University of Groningen
Molecular fluorescence imaging facilitating clinical decision making in the treatment of solid
cancers
Koller, Marjory
DOI:10.33612/diss.99700036
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Publication date: 2019
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Koller, M. (2019). Molecular fluorescence imaging facilitating clinical decision making in the treatment of solid cancers. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.99700036
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1
General introduction
and outline of the thesis
General introduction
and outline of the thesis
CHAPTER 1
GENERAL INTRODUCTION AND OUTLINE OF THE THESIS
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GENERAL INTRODUCTION
To date, in clinical oncology, a non-radioactive molecular imaging technique that facilitates real-time clinical decision making and individualized treatment of various solid cancers is lacking. Especially in two disciplines the aspect of ‘real-time imaging’ is key for clinical decision making; during surgery to discriminate tumor tissue from benign tissue, and during endoscopy for diagnosing, monitoring treatment response and selection of patients for the most optimal treatment strategy. Molecular fluorescence imaging allows real-time imaging of tumor tissue by enabling visualization of tumor-specific, upregulated proteins and biological processes involved in oncogenesis using targeted fluorescent tracers, and therefore seems to be the ideal imaging modality to be used during surgery and endoscopy.1-3
Surgery remains the cornerstone in the curative treatment of solid cancers. In oncological surgery, it is crucial to completely resect all tumor tissue without leaving any residual disease for reaching the optimal treatment outcome. Despite a strong increase in the availability of preoperative imaging modalities like computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and single photo emission computed tomography (SPECT), intraoperatively, surgeons are still mainly dependent on visual inspection and palpation alone for discriminating tumor tissue from benign tissue. Consequently, to date tumor positive surgical margin rates still range from 10% till 60% in different solid cancer types, resulting in a high risk for locoregional or distant recurrence and poor treatment outcome.4 Current existing
intraoperative techniques for margin assessment have not gained universal international adoption. Frozen section analysis and imaging techniques like specimen radiography are time consuming and lack diagnostic accuracy.5 Anatomical imaging modalities like
CT and MRI are adapted to be used in the operating theatre, however, these cannot be used in real-time, require a substantial investment in infrastructure with the presence of radiation (CT) or MRI-safe surgical and anesthesia instruments, all together with a limited tumor specificity. Consequently, there is an unmet need for real-time tumor specific imaging which fits the current clinical workflow within the operating theatre that can be used for different solid tumor types, such as breast cancer, head and neck cancer and colorectal cancer.
Besides using molecular fluorescence imaging during surgery, this technique can also be applied during endoscopy procedures using a fluorescence fiber that can be inserted through the working channel of a clinical endoscope. Molecular fluorescence endoscopy is a novel technique that might be used for improved diagnosis of small (pre)-cancerous lesions, like adenomatous polyps in the colon or dysplastic lesions in patients with a Barrett’s oesophagus.2,3 Furthermore, molecular fluorescence endoscopy might
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play a role in implementing theranostics in oncology, by visualization and quantification of the presence of targeted fluorescent tracers and drug concentrations in tissue. With the recent advancement in molecular targeted therapies to treat cancer, more dedicated techniques are needed to select patients benefiting from these targeted therapies, enabling an enrichment of the target population for treatment. Patients who are likely to benefit from a particular targeted therapy have to be selected carefully, and target expression needs to be demonstrated. To date, target expression is predominantly determined by ex vivo immunohistochemistry on tissue biopsies, which are prone to be biased by sampling error due to heterogeneity of tumors and metastases. Theranostics, which integrate diagnostics and therapeutics by fluorescent labeling of drugs can provide insight in pharmacokinetics, tumor uptake, and biodistribution of drugs that might be used for drug development purposes (earlier go/no-go decision-making for on- and off-target characteristics), clinical decision making and individualized management of disease.
To optimally implement the theranostic approach in oncology, relevant targets need to be identified and prioritized. An attractive method to find relevant targets is functional genomic messenger RNA (FGmRNA) profiling. This method is capable to predict overexpression of target antigens on the protein level, which are considered not to be relevant for the observed tumor phenotype and characteristics, by correcting a gene expression profile of an individual tumor for physiologic and experimental factors.6 Especially in pancreatic cancer in which the 5-year survival is only 20%, the need
to identify potential target antigens is apparent in order to assist clinicians and drug developers in deciding which theranostic targets should be taken for further evaluation in the near future.
The aim of this thesis is to address the clinical potential of molecular fluorescence imaging using the NIR fluorescent tracer bevacizumab-800CW to facilitate clinical decision making and individualized management of disease in several cancer types; during surgery in breast cancer and colorectal cancer patients, during endoscopy in rectal cancer patients, and furthermore, to identify relevant molecular targets for future molecular approaches in pancreatic cancer.
