Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Bevacizumab

Irinotecan

Leucovorin

Fluorouracil

Oxaliplatin

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Patients will first undergo upfront staging laparoscopy with retrieval of tumor tissue for standard pathology.

Two to 4 weeks after initial surgical exploration, patients will receive 4 cycles of FOLFOXIRI + bevacizumab, q2w. The last chemotherapy cycle will be given without bevacizumab.

Five to 7 weeks after the last administration of bevacizumab (i.e., 3 to 5 weeks after completion of chemotherapy), patients will undergo surgery with the intent to perform complete surgical cytoreduction of all peritoneal tumor deposits. Further chemotherapy according to the currently available treatment guidelines, including intraperitoneal hyperthermic chemotherapy in patients where complete surgical cytoreduction has been achieved, will be given at the discretion of the investigator.

Upfront staging laparoscopy with biopsy of peritoneal tumor deposits, assessment of peritoneal cancer index and resectability.

Upfront staging laparoscopy + peritoneal biopsy

Patients will receive 4 cycles of FOLFOXIRI + bevacizumab; the last cycle will be given w/o bevacizumab

Dosage: Bevacizumab: 5 mg/kg via 30 min. IV infusion, day 1; Oxaliplatin: 85 mg/m2 via 2-hour IV infusion, day 1; Irinotecan: 165 mg/m2 via 1-hour IV infusion, day 1; Leucovorin: 200 mg/m2 via 2-hour IV infusion, day 1; 5-Fluorouracil: 3200 mg/m2 via 48-hour IV infusion, day 1;

Neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab

Three to 5 weeks after completion of FOLFOXIRI + bevacizumab chemotherapy, patients will undergo surgical re-exploration with the intent to perform a complete surgical cytoreduction. Further chemotherapy according to the currently available treatment guidelines, including intraperitoneal hyperthermic chemotherapy in patients where complete surgical cytoreduction has been achieved, may be given at the discretion of the investigator. Systemic chemotherapy may be started beginning 4 weeks post-surgery and after complete wound healing.

Surgical re-exploration

Thomas Bachleitner-Hofmann, MD

Gerald Prager, MD

Anja Grah

Daniela Truzla

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

Histopathological Response to FOLFOXIRI + Bevacizumab in Peritoneal Metastasis From Colorectal Cancer

Assessment of Histopathological Response to Combination Chemotherapy With Oxaliplatin, Irinotecan, Fluorouracil and Bevacizumab in Patients With Peritoneal Metastasis From Colorectal Cancer

The percentage of viable cells within the resected specimen after completion of neoadjuvant chemotherapy will be determined. For patients with multiple peritoneal specimens, the median percentage of viable cells in all specimens will be calculated. Patients with 0-49 % of viable cells will be considered as responders.

In case of multiple specimens, the change in the median percentages of viable cells in peritoneal tumor deposits between baseline and after completion of neoadjuvant chemotherapy will be compared.

Medical University of Vienna

ao.Univ.-Prof.Dr.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Histopathological Response to FOLFOXIRI + Bevacizumab in Peritoneal Metastasis From Colorectal Cancer	NCT02591667	Colorectal Canc... Peritoneal Meta...	Upfront staging... Neoadjuvant che... Surgical re-exp...	18 Years -	Medical University of Vienna
Histopathological Response to FOLFOXIRI + Bevacizumab in Peritoneal Metastasis From Colorectal Cancer	NCT02591667	Colorectal Canc... Peritoneal Meta...	Upfront staging... Neoadjuvant che... Surgical re-exp...	18 Years -	Medical University of Vienna

Spots Global Cancer Trial Database for upfront staging laparoscopy + peritoneal biopsy