Colorectal Cancer Clinical Trial
Official title:
Assessment of Histopathological Response to Combination Chemotherapy With Oxaliplatin, Irinotecan, Fluorouracil and Bevacizumab in Patients With 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
;
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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