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. Author manuscript; available in PMC: 2016 Mar 15.
Published in final edited form as: Cancer. 2014 Sep 9;121(6):817–827. doi: 10.1002/cncr.29012

Multimodal Imaging for Improved Diagnosis and Treatment of Cancers

Clare Tempany 1, Jagadeesan Jayender 1, Tina Kapur 1, Raphael Bueno 1, Alexandra Golby 1, Nathalie Agar 1, Ferenc Jolesz 1
PMCID: PMC4352132  NIHMSID: NIHMS625470  PMID: 25204551

Abstract

This article reviews methods for image-guided diagnosis and therapy that increase precision in detection, characterization, and localization of many forms of cancer to achieve optimal target definition and complete resection or ablation. We present a new model of translational clinical image guided therapy research and describe the Advanced Multimodality Image Guided Operating (AMIGO) suite. AMIGO was conceived and designed to allow for the full integration of imaging in cancer diagnosis and treatment. We draw examples from over 500 cases performed on brain, neck, spine, thorax (breast, lung), and pelvis (prostate and gynecologic areas) and describe how they address some of the many challenges of treating brain, prostate and lung tumors.

Keywords: Brain Tumor, Interventional MRI, Intraoperative Monitoring, Lung Cancer, Mass Spectroscopy, Multimodal Imaging, Neuroimaging, Neuronavigation, Prostate Biopsy, Prostate Cancer

IMAGE-GUIDED THERAPY

Traditional cancer interventions and surgeries rely heavily on the eye-hand coordination skills of the physician and may be limited by the inadequacies of human visualization and dexterity. As visible light cannot penetrate the skin or exposed surfaces, without the guidance of advanced imaging technologies, the treating physician – be it a surgeon or an interventional radiologist – cannot physically visualize a 3D operating volume and is forced to access the targeted tissues layer by layer. Further, the human eye cannot distinguish most of the malignant, infiltrating tumors such as found in brain or lung from the surrounding normal tissue. Inability to recognize tumor margins and related critical anatomical structures renders intra-procedural decisions extremely difficult. The human eye cannot visualize essential 3D morphological or functional information about a given tumor, much less monitor tissue temperature, perfusion, or metabolism, which are all essential for precise delivery of therapy. Imaging can play a new and important role in compensating for these deficits to achieve the optimal target definition that is the prerequisite of all successful interventions or surgeries. Prior to all such procedures, the patient undergoes a set of diagnostic imaging tests. These images are then processed in various ways, converted into 3D images and models representing the patient’s disease and anatomy. This information is subsequently used for preoperative surgical planning and/or intraoperative surgical decision-making. If correct target definition is available during a procedure, an image guided navigation system can be utilized to precisely visualize instrument motion with respect to the surrounding anatomy, thereby allowing the proceduralist to navigate to the organs, distinguish between normal and abnormal tissue and enabling more accurate procedures with minimal damage to normal tissue. Navigation systems are commercially available for brain tumor surgeries, spinal procedures, endoscopic sinus surgeries and for orthopedic applications. Robotic systems, such as da Vinci (Intuitive Surgical, Inc., CA), are also available for minimally invasive surgery, for e.g., radical prostatectomy. Many new systems for image display and navigation in the abdomen, pelvis, thoracic, and cardiovascular areas are currently being developed by industrial and academic institutions.

Modern Image Guided Therapy (IGT) is designed to use imaging not only to improve the localization and targeting of diseased tissue but also to monitor and control treatments. This new paradigm is becoming broadly applied and accepted in the fields of image-guided surgery and interventional radiology. Scanners for magnetic resonance imaging (MRI), computed tomography (CT), and even positron emission tomography (PET) have entered operating rooms (OR) and interventional suites all over the world (see chapter 20–24 of1).

A multidisciplinary team approach is advantageous while developing and deploying integrated imaging, guidance, and therapy devices (so called therapy delivery systems) for successful outcomes in IGT. These technologies require extensive multi-disciplinary cooperation and collaboration among teams of surgeons, interventional radiologists, imaging physicists, computer scientists, biomedical engineers, nurses, and technologists to achieve the common goal of delivering safe and effective state-of-the-art therapy to patients in a continuously improving, technologically advanced but patient-friendly environment (chapter 24 of1).

The AMIGO Suite at Brigham and Women’s Hospital

The Advanced Multimodal Image-Guided Operating (AMIGO) suite was conceived, designed, and implemented through the vision of Drs. Ferenc Jolesz and Clare Tempany.2 It is co-funded by NIH grants and the Brigham and Women's Hospital (BWH) in Boston. The developmental stages involved in the design and construction of AMIGO is detailed in Table 1. It covers a 5,700 square foot area divided into three sterile procedure (MRI, OR, PET/CT) rooms, as shown in Figure 1.

