Histopathological Response to FOLFOXIRI + Bevacizumab in Peritoneal Metastasis From Colorectal Cancer
Histopathological Response to FOLFOXIRI + Bevacizumab in Peritoneal Metastasis From Colorectal Cancer
There is a paucity of data on the histopathological response of peritoneal tumor deposits
 from colorectal cancer to neoadjuvant chemotherapy. Particularly, no prospective assessment
 of chemotherapy-associated histopathological response within the peritoneum has been
 performed so far. Therefore, there is an urgent need to conduct a clinical trial aimed at
 prospectively assessing the histopathological response within the peritoneum in patients with
 peritoneal metastasis from colorectal cancer.

 Recently, Loupakis et al. reported that the triplet regimen of 5-fluorouracil, oxaliplatin
 and irinotecan (FOLFOXIRI) in combination with bevacizumab significantly improved median
 progression-free survival in metastatic colorectal cancer patients from 9.7 to 12.1 months as
 compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab. In view of
 these data, it is likely that FOLFOXIRI + bevacizumab will also lead to a significant
 improvement of the histopathological response within the peritoneum of patients with
 peritoneal metastasis from colorectal cancer (pcCRC) as compared with previous standard
 chemotherapy.

 The investigators hypothesize that FOLFOXIRI + bevacizumab will induce a pCR or major
 response in peritoneal tumor deposits in >30% of patients (taking the response rate to
 FOLFOX- or FOLFIRI-based neoadjuvant chemotherapy from the published literature as a
 reference).
Peritoneal carcinomatosis from colorectal cancer (pcCRC) has a dismal prognosis. In the era
 of 5-fluorouracil treatment and palliative surgery only, median survival ranged from 5.2 to
 7.0 months. In patients with bowel obstruction due to peritoneal carcinomatosis outcome was
 even worse, with a median overall survival of less than 4 months and a 1-year survival rate
 of 17%. With the advent of modern chemotherapy regimens, survival has improved considerably.
 However, the presence of pcCRC is still associated with a significantly worse prognosis as
 compared with other manifestations of metastatic CRC (e.g. liver and/or lung metastasis). A
 recent retrospective analysis of 2095 patients from 2 prospective randomized trials showed
 that both median PFS and OS were significantly shorter for patients with pcCRC as compared
 with patients without pcCRC (PFS: 5.8 vs. 7.2 months, HR=1.2; 95% CI 1.1 to 1.3, p=0.001; OS:
 12.7 vs. 17.6 months, HR=1.3; 95% CI 1.2 to 1.5, p<0.001).

 The combination of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy
 (HIPEC) has led to a remarkable improvement of survival in selected patients with pcCRC as
 illustrated by a prospective randomized trial and several retrospective series. The concept
 of CRS + HIPEC has therefore recently been incorporated into national treatment guidelines
 and is being increasingly performed in pcCRC patients with promising long-term results. The
 subgroup who benefits most of this multimodal therapeutic approach are patients with limited
 pcCRC where a complete removal of all cancer deposits within the peritoneum can be achieved.

 There is increasing evidence that the addition of neoadjuvant systemic chemotherapy to CRS +
 HIPEC may further improve the outcome of patients with pcCRC. Neoadjuvant chemotherapy, i.e.,
 chemotherapy that is given upfront before CRS + HIPEC is performed, offers several possible
 advantages for patients: First, it can help to identify nonresponders to treatment who may be
 unsuitable candidates for CRS. Second, neoadjuvant chemotherapy may limit extraabdominal
 systemic spread of the disease. Third, upfront chemotherapy may help to reduce the extent of
 peritoneal metastasis, thus facilitating CRS and increasing the likelihood of a complete
 surgical cytoreduction.

 Importantly, it has recently been shown that the efficacy of neoadjuvant chemotherapy can be
 easily quantified by assessing the chemotherapy-induced histopathological response within the
 peritoneum and that the histopathological response is an independent predictor of survival.
 In a retrospective analysis of 115 pcCRC patients who underwent neoadjuvant chemotherapy
 followed by CRS, patients were grouped into three distinct categories depending on the
 histopathological response to neoadjuvant chemotherapy:

 1. patients with complete pathologic response (pCR; no remaining viable tumor cells in
 peritoneal tumor nodules),

 2. patients with major response (1-49% remaining viable tumor cells) or

 3. patients with minor/no response (≥50% remaining viable tumor cells).

 The study was able to show that the cumulative 5-year survival rate was 75% for patients with
 a pCR (HR=1) as compared with 57% for patients with a major response (HR=4.91) and only 13%
 for patients with a minor or no response (HR=13.46) (p=0.01). Overall, approximately 30% of
 patients were considered to be responders to neoadjuvant chemotherapy (9.7% pCR + 20.2% major
 response), while about 70% of patients were considered non-responders to treatment. Treatment
 consisted of a FOLFOX- or FOLFIRI-based regimen in the majority of patients.

