Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06101394 |
| Other study ID # |
23537 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
January 2024 |
| Est. completion date |
December 2025 |
Study information
| Verified date |
January 2024 |
| Source |
University of Turin, Italy |
| Contact |
Francesco Guerrera, M.D. Ph.D. |
| Phone |
+39 011 633 6777 |
| Email |
francesco.guerrera[@]unito.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
To date, lung resection and lymphadenectomy remain the best curative option in patients with
early-stage non-small cell lung cancer. Moreover, cancer screening programs have led to a
frequent diagnoses of indeterminate lung lesions, many of which require surgical biopsy for
diagnosis and intervention. Additionally, pre-operative imaging assessment frequently
underestimates lymph-node involvement. Finally, the increase in the utilization of minimally
invasive procedures remains mandatory.
The aim of our project is to verify if Cetuximab-IRDye800 could detect cancer nodules and
lymph node metastases during minimally invasive thoracic surgery. A result favoring the use
of Cetuximab-IRDye800 would permit the use of a minimally invasive approach to a more
significant number of patients, which are presently operable only by a traditional "open"
approach. Consequentially, it would lead to an improvement in surgical outcomes, a reduction
of costs, and an enhanced patient quality of life.
In addition, a result favoring Cetuximab-IRDye800 could consent to correctly remove mislead
metastatic lymph nodes (i.e., unexpected lymph-nodes metastasis) and neoplastic localization
unidentified at pre-operative diagnostic assessments. It would lead to more accurate cancer
staging, and a tailored post-operative treatment. Finally, the investigators expect to
validate using Cetuximab-IRDye800 as an optimal tracker that can be easily applied
intraoperatively during minimally invasive surgical procedures.
Description:
Lung cancer is the leading cause of cancer deaths in the European Union (EU) (267,000
deaths/year) and the fourth most common cancer (321,000 new cases/year). To date, radical
surgery remains the best curative option in patients with early-stage lung cancer. Moreover,
cancer screening programs have led to frequent diagnoses of indeterminate lung lesions, many
requiring surgical biopsy for diagnosis and intervention.
For example, available data showed that 5.9 % of the European population over 15 years of age
consumed at least 20 cigarettes per day (8.4 % in the male population), and around 12.6 %
consumed less than 20. The recent lung cancer screening studies documented a prevalence of
indeterminate pulmonary nodules as high as 50% in high-risk smokers, with a cancer detection
rate in the overall screened population of 1%. Fascinatingly, 69% of screen-detected lung
cancers were detected at early stage IA or IB.
Finally, studies on lung cancer screening, like the NELSON trial, showed a 26% reduction in
lung cancer deaths at 10 years. The potential social impact of the present project is linked
to establishing this screening program in Europe. One could estimate that if applied in the
high-risk European population (i.e., high smokers), the screening could identify 3.5 million
indeterminate pulmonary nodules, of which 250,000 are early-stage lung cancer. [2] Therefore,
using the NIR-tracker the investigators propose could consent to a minimally invasive surgery
in this scenario as a diagnostic and therapeutic procedure. Consequently, it could determine
the reduction of time to diagnosis, morbidity, mortality, and costs of postoperative care
associated with more invasive surgical procedures.
To date, lung anatomical resection with lymphadenectomy remains the best curative option in
patients with early-stage non-small cell lung cancer. Moreover, cancer screening programs
have led to frequent diagnoses of indeterminate lungs, many requiring surgical biopsy for
diagnosis and intervention.
Nevertheless, the increase in the utilization of minimally invasive procedures (e.g.,
video-assisted thoracic surgery -VATS- and robotic-assisted thoracic surgery -RATS- ) remains
mandatory in order to reduce the significant morbidity of classic surgery, the surgical
trauma, to preserve organs function and to improve patient's quality of life. Nevertheless,
minimally invasive surgery represents the surgical approach of choice in less than 40% of
lung anatomical resections conducted in Europe. One of the significant issues that hinder the
application of VATS and RATS to most early-stage NSCLC patients is the difficulty of
recognizing lung nodules located deep in the lung parenchyma and, consequently, not visible
with the traditional camera system. Indeed, VATS and RATS do not consent to manual lung
palpation, making localizing the not superficial lung nodule problematic.
Several approaches have been developed to enhance the localization of indeterminate lung
nodules and decrease the time to diagnosis and rate of conversion to open surgery.
Nevertheless, none of these is 100% sensitive or without complications, also of severe grade.
Numerous pre-operative methods are being employed, including percutaneous CT-guided placement
techniques, encompassing the use of microcoils, hook-wires, and spiral-wires. These devices
can support nodule localization during minimally invasive lung procedures; nevertheless, they
could be easily displaced during patient transport and positioning, intraoperative
atelectasis, single lung ventilation, and surgeon manipulation. Moreover, some locations of
the lung as the apex, near the diaphragm, and the proximity of mediastinum and great vessels.