Table 1.

Amigo Technical Development

Year Landmark
1999 The Magnetic Resonance Therapy team that worked on the “double donut” MRI magnet began discussions on how to expand the program.
2008 5,700 square foot, three-room interconnected hybrid operating room with a floor-mounted MRI and PET/CT adjoining each side of the OR approved.
2009 Final construction plan submitted.
2010 Magnet delivered.
2011 Clinical use of AMIGO initiated.
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Figure 1.

Figure 1

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Overview of the AMIGO suite showing the layout of the CT, Operating and MRI rooms.

MRI Room

This room houses an IMRIS system comprised of a high-field (3 Tesla) wide-bore (70 cm) Siemens Verio MRI scanner integrated with full OR-grade medical gases, MRI-compatible anesthesia delivery and monitoring system, and therapy delivery equipment. The MR scanner is mounted on the ceiling and can traverse on ceiling rails to a fully draped patient in the middle room on the OR table, a typical scenario for brain tumor surgery. The MR room design is such that it can be used independently for MR-interventional radiology procedures such as prostate biopsy and focal ablation therapy. There are now 57 IMRIS installations worldwide and 82 ORs using this intra-operative MRI technology, mostly for neurosurgical applications.

Operating Room (OR)

The center room of the AMIGO is a hybrid OR (Figure 2), flanked by the adjoining MRI and PET/CT rooms. The room is equipped with MRI-compatible anesthesia delivery and monitoring systems, a surgical microscope with near-infrared capability, surgical navigation systems that track handheld tools, probes, a ceiling-mounted single plane angiographic x-ray system, and 2D and 3D ultrasound imagers. Brain tumor surgery and lung wedge resection surgery take place in this room, with the use of ceiling mounted MRI and angiographic imaging, respectively.

Figure 2.

Figure 2

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Operating room with access to the 3T MRI, interventional C-arm CT, and additional navigation devices.

PET/CT Room

The AMIGO Suite is the first to use PET/CT and MRI in an operating room environment for image guided therapy applications. The PET/CT imaging enables the use of molecular imaging intraoperatively for guiding not only biopsies but also surgical interventions.3 There is a transfer table for moving patients between the PET/CT table for imaging and the OR table for surgery.

A detailed description of the design and operational analysis of AMIGO can be found in Chapter 24 of our recently published book.1 The overall goal of AMIGO is to provide a clinical translational research test-bed with different imaging modalities to evaluate the utility of combined pre-procedural and intraprocedural imaging during surgery and interventions to enable precise definition of the tumor to ensure targeted biopsy, complete resection or in situ destruction. Once the safety and feasibility of integrating the imaging modality with the surgical procedure has been evaluated and all the imaging findings and overall application are validated, the procedures will be transferred to dedicated IGT suites or hybrid ORs that may not have all the features of AMIGO, but only those that are necessary to the procedure. Table 2 shows the list of procedures done in AMIGO as of 06/06/2014 while Table 3 shows the typical monthly block schedule of the procedures in AMIGO. The multidisciplinary nature of the program is reflected in the distribution of the projects between surgery, radiology and radiation therapy.

Table 2.

552 Procedures completed in AMIGO from 08/31/2011 to 06/06/2014.

Neuro 114

  • 74 Craniotomies/Biopsies

  • 22 Transsphenoidals

  • 9 Deep Brain Stimulation

  • 7 Laser Ablations

  • 1 Epilepsy Electrode Placement

  • 1 Skull Base

Head and Neck 7

  • 5 Parathyroidectomies/Hemithyroidecotmies

  • 2 MR Guided Soft Tissue Neck

Spine 1

  • 1 MR Cryoablation/Biopsy

Thorax 53

  • 21 Video Assisted Thoracic surgeries (iVats)

  • 8 Breast Lumpectomies

  • 7 EP Cardiac Ablations

  • 7 Microwave ablations PET/CT guided (lung)

  • 6 Biopsy PET/CT guided (lung)

  • 3 Cryoablations PET/CT guided (lung, rib)

  • 1 Cryoablation MR guided (paraspinal met)

Abdomen 174

  • 106 Cryoablations MR guided (liver, kidney)

  • 25 Biopsies MR guided (liver, kidney)

  • 16 Cryoablations PET/CT guided (liver, kidney)

  • 16 Microwave Ablations PET/CT guided (liver, kidney)

  • 9 Cryoablations & Biopsies MR guided (liver, kidney)

  • 1 Cryoablation & Biopsy PET/CT guided (liver)

  • 1 FDG PET/CT Guided Interventions (liver)

Pelvis 203

  • 122 Prostate Biopsies

  • 67 Gynecologic Brachytherapy

  • 7 Prostate Brachