Barriers to Referral for Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Identified Using a Tailoring Grid Methodology: Interviews with Stakeholders in New York State.

INTRODUCTION: Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) has variable uptake, with referrals reliant on other physicians. To characterize barriers to referral for CS/HIPEC, we created a pragmatic "tailoring grid", incorporating the concepts of Pathman's 4 As of awareness, agreement, adoption, and adherence and barriers acting at the individual, practice group, and organization level. METHODS AND MATERIALS: We invited surgeons and medical oncologists from Western New York State who potentially refer patients for CS/HIPEC to participate in tailoring grid interviews. RESULTS: Interviews of 10 surgeons and 10 medical oncologists were completed. The participants were positioned in the Pathman 4 A's with respect to referrals for CS/HIPEC as follows: (1) A 19 aware (1 not aware); (2) A 3 in agreement (17 not in agreement); (3) A 9 adopters; and (4) A 6 adherent. Among the 9 participants who had referred at least one patient for CS/HIPEC (adopters/adherent), only 2 were in agreement with the appropriateness of CS/HIPEC. Barriers to awareness of included lack of interaction with colleagues and knowledge of indications. Barriers to agreement included lack of high quality of evidence supporting CS/HIPEC such as well-designed RCTs. Barriers to adoption included lack of communication with CS/HIPEC surgeons; lack of inclusion of the procedure into algorithms and defined morbidity/mortality rates. Barriers to adherence included lack of inclusion into guidelines by major societies; perceptions that the procedure is resource-intensive; lack of defined quality measures. CONCLUSIONS: The tailoring grid efficiently identified barriers to awareness, agreement, adoption and adherence for routine referral for CS/HIPEC. Barriers to increased referrals included lack of high-quality evidence supporting CS/HIPEC. Barriers more easily addressed included communication between referring and CS/HIPEC surgeons, and outcomes at the individual patient and hospital level.

Outcomes After Adjuvant Hyperthermic Intraperitoneal Chemotherapy for High-Risk Primary Appendiceal Neoplasms After Complete Resection.

INTRODUCTION: Appendiceal neoplasms are uncommon tumors. Optimal treatment for patients with perforation or high-grade pathology after initial resection is unknown. This study evaluated patients with increased risk for peritoneal dissemination after primary resection, but no evidence of peritoneal disease, who underwent adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: This multi-institutional cohort study evaluated 56 patients with high-risk (HR) appendiceal neoplasms with a peritoneal carcinomatosis index of 0 who underwent HIPEC. The patients were divided into two groups: perforated low-grade appendiceal (LGA) carcinoma and HR neoplasms, which included perforated high-grade appendiceal carcinoma, positive margins after initial resection, minimal macroscopic peritoneal disease that was previously resected or completely responded to systemic chemotherapy prior to HIPEC, goblet cell carcinoma, and adenocarcinoma with signet ring cell features. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan-Meier analysis. RESULTS: Thirty-eight percent of patients had perforated LGA and 68% had HR features. Five-year OS probability was 82.1% for the entire cohort, and 100% and 70.1% for patients with perforated LGA and HR features, respectively (p = 0.024). Five-year RFS probability was 79.3% for the entire cohort, and 90.0% and 72.4% for patients with perforated LGA and HR features, respectively (p = 0.025). Eight patients recurred after HIPEC and their OS was significantly worse (p < 0.001). CONCLUSION: While adjuvant HIPEC is both safe and feasible, there appears to be little benefit over close surveillance when outcomes are compared with historical and prospective studies, especially for perforated LGA carcinoma.

Current Delivery of Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery (CS/HIPEC) and Perioperative Practices: An International Survey of High-Volume Surgeons.

BACKGROUND: Cytoreductive surgery and heated intraperitoneal chemotherapy (CS/HIPEC) is performed for selected indications at a limited number of specialized centers worldwide. Currently there is no standardized approach to the perioperative care process. We sought to capture current practices in the perioperative management of patients who undergo CS/HIPEC at high-volume centers. METHODS: Surgeon members of the American Society of Peritoneal Surface Malignancies working at high-volume CS/HIPEC centers (>10 cases/year) were invited to complete an online survey. The survey included questions relating to preoperative preparation of patients, intraoperative practices, and postoperative care. RESULTS: Ninety-seven surgeons from five continents completed the survey (response rate 55%). The majority (80%) practiced in academic environments. Most respondents (68%) indicated that a formal preoperative preparatory pathway for CS/HIPEC surgery existed at their centers, but few (26%) had used enhanced recovery protocols in this group of patients. Whereas the intraoperative technical practices of the CS/HIPEC procedure were relatively consistent across respondents, there was little agreement on pre- and postoperative care practices, including use of mechanical bowel preparation, nutritional supplementation, methods of perioperative analgesia, timing of physical therapy and ambulation, nasogastric tube and Foley removal, intravenous fluids, blood transfusion parameters, and postoperative use of deep-vein thrombosis prophylaxis and antibiotics. CONCLUSIONS: Perioperative care practices for CS/HIPEC are widely variable nationally and internationally. Standardization of such practices offers an opportunity to incorporate evidence-based interventions and may enhance patient outcomes and improve care standards across all centers that offer this procedure.

