Clinical trial NCT04339374: Ultrasound and Photoacoustic Imaging for Enhanced Differential Diagnosis of Rectal Cancer
Official title: Diagnosis and Risk Assessment of Locally Advanced Rectal Cancer Using Co-registered Ultrasound and Photoacoustic Imaging
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Rectal Cancer
Colorectal Cancer
Keywords: Rectal cancer
Nonoperative management
Watch and wait
Complete clinical response
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Institute for Biomedical Imaging and Bioengineering (NIBIB)
First posted: 2020-04-09
Enrollment: 90
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The purpose of this study is to demonstrate the functionality of a novel endorectal photoacoustic ultrasound imaging modality in humans with rectal cancer. The study involves testing a previously developed endorectal device to determine its ability to accurately assess rectal tumor response to preoperative treatment. Investigators hypothesize that a co-registered photoacoustic ultrasound endorectal device can significantly reduce unnecessary surgeries in rectal cancer patients with complete clinical response while maintaining high sensitivity in identifying those with residual cancer.

Detailed description: The investigators hypothesize that a co-registered photoacoustic ultrasound endorectal device can significantly reduce unnecessary surgeries in rectal cancer patients with complete clinical response while maintaining high sensitivity in identifying those with residual cancer. The proposed new imaging technique combined with deep-learning algorithms will provide a real-time imaging tool to assist surgeons in predicting the neoadjuvant treatment response of rectal cancer patients. Such a tool will offer sensitive vascular and %sO2 contrast for identifying complete responses, thereby assisting surgeons in significantly improving sensitivity and specificity in surgery recommendations. The study will 1) rigorously validate the technique in a group of LARC patients who will undergo surgical resection of their rectum based on the SOC, and 2) explore the technique's potential in assessing a sub-group of LARC patients through the course of neoadjuvant treatment and in post-treatment surveillance. Successful completion of the project will result in a new imaging tool that can significantly improve the SOC by reducing unnecessary surgery without compromising cancer-related outcomes and thereby lowering morbidity and health care cost.

In this trial, the investigators will recruit patients with rectal cancer who have completed neoadjuvant therapy and will undergo surgery or nonoperative management. Approximately 86 patients will be recruited. The first group of 30 patients (group #1) will be used to train/validate identification algorithm. The second group of 56 patients (group #2) will be used as the testing cohort to train the reader team comprised of 3 surgeons and 1 radiologist. Eligible patients will include those with rectal cancer who received neoadjuvant therapy and were deemed to either have incomplete or indeterminant response based on standard endoscopy and axial imaging with magnetic resonance. PAM/US will be performed before their surgery.

After initial training, the study surgeon will grade the lesion as either PAM/US non-cCR or PAM/US cCR at the time of PAM/US imaging. The study radiologist, blinded from the surgeon's read, will also grade the lesion based on MRI and other clinical information. PAM/US-CNNs provide a real-time imaging tool to assist the reader team in diagnosis. The pathological outcomes of the patients will be assessed based on Tumor Regression Score by standard pathologic evaluation. The sensitivity and specificity of the reader team assisted by PAM/US-CNNs will be obtained from the testing cohort of patients.

The study surgeon will review each patient's record and decide on surgery (clinical non-responders, non-cCR) for two types of patients of 1) those deemed non-cCR based on SOC at the treatment completion; 2) those deemed cCR at the treatment completion, however, later have tumor recurrence based on SOC assessment (non-cCR). PAM/US will be performed before their surgery. After initial training, the study surgeon will grade the lesion as either PAM/US non-cCR or PAM/US cCR at the time of PAM/US imaging. The study radiologist, blinded from the surgeon's read, will also grade the lesion. PAM/US-CNNs provide a real-time imaging tool to assist the reader team in diagnosis. The pathological outcomes of the patients will be assessed based on the Modified Ryan Scheme for Tumor Regression Score. Score 0, No viable cancer cells (pCR); Score 1, Single cells or rare small groups of cancer cells (near pCR); Score 2, Residual cancer with evident tumor regression, but more than single cells or rare small groups of cancer cells; Score 3, Extensive residual cancer with no evident tumor regression. Scores 2 and 3 are considered as non-pCRs. The sensitivity and specificity of the reader team assisted by PAM/US-CNNs will be obtained from the testing cohort of patients. If the methodology is validated from this prospective study, surgeries could be significantly reduced in this group of patients who are pCRs or near pCRs and whose PAM/US imaging scores provided by reader team classify them as responders. The investigators will also correlate MRI/DWI findings with PAM/US and document agreement/discordance with explanations.