OUTLINE OF THE THESIS
During the last decade, the emerging field of molecular fluorescence imaging has led to an exponential development of tumor-specific fluorescent tracers and an increase in early-phase clinical trials without having consensus on a standard methodology for evaluating an optical tracer, as often observed in innovative developments in medicine. In Chapter 2, we describe a novel analytical framework for the clinical translation and
GENERAL INTRODUCTION AND OUTLINE OF THE THESIS
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evaluation of tumor-targeted fluorescent tracers for molecular fluorescence imagingthat can be used for a range of tumor types and with different optical tracers by combining multiple complementary state-of-the-art clinical optical imaging techniques. Furthermore, we investigate the clinical implementation of this analytical framework and the tumor-specific targeting of escalating doses of the near-infrared fluorescent tracer bevacizumab-800CW on a macroscopic and microscopic level in breast cancer patients. In patients with peritoneal carcinomatosis, optimum cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is essential for the curative treatment of the disease. Intraoperatively, the differentiation between benign and tumor lesions is often difficult, most likely leading to unnecessary resection of clinically suspicious but benign lesions, and leaving behind of small tumor lesions. In Chapter 3 we describe the feasibility of molecular fluorescence-guided surgery for the improved detection of lesions intraoperatively, to prevent overtreatment and undertreatment of patients in the future. In a small series of patients with peritoneal carcinomatosis of colorectal origin treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), we evaluate whether the NIR fluorescent tracer bevacizumab-800CW can be detected intraoperatively. Furthermore, we correlate fluorescence with histopathology by so-called back-table imaging of the fresh surgical specimen and perform semi-quantitative analyses of formalin-fixed paraffin embedded tissue of all peritoneal lesions detected.
Tumor-positive surgical margins are detected in 18% of patients with locally advanced rectal cancer that are curatively treated with neoadjuvant chemoradiotherapy followed by surgery. In Chapter 4 we investigated in a feasibility study whether molecular fluorescence imaging can aid in the evaluation of circumferential resection margins (CRM) perioperatively. Locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy were administered intravenously with 4.5 mg bevacizumab-800CW two to three days prior to surgery. During surgery peri-operative fluorescence imaging was performed, and additional fluorescence imaging took place during pathological analyses. First, we describe a method that measures the local tracer accumulation to determine the sensitivity and specificity of the tracer for discrimination of tumor tissue from benign tissue. Next, we evaluate the CRM status using optical molecular imaging of fresh surgical specimens and correlate the measured fluorescence intensity to standard histopathology.
In clinical oncology the individual management of disease is getting more important, due to the presence of variable expression of therapeutic targets between patients and tumor heterogeneity within patients. With the growing number of targeted therapies patients that are likely to benefit from a particular therapy need to be selected carefully. As a step-up to this future theranostic approach, we describe in Chapter 5 the feasibility
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if molecular fluorescence endoscopy (MFE) can be used for treatment response evaluation to aid in clinical decision making and individualized management of disease by identifying the presence or absence of residual tumor. Locally advanced rectal cancer patients with a clinical complete response to nCRT prior to surgery might benefit from a watchful waiting strategy instead of aggressive surgery. In patients with locally advanced rectal cancer that are treated with neoadjuvant chemoradiotherapy (nCRT) we evaluate if MFE can be used determine the response to nCRT. In 25 patients with locally advanced rectal cancer we performed MFE using bevacizumab-IRDye800CW for fluorescent guidance and multi-diameter single fiber reflectance and single fiber fluorescence (MDFSR/SFF) spectroscopy for quantification of fluorescence signals from the NIR tracer. Fluorescence intensities are correlated with the current clinical gold-standards: radiological restaging, white-light endoscopy and the pathological staging of the surgical specimen.
For the further development of theranostic approaches in medicine, relevant targets need to be identified. To facilitate clinicians and drug developers in deciding which theranostic targets should be taken into further evaluation in pancreatic cancer to improve the poor outcome of pancreatic cancer patients, we identify in Chapter 6 relevant molecular targets directed at aberrant signaling-pathways in pancreatic cancer. We collect publicly available expression profiles of patient derived normal pancreatic tissue and pancreatic cancer samples. Functional Genomic mRNA (FGmRNA) profiling is applied to predict overexpression of target antigens on the protein level. In addition, a review of the literature is performed to prioritize these potential target antigens for their utilization in a theranostic approach in the near-future, based on current status of (pre)-clinical therapeutic and imaging evaluation in pancreatic cancer.
Finally, Chapter 7 summarizes the findings of this thesis which is followed by a discussion on the implications of our findings and an overview of the future perspectives of molecular fluorescence imaging in medicine.
GENERAL INTRODUCTION AND OUTLINE OF THE THESIS
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REFERENCES
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4. Houssami, N., Macaskill, P., Marinovich, M. L. & Morrow, M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann. Surg. Oncol. 21, 717–730 (2014).
5. St John, E. R. et al. Diagnostic Accuracy of Intraoperative Techniques for Margin Assessment in Breast Cancer Surgery: A Meta-analysis. Annals of Surgery 265, 300–310 (2017).
6. Fehrmann RSN, Karjalainen JM, Krajewska M, et al. Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat Genet. 2015;47:115–125.
7. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310:1473–1481.