Furthermore, all these pre-operative localization techniques require two different
procedures, one for the CT-guided referral placement and one for surgical treatment. Finally,
the rate of pneumothorax, hemorrhage, and subcutaneous emphysema are not insignificant, and
these complications are mandatory to avoid in several sub-groups of patients. Other
pre-operative methods encompass the use of dye marking by methylene blue or fluorescent. [8]
Nevertheless, the accuracy of the staining of the targeted area is greatly affected by the
time between tumor marking and thoracoscopy. In particular, the significant impact is on the
difficulty in dye visualization during operation, limited information on lesion depth, and
rapid diffusion of dye into surrounding lung parenchyma between the time of injection and
surgery. Of note, methylene blue has limited application in patients with anthracotic
pigmentation. Moreover, also these techniques require two procedures for diagnosis and
treatment. Lastly, these procedures remain complicated by the risk of pneumothorax,
hemorrhage, dye air embolism, and cerebrovascular accident, and cases of lethal anaphylaxis
to the dye of choice.
On the other hand, clinical pre-operative staging and surgical planning are based on
pre-operative images taken before surgery, either by computed tomography (CT), positron
emission tomography (PET), or magnetic resonance imaging (MRI). These pre-operative imaging
assessments frequently underestimate lymph node involvement and secondary localizations. This
results in an upstaging after surgical resection ranging from 9 to 24 % in clinical Stage I
lung cancer. [10, 11] Nevertheless, the current system of intraoperative imaging, based on
direct injection of a tracker in the principal tumoral mass, demonstrated a substantial
limitation in lung cancer. This is principally due to the deeper location of the lymph node,
usually profoundly engaged in normal fat tissue, and to the irregular lymph node drain system
in the respiratory region.
In this context, intraoperative fluorescence imaging can enhance the real-time identification
of cancer cells during minimally invasive surgical procedures. This could overcome the
difficulty of finding cancer nodules located deep in the lung parenchyma, not visible on the
surface of normal, uninvolved tissue. The Near-infrared (NIR) fluorescence (700-1,000 nm)
detection avoids the natural background fluorescence interference of biomolecules, which
provides high contrast between the target and background tissues in small animals. NIR
fluorophores have a more comprehensive dynamic range and minimal background fluorescence
because of reduced scattering compared with visible fluorescence detection. However, the
conventional near-infrared (NIR) indocyanine green (ICG) method demonstrated a significant
limitation in deep cancer recognition, principally due to its intrinsic low-depth tissue
penetration. Similarly, the lymph-node sentinel approach conducted by the ICG method proved
to be inefficient, mainly due to the non-specificity of the tracker and the irregular pathway
of pulmonary lymph node drainage.
The IRDye® 800CW is an indocyanine-type NIR fluorophore with peak absorption at 775 nm and
peak excitation emission at 796 nm. It provides a quantum yield of 9% with an extinction
coefficient of 242,000 M-1cm-1. It has a molecular weight of 962 Da. The IRDye® 800CW
demonstrated enhanced tissue penetration compared to other NIR dyes.
Epidermal growth factor (EGF) is a 53-amino acid cytokine (6.2 kDa) that is secreted by
ectodermic cells, monocytes, kidneys, and duodenal glands. EGF stimulates the growth of
epidermal and epithelial cells. EGF and at least seven other growth factors and their
transmembrane receptor kinases play essential roles in cell proliferation, invasion,
metastasis, neovascularization, adhesion, migration, differentiation, and inhibition of
apoptosis. The EGF receptor (EGFR) family consists of four transmembrane receptors, which
include EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4); and is
commonly overexpressed in lung cancer. Cetuximab is a monoclonal antibody able to inhibit and
degrade the EGFR. Given by intravenous infusion (IV), Cetuximab binds to the EGFR and stops
the binding and activation of the downstream signaling pathways. Moreover, as the
investigators previously published, EGFR mutation is linked with skip-metastasis phenomena
(i.e., pathologically proved mediastinal lymph node involvement in the absence of
intrapulmonary or hilar lymph node disease).
The combination with the clinical approved monoclonal antibody anti-epidermal growth factor
EGFR Cetuximab (Cetuximab-IRDye800) has shown promising results as a specific tracker in
other cancer types (i.e., brain, pancreas, head, and neck). The investigators hypothesize
that using Cetuximab-IRDye800 during minimally invasive surgical procedures for lung cancer
could overcome the limitation demonstrated by ICG and the traditional localization strategies
(e.g., coil, hook, dye intra-tumoral injection). The investigators expect to validate using
an optimal tracker that can be easily applied intraoperatively during minimally invasive lung
surgical procedures. The investigators expect to define the optimal time window and the
optimal dose of administration of the tracker. The investigators expect to discover
neoplastic localization in lymph nodes and lung parenchyma not predictable pre-operatively.
