In vivo REsponse evaluation of colorectal liver metastases during systemic therapy using optical SPECTroscopy techniques: a pilot study

Clinical problem:
Colorectal cancer is a major health problem with more than 12.000 newly
diagnosed patients yearly in the Netherlands (Netherlands Cancer Registry -
www.ikc.nl). Approximately 20% of patients will present with liver metastases
at initial diagnosis and eventually 50-60% of patients develop liver metastases
during the course of the disease.
Only 20% of patients with synchronous or metachronous colorectal liver
metastases are suitable for liver resection2. At best, these patients have a
five-year survival of approximately 30-40%. The remaining patients undergo
systemic therapy aimed at stabilizing or reducing metastatic disease. For
systemic treatment with or without addition of targeted drugs the overall
response rate is between 20 and 50%, the median survival is 12-20 months and
five-year survival is 2-5%. When disease progression is observed during first
line systemic therapy, a change to an alternative second line regimen is
recommended. The response rate to second line systemic therapy is approximately
4-28%.
The actual response to systemic therapy is generally evaluated after 2-3 months
by computed tomography (CT) imaging using standardized RECIST (response
evaluation criteria in solid tumors) criteria. However, the response in
patients receiving new targeted drugs such as bevacizumab that lack direct
intrinsic cytotoxic activity, challenges the concept of tumour size alone (and
thus RECIST-criteria) as a good indicator for response. Tumour shrinkage alone
is not strongly correlated to response to bevacizumab-containing regimens and
combination of tumour size and density might be a better predictor. Other
modalities to assess the response to systemic therapy are under investigation.
Experimental studies show that FDG-PET/CT could be of use for early outcome
prediction in patients undergoing systemic therapy for metastatic colorectal
cancer, although results are conficting. Contrast enhanced ultrasonography
might also serve as a surrogate marker to predict treatment response in
patients with metastasized colorectal cancer receiving bevacizumab.
In summary, response monitoring of patients undergoing systemic therapy for
colorectal liver metastases, especially in the era of new targeted drugs, is
troublesome and the development of novel monitoring tools are needed.

The aim of the present pilot study is to assess whether percutaneous optical
spectroscopy can serve as a novel tool for tumour response evaluation in
patients with unresectable colorectal liver metastases receiving first line
systemic therapy.

The study is designed as an observational pilot study.

Patients eligible for inclusion into this study are patients admitted to The
Netherlands Cancer Institute (NKI-AvL) for first line systemic therapy for
unresectable colorectal liver metastases.

In this pilot we investigate whether optical spectroscopy can be used to detect
systemic therapy response after treatment. For that purpose optical
spectroscopy results will be compared with standard pre- and post-systemic
therapy CT imaging and with histopathological analysis of the tissue samples
taken during the spectroscopic measurements.

Procedures
CT imaging is the gold standard procedure for response evaluation in patients
with colorectal liver metastases undergoing systemic therapy. Prior to
treatment, CT-imaging is performed to determine the size and shape of the liver
lesions. After about three months a next CT-scan is performed to determine
treatment response. In this pilot study optical measurements in combination
with a tissue biopsy will be performed at the same interval as the CT-scans,
thus prior to systemic treatment and after three months. The anticipated total
time for the whole procedure will be about 10 minutes (twice).

Based on the extent of the planned intervention (optical spectroscopy and
biopsy) as well as experiences with the optical spectroscopy system in vivo and
ex vivo, the risk of SAE*s is comparable to that of a regular liver biopsy.
Bleeding is generally considered the major complication after percutaneous
liver biopsy. In literature, an overall bleeding rate between is described
between 0.06 and 1.7%. The results of a multivariate analysis by Terjung et al.
imply that the bleeding risk after a percutaneous liver biopsy can be
effectively reduced by careful patient selection and by avoiding potentially
hazardous co-therapy. Therefore, patients with a higher bleeding risk are
excluded for this study.
In the future, patients could benefit from a better response monitoring system,
laeding to an optimalized and if needed adapted systemic therapeutic regimen.