As an exploratory part of this trial, a subset of eligible patients of group #2 of will be selected to undergo three serial imaging studies: at pre-treatment, halfway through treatment (after completion of one week of radiation followed by 2 months of chemotherapy), and at treatment conclusion (after one week of radiation followed by 4 months of chemotherapy). At the treatment conclusion, those deemed to have residual tumor by standard clinical methods (\~65%) will proceed to surgery. For the remaining 35% of patients, with no evidence of active disease, surveillance will be initiated. For these patients, serial imaging examinations will be performed every six months (coordinated with standard examinations). Patients deemed to have a recurrence will undergo surgery.

Once every enrolled patient has completed either surgery or two years of surveillance, the participants will be divided into two groups: Group A (those who underwent surgery) and Group B (those treated solely with nonoperative surveillance). As the primary outcome, Group A will demonstrate the accuracy of photoacoustic imaging. As a secondary outcome, Group A will reveal how the tumor vasculature and %sO2 changes over time, which may provide new insight into how complete response patients respond differently from non-pCR patients and how PAM/US can capture these earlier changes. The investigators will follow up on their SOC results in the clinical system and correlate their PAM/US results during the 2-year surveillance with their five-year disease-free survival.

To identify each patient as a complete or non-complete responder, the investigators will analyze photoacoustic images of all group #2 56 patients serially with the reader team assisted by deep learning algorithms developed earlier in the trial. These quantitative measures, as well as any qualitative local vasculature and %sO2 changes and US morphological changes, will be recorded at each time point. Standard MRI and endoscopic images will be independently collected and analyzed.

As a final part of this trial, the investigators will explore patterns of post-treatment vascular and %sO2 changes during preoperative treatment and serial surveillance. Tumor angiogenesis in colorectal cancer has been well studied using microvessel density (MVD) as a surrogate marker. While high levels of MVD and vascular endothelial growth factor (VEGF) significantly predict poor survival, little is known about the dynamics of vascular and %sO2 changes and the mechanisms of neovascularization after chemoradiation.

The investigators have observed tumor beds revert from oncologically-disrupted microvascular patterns to highly regular architecture typical of the normal rectum where pCR has occurred, though this mechanism is not well-understood. In contrast, heterogeneous and often microvascular-deficient regions have been found consistently in tumor beds with residual cancer at treatment completion. This novel imaging device could serve as a new platform for investigating the dynamics of vascular and %sO2 changes during and after therapy and for assessing potential rectal cancer recurrence early on. In addition to PAM/US imaging studies, the surgeon will perform biopsies at the central region and edges of the tumor bed before treatment, at treatment completion (if no surgery), and at the point of tumor reoccurrence. For patients with surgery, surgical samples will be used. Specifically, MVD and VEGF expression will be assessed by immunohistochemical staining, and both will be quantitatively correlated with PAM/US findings at the center of the tumor bed and at the tumor edges. The results will help the investigators understand how vasculature changes during treatment and at recurrence are correlated with imaging findings.

Eligibility criteria: Inclusion Criteria:

* Patients with any stage of rectal cancer undergoing surgical resection and the 3 surgeons and 1 radiologist as part of the reader team who diagnose the images obtained in these patients using the PAM/US probe.
* Age \>18 years
* Able to provide informed consent

Additional Inclusion Criterion for in vivo imaging

* In patients: Lesion located within 15cm of the anal verge

Exclusion Criteria:

* In patients: Inability to provide consent
* In patients: Collection of intraoperative specimen for frozen section analysis will disqualify patients from participation

Primary outcomes:
measure: Sensitivity and Specificity of the diagnosis by reader team assisted by PAM/US-CNNs
timeFrame: Approximately 30 minutes
Secondary outcomes:
measure: Area under the receiver operating curve (ROC)
timeFrame: Approximately 30 minutes
measure: Characterize in vivo tissue samples with photoacoustic imaging
timeFrame: Approximately 30 minutes
measure: Performance characteristics of the novel endorectal ultrasound probe as measured by number of adverse events
timeFrame: Approximately 30 minutes
measure: Performance characteristics of the novel endorectal ultrasound probe as measured by evidence of tissue damage from the imaging laser
timeFrame: Approximately 30 minutes
measure: Performance characteristics of the novel endorectal ultrasound probe as measured by time required to complete study
timeFrame: Approximately 30 minutes
measure: Performance characteristics of the novel endorectal ultrasound probe as measured by variability in image production
timeFrame: Approximately 30 minutes
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: William Chapman, Jr., M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Leng X, Uddin KMS, Chapman W Jr, Luo H, Kou S, Amidi E, Yang G, Chatterjee D, Shetty A, Hunt S, Mutch M, Zhu Q. Assessing Rectal Cancer Treatment Response Using Coregistered Endorectal Photoacoustic and US Imaging Paired with Deep Learning. Radiology. 2021 May;299(2):349-358. doi: 10.1148/radiol.2021202208. Epub 2021 Mar 23.