A contemporary analysis of morbidity and outcomes in cytoreduction/hyperthermic intraperitoneal chemoperfusion.

The risks and benefits of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CS/HIPEC) continue to be debated by the oncology community. A retrospective analysis of contemporary data (2003-2011) was performed to provide objective information regarding surgical morbidity, mortality, and survival for patients undergoing CS/HIPEC at a comprehensive cancer center. While procedure-associated morbidity was comparable to other major surgical oncology procedures, there was no operative or 30-day mortality and 60-day mortality was 2.7%. Increasing numbers of bowel resections were found to correlate to an increased incidence of deep surgical site infections (including abscess and enterocutaneous fistula) and need for reoperation which was in turn associated with a decreased overall survival (OS) and progression-free survival (PFS). Five-year OS rates varied by site of tumor origin and histology (disseminated peritoneal adenomucinosis [91.3%], Mesothelioma [80.8%], Appendiceal Adenocarcinoma [38.7%], and Colorectal Adenocarcinoma [38.2%]). With an acceptable morbidity and mortality rate, CS/HIPEC should be included as an effective treatment modality in the multidisciplinary care of select patients with peritoneal metastases.

The benefit of intraperitoneal chemotherapy for the treatment of colorectal carcinomatosis.

The clinical practice of hyperthermic intraperitoneal chemoperfusion (HIPEC) for carcinomatosis has lacked preclinical justification. A standardized mouse model was created to evaluate the independent effects of intraperitoneal chemotherapy. Diffuse colorectal carcinomatosis was generated in mice prior to intraperitoneal lavage with mitomycin C (MMC) at clinically comparable dosing for variable lengths of time. Tumor volumes, MMC tissue concentrations and survival were measured in comparison to saline lavage and intravenous MMC. Magnetic resonance imaging revealed a direct correlation between tumor volume, MMC dose and exposure time and survival. Intravenous MMC demonstrated a rapid clearance from the blood, lower peritoneal tissue concentrations, less tumor growth inhibition and decreased survival compared to intraperitoneal administration. Intraperitoneal chemotherapy inhibited tumor growth independent of cytoreduction or hyperthermia, demonstrated improved peritoneal tissue concentration and was associated with increased survival. These data support the clinical utility of the intraperitoneal chemotherapy component of HIPEC.

IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells.

Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8+ T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5°C ± 0.5°C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8+ effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor-α fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6-dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6-rich tumor microenvironment can be exploited to create a therapeutic window to boost T cell-mediated antitumor immunity and immunotherapy.

Hyperthermia as an immunotherapy strategy for cancer.

The use of hyperthermia as an adjunct to cancer immunotherapy is supported by an increasing number of research data. Both preclinical and clinical data results have demonstrated improved antitumor immune responses with the addition of mild hyperthermia. The molecular mechanisms responsible for the improved immune reactivity observed in the presence of hyperthermia include the generation of Hsps, the activation of antigen-presenting cells and changes in lymphocyte trafficking. Understanding these hyperthermia-induced processes can serve as the foundation for analyzing current clinical trials, as well as designing future trials in cancer immunotherapy.

Targeted regulation of a lymphocyte-endothelial-interleukin-6 axis by thermal stress.

Immune protection from microbial invaders or malignant progression is dependent on the ability of lymphocytes to efficiently traffic across morphologically and biochemically distinct vascular sites throughout the body. Lymphocyte trafficking to target tissues is orchestrated by adhesion molecules and chemokines that stabilize dynamic interactions between circulating lymphocytes and endothelial cells lining blood vessels. While the molecular mechanisms that regulate the efficient migration of lymphocytes across specialized high endothelial venules (HEVs) in secondary lymphoid organs have been extensively characterized, there is a paucity of information available regarding the mechanisms that dictate the rate of lymphocyte entry into tumor tissues. This article summarizes recent evidence that inflammatory cues associated with fever-range thermal stress promote lymphocyte extravasation across HEVs of lymphoid organs through a highly regulated lymphocyte-endothelial-interleukin-6 (IL-6) biological axis. The potential for using thermally-based strategies to improve lymphocyte delivery to the tumor microenvironment during T cell-based immunotherapy will also be discussed.

Primary immune surveillance: some like it hot.

The thermal element of fever has been found to be beneficial in models of infectious disease. The contributions of fever-range temperatures to the efficacy of the adaptive immune response have only begun to be delineated. There is accumulating evidence that fever-range thermal stress bolsters primary immune surveillance of lymph nodes and Peyer patches by augmenting lymphocyte extravasation across specialized vessels termed high endothelial venules. Molecular mechanisms have recently come to light by which the thermal component of fever alone may promote lymphocyte trafficking, and thereby the probability of mounting a defense against microbial infection. Acquired knowledge of the molecular changes associated with thermal stress may allow for the development of novel therapies for a variety of disease processes.