may prevent development of PM include the eradication of microscopic tumor cells that were previously present (false negative peritoneal cytology) or released from severed lymphatics, manipulation of the primary tumor, or intraoperative blood loss during curative intent surgical resection. Determining which patients would benefit from prophylactic HIPEC involves identification of patients at highest risk of PM through clinical tools such as the gastric cancer peritoneal carcinomatosis score, a nomogram that accounts for high-risk clinical factors including age, race/ethnicity, T category, histology, tumor grade, and location.¹⁰

Prophylactic HIPEC for the prevention of PM from gastric cancer is an evolving approach. In 1988, Koga and colleagues demonstrated a statistically significant improvement in survival with the addition of HIPEC to gastrectomy in both a historical cohort and a randomized cohort of patients. They found no difference in postoperative complications, including anastomotic leak.¹¹ Kaibara and colleagues then reported five-year overall survival of 71.5 percent for patients treated with gastrectomy and HIPEC versus 59.7 percent for gastrectomy alone, although this difference fell short of statistical significance.¹² In 1994, Hamazoe and colleagues reported five-year survival for patients treated with gastrectomy and HIPEC (64.2 percent) versus gastrectomy (52.5 percent)—again, not statistically significant.¹³

Subsequent studies, however, have shown statistically significant improved survival with the addition of HIPEC to gastrectomy.^14,15 More recently, two randomized controlled trials demonstrated improved survival when HIPEC is added to gastrectomy.^16,17 Furthermore, two meta-analysis and systematic reviews show improved outcomes with adjuvant HIPEC, but caution that the data are heterogeneous and at risk of bias because most studies are outdated, included exclusively Asian populations, and did not include modern systemic chemotherapy.^18,19 Therefore, the appropriateness of generalizing use of HIPEC in gastric adenocarcinoma to Western populations treated with perioperative systemic chemotherapy remains unclear.

Ongoing trials

Several prospective trials seeking to better elucidate the role of HIPEC as a prophylactic treatment are under way as summarized in Table 1. For reference, prospective clinical trials evaluating the role of HIPEC in combination with cytoreductive surgery in patients with peritoneal disease are included in Table 1 as well. The ongoing GASTRICHIP (D2 Resection and HIPEC [Hyperthermic Intraperitoneal Chemoperfusion] in Locally Advanced Gastric Carcinoma) (NCT01882933) is a randomized trial comparing gastrectomy and HIPEC with oxaliplatin versus gastrectomy alone for advanced gastric cancer (T3, T4 and/or N+ and/or with positive peritoneal cytology). Estimated completion of this study is 2025.²⁰

Other ongoing studies include a Chinese phase III trial (HIPEC01) (NCT02356276) that randomizes locally advanced (T3 or T4) patients to gastrectomy and adjuvant systemic chemotherapy +/- two HIPEC treatments with paclitaxel. A German single-arm phase II trial (ProPeC) (NCT04180761) is now enrolling locally advanced gastric cancer (>cT3 and/or cN+ and cM0) patients for adjuvant HIPEC with cisplatin and doxorubicin. In addition, a phase II, single-arm study of patients with locally advanced gastric cancer (T3, T4 and/or N+ and M0) treated with perioperative systemic chemotherapy and/or chemoradiation with neoadjuvant HIPEC at the time of staging laparoscopy (before gastrectomy) is enrolling in the U.S. (NCT04308837).

Lastly, a newly opened phase III multicenter study in Italy (GOETH) randomizes advanced gastric cancer (T3, T4 and/or N+ and/or with positive peritoneal cytology) patients to prophylactic HIPEC with mitomycin C and cisplatin before standard resection versus standard resection alone (NCT03917173).

A still unmet need

In conclusion, gastric cancer patients have an unmet need for improved therapeutic options to prevent peritoneal relapse after gastrectomy. Prophylactic intraperitoneal chemotherapy at the time of resection may have the potential to prevent peritoneal recurrence and is under worldwide investigation. The benefits of HIPEC will need to be weighed against the potential increase in postoperative complications to maximize efficacy and to minimize morbidity and mortality as much as possible.

It is important to note that prophylactic HIPEC in the treatment of gastric cancer remains investigational as we await results from the ongoing studies. Until more data become available, surgeons should consider referring patients to centers that are enrolling patients in clinical trials or with expertise in the multimodal management of gastric cancer.

References

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