 The primary objective of the study is to prospectively assess the histopathological response
 to neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab in peritoneal tumor deposits of 30
 patients with pcCRC by determining the percentage of viable tumor cells in the resected
 specimen after neoadjuvant chemotherapy. For patients with multiple peritoneal specimens, the
 median percentage of viable cells in all specimens will be used. Patients with 0-49% of
 viable cells will be considered as responders. The timepoint of the assessment of the primary
 objective will be during re-exploratory surgery/surgical cytoreduction between days 78 and
 106 of the treatment phase of the study. The investigators hypothesize that there will be
 >30% responders after neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab.

 Responders will be defined as patients with pCR (0% viable tumor cells) and major response
 (1-49% viable tumor cells) after FOLFOXIRI + bevacizumab chemotherapy.

 Non-responders will be defined as patients with minor/no response (≥50% viable tumor cells)
 after FOLFOXIRI + bevacizumab chemotherapy.

 The following patients will also be counted as non-responders:

 -  Patients who do not undergo surgical re-exploration

 -  Patients who develop extraabdominal metastases

 -  Deaths before surgical re-exploration
Inclusion Criteria:

 1. Histologically confirmed carcinoma of the colon or rectum with synchronous or
 metachronous peritoneal metastasis.

 2. Male and female patients, aged ≥ 18 years.

 3. Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

 4. Life expectancy ≥ 26 weeks.

 5. Neutrophils (absolute count) ≥ 1.5 g/l.

 6. Platelet count ≥ 100 g/l.

 7. Hemoglobin > 9 g/dL.

 8. Total bilirubin ≤ 1.8 mg/dl.

 9. Aspartate aminotransferase (AST) and Alanine transaminase (ALT) ≤ 88 U/l (≤ 175 U/l if
 liver metastases are present).

 10. Alkaline phosphatase ≤ 325 U/l (≤ 650 U/l if liver metastases are present).

 11. Calculated creatinine clearance > 50 mL/min OR serum creatinine ≤ 1.5 mg/dl.

 12. Proteinuria < 2+ by dipstick or urine protein <1 g by 24-hr urine collection.

 13. Not pregnant or nursing.

 14. Negative pregnancy test (for females of childbearing potential).

 15. Patients of childbearing / reproductive potential should use adequate birth control
 measures, as defined by the investigator, during the study treatment period and for at
 least 6 months after the last study treatment.

 16. Written informed consent.

 17. General condition considered feasible for major abdominal surgery after systemic
 chemotherapy.

 18. ≤3 liver metastases amenable to curative resection using a minor liver resection.

 Exclusion Criteria:

 1. Major surgical procedure or significant traumatic injury within 28 days prior to study
 enrolment (surgical exploration with diagnostic biopsy/sampling of peritoneal tumor
 deposits but without bowel resection or comparable surgical procedure is allowed).

 2. History of previous cytoreductive surgery in combination with hyperthermic
 intraperitoneal chemotherapy.

 3. Pregnancy or lactation.

 4. Inability or unwillingness to comply with the protocol.

 5. Evidence of current extraabdominal metastatic disease. Prior extraabdominal metastatic
 disease is allowed, provided that it has been curatively resected ≥6 months before
 study entry and that current staging shows no evidence of disease recurrence.

 6. >3 liver metastases or any liver metastases not amenable to upfront curative resection
 using a minor liver resection.

 7. Prior systemic chemotherapy completed ≤3 months before study inclusion.

 8. Treatment with any other investigational agent, or participation in another clinical
 trial within 30 days prior to entering this study.

 9. History or evidence upon physical/neurological examination of central nervous system
 (CNS) disease (unrelated to cancer) unless adequately treated with standard medical
 therapy (e.g. uncontrolled seizures).

 10. Untreated brain metastases, spinal cord compression or primary brain tumors.

 11. Past or current history (within the last 2 years prior to treatment start) of other
 malignancies except colorectal cancer (patients with curatively treated basal and
 squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).

 12. Clinically significant cardiovascular disease, for example cerebrovascular accident
 (CVA), myocardial infarction (≤12 months before treatment start), unstable angina, New
 York Heart Association (NYHA) > Class II congestive heart failure (CHF), arrhythmia
 requiring medication, or uncontrolled hypertension.

 13. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent
 arterial thrombosis) within 6 months of study enrolment.

 14. Any previous venous thromboembolism > NCI Common Toxicity Criteria for Adverse Effects
 (CTCAE) Grade 3.

 15. Prior history of hypertensive crisis or hypertensive encephalopathy.

 16. Evidence of bleeding diathesis or significant coagulopathy.

 17. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or
 active gastrointestinal bleeding within 6 months prior to the first study treatment.

 18. Known hypersensitivity to any of the study drugs.

 19. Serious, non-healing wound, ulcer or bone fracture.

 20. Evidence of any other disease, metabolic dysfunction, physical examination finding or
 laboratory finding giving reasonable suspicion of a disease or condition that puts the
 patient at high risk for treatment-related complications.

 21. Symptomatic peripheral neuropathy ≥ grade 1 according to the NCI Common Toxicity
 Criteria.