William F. Morano

Intraperitoneal immunotherapy: historical perspectives and modern therapy

Intraperitoneal immunotherapy represents a novel strategy for the management of peritoneal metastases (PM). Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has remained the gold standard of treatment for patients with PM, yet despite optimal treatment, recurrence rates remain high and long-term survival poor. From Coley’s toxins to immune checkpoint inhibitors, the wide variety of anticancer immunotherapeutic strategies are now garnering attention for control of regional disease of the peritoneal cavity. Early studies with vaccine-based therapies, adoptive cell transfer, immune checkpoint inhibitors, and chimeric T cells with tumor-specific antigen receptors (CAR-T cells) are being performed, showing promise for control of peritoneal spread and induction of lasting anticancer immunity. In addition, catumaxomab, a trifunctional antibody, has been approved for intraperitoneal immunotherapy in Europe for the control of malignant ascites in patients with epithelial cell adhesion molecule positive cancers. We review a brief history of immunotherapy and current modalities under investigation for intraperitoneal use in the treatment of PM.

Complete Response after Treatment with Neoadjuvant Chemoradiation with Prolonged Chemotherapy for Locally Advanced, Unresectable Adenocarcinoma of the Pancreas

Surgery is the only chance for cure in pancreatic ductal adenocarcinoma. In unresectable, locally advanced pancreatic cancer (LAPC), the National Comprehensive Cancer Network (NCCN) suggests chemotherapy and consideration for radiation in cases of unresectable LAPC. Here we present a rare case of unresectable LAPC with a complete histopathological response after chemoradiation followed by surgical resection. A 54-year-old female presented to our clinic in December 2013 with complaints of abdominal pain and 30-pound weight loss. An MRI demonstrated a mass in the pancreatic body measuring 6.2 × 3.2 cm; biopsy revealed proven ductal adenocarcinoma. Due to splenic vein/artery and contiguous celiac artery encasement, she was deemed surgically unresectable. She was started on FOLFIRINOX therapy (three cycles), intensity modulated radiation to a dose of 54 Gy in 30 fractions concurrent with capecitabine, followed by FOLFIRI, and finally XELIRI. After 8 cycles of ongoing XELIRI completed in March 2015, restaging showed a remarkable decrease in tumor size, along with PET-CT revealing no FDG-avid uptake. She was reevaluated by surgery and taken for definitive resection. Histopathological evaluation demonstrated a complete R0 resection and no residual tumor. Based on this patient and literature review, this strategy demonstrates potential efficacy of neoadjuvant chemoradiation with prolonged chemotherapy, followed by surgery, which may improve outcomes in patients deemed previously unresectable.

Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis

Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM. IP delivery of CAR-T cells has shown demonstrable suppression of tumors expressing carcinoembryonic antigen. This response was enhanced when IP injected CAR-T cells were combined with anti-PD-L1 or anti-Gr1. Similarly, CAR-T cells against folate receptor α expressing tumors improved T-cell tumor localization and survival when combined with CD137 co-stimulatory signaling. Moreover, IP immunotherapy with catumaxomab, a trifunctional antibody approved in Europe, targets epithelial cell adhesion molecule (EpCAM) and has shown considerable promise with control of malignant ascites. Herein, we discuss immunologic approaches under investigation for treatment of PM.

Clinical Trials in CRS and HIPEC: Ongoing Trials and Future Directives

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have gained momentum as a viable treatment option for primary or recurrent malignancies with peritoneal metastasis (PM). Despite significant progress over the last 30 years, this field has lacked in high-quality randomized, controlled trials, with most data supporting the use of CRS and HIPEC coming from smaller retrospective and prospective trials. Ultimately, validation of treatment efficacy and outcomes will require large, collaborative, well-organized, outcomes-based studies. Thus far, the use of CRS and HIPEC in metastatic gastric, ovarian, pancreatic, and other gastrointestinal malignancies has spurred further development of a growing number of prospective clinical trials to study outcomes and survival benefit. This chapter summarizes some of the notable, completed clinical trials and current trials being conducted.

Clinical studies in CRS and HIPEC: Trials, tribulations, and future directions-A systematic review

The field of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has suffered from a lack of clinical trials to validate its expanding use.

Recurrent Gastrointestinal Stromal Tumors in the Imatinib Mesylate Era: Treatment Strategies for an Incurable Disease

Introduction Recurrence of gastrointestinal stromal tumors (GISTs) after surgical resection and imatinib mesylate (IM) adjuvant therapy poses a significant treatment challenge. We present the case of a patient who underwent surgical resection after recurrence and review the current literature regarding treatment. Case Presentation A 58-year-old man with a large intra-abdominal jejunal GIST was treated with complete surgical resection followed by IM. The patient experienced disease recurrence 3.5 years later and underwent IM dose escalation and reresection. Conclusion Current strategies to treat recurrent GIST include dose escalation, modifying adjuvant tyrosine kinase inhibitor therapy, and surgery. High-level evidence will be required to better define the combinatory roles of tyrosine kinase inhibitor therapy, guided by molecular profiling, and surgery in the management of recurrent GIST.

Incidentally discovered low-grade appendiceal mucinous neoplasm: a precursor to pseudomyxoma peritonei

Appendiceal mucoceles (AMs) infrequently arise from an underlying malignancy. Treatment has progressed toward a less aggressive approach over time; they can be managed by appendectomy‐only unless pathology reveals malignancy. The ultimate goal of management is to prevent AM rupture, avoiding the syndrome of pseudomyxoma peritonei.