Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging.

BACKGROUND: In colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) is associated with therapy resistance and poor prognosis. Clinical diagnosis of CMS4 is hampered by locoregional and temporal variables influencing CMS classification. Diagnostic tools that comprehensively detect CMS4 are therefore urgently needed. METHODS: To identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. Heterogeneity of marker expression in relation to CMS4 status was assessed by analysing 3-5 tumour regions and 91.103 single-tumour cells (7 and 29 tumours, respectively). Candidate marker expression was validated in CMS4 peritoneal metastases (PM; n = 59). Molecular imaging was performed using the 68Ga-DOTA-FAPI-46 PET tracer. RESULTS: Fibroblast activation protein (FAP) mRNA identified CMS4 with very high sensitivity and specificity (AUROC > 0.91), and was associated with significantly shorter relapse-free survival (P = 0.0038). Heterogeneous expression of FAP among and within tumour lesions correlated with CMS4 heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were missed using conventional imaging. Extra-peritoneal metastases displayed extensive heterogeneity of tracer uptake. CONCLUSION: FAP expression identifies CMS4 CRC. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking.

Unusual site of pseudomyxoma peritonei recurrence after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a case report of intraluminal disease manifestation in the small bowel.

BACKGROUND: Pseudomyxoma peritonei (PMP) is an uncommon clinical condition characterized by the presence of mucinous ascites, mainly induced by perforated appendiceal mucinous neoplasms (AMN). The peritoneal surface of the small bowel is usually spared from disease manifestation due to peristaltic movements. Mucinous tumours can disseminate as PMP on the entire peritoneum, but are rarely intraluminal. For the first time in literature, we report a case of intraluminal PMP involving the ileum. CASE PRESENTATION: A 75-year-old male was treated for perforated AMN and disseminated PMP with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. During follow-up, the patient developed intraperitoneal recurrence together with intraluminal depositions in the ileum, both disease manifestations with identical KRAS and SMAD4 mutations. Hereafter, the patient was treated with palliative care. CONCLUSION: This case illustrates the variation in the biological and clinical behaviour of this rare disease. Clinicians should be aware of unusual tumour distribution patterns of PMP, including the presence of mucinous tumour within the small bowel.

First-line palliative systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: A single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy. METHODS: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached). CONCLUSIONS: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

Comparing patient reported abdominal pain between patients treated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) and primary colorectal cancer surgery.

Oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) is an emerging palliative treatment for patients with unresectable colorectal peritoneal metastases. Previously, our study group reported that patients experienced abdominal pain for several weeks after PIPAC-OX. However, it is unknown how this compares to abdominal pain after regular colorectal cancer surgery. To provide some perspective, this study compared the presence of abdominal pain after PIPAC-OX to the presence of abdominal pain after primary tumor surgery. Patient reported abdominal pain scores (EORTC QLQ-CR-29), from two prospective, Dutch cohorts were used in this study. Scores ranged from 0 to 100, a higher score represents more abdominal pain. Abdominal pain at baseline and at four weeks after treatment were compared between the two groups. Twenty patients who underwent PIPAC-OX and 322 patients who underwent primary tumor surgery were included in the analysis. At baseline, there were no differences in abdominal pain between both groups (mean 20 vs. 18, respectively; p = 0.688). Four weeks after treatment, abdominal pain was significantly worse in the PIPAC group (39 vs 15, respectively; p < 0.001; Cohen's d = 0.99). The differential effect over time for abdominal pain differed significantly between both groups (mean difference: 19 vs - 3, respectively; p = 0.004; Cohen's d = 0.88). PIPAC-OX resulted in significantly worse postoperative abdominal pain than primary tumor surgery. These results can be used for patient counseling and stress the need for adequate analgesia during and after PIPAC-OX. Further research is required to prevent or reduce abdominal pain after PIPAC-OX.Trial registration CRC-PIPAC: Clinicaltrails.gov NCT03246321 (01-10-2017).

First-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy (oxaliplatin) for isolated unresectable colorectal peritoneal metastases: protocol of a multicentre, single-arm, phase II study (CRC-PIPAC-II).

INTRODUCTION: Despite its increasing use, first-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX), hereinafter referred to as first-line bidirectional therapy, has never been prospectively investigated in patients with colorectal peritoneal metastases (CPM). As a first step to address this evidence gap, the present study aims to assess the safety, feasibility, antitumour activity, patient-reported outcomes, costs and systemic pharmacokinetics of first-line bidirectional therapy in patients with isolated unresectable CPM. METHODS AND ANALYSIS: In this single-arm, phase II study in two Dutch tertiary referral centres, 20 patients are enrolled. Key eligibility criteria are a good performance status, pathologically proven isolated unresectable CPM, no previous palliative systemic therapy for colorectal cancer, no (neo)adjuvant systemic therapy ≤6 months prior to enrolment and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC). Patients receive three cycles of bidirectional therapy. Each cycle consists of 6 weeks first-line palliative systemic therapy at the medical oncologists' decision (CAPOX-bevacizumab, FOLFOX-bevacizumab, FOLFIRI-bevacizumab or FOLFOXIRI-bevacizumab) followed by ePIPAC-OX (92 mg/m2) with an intraoperative bolus of intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Study treatment ends after the third ePIPAC-OX. The primary outcome is the number of patients with-and procedures leading to-grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0) up to 4 weeks after the last procedure. Key secondary outcomes include the number of bidirectional cycles in each patient, treatment-related characteristics, grade ≤2 adverse events, tumour response (histopathological, cytological, radiological, biochemical, macroscopic and ascites), patient-reported outcomes, systemic pharmacokinetics of oxaliplatin, costs, progression-free survival and overall survival. ETHICS AND DISSEMINATION: This study is approved by the Dutch competent authority, a medical ethics committee and the institutional review boards of both study centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals. TRIAL REGISTRATION NUMBER: NL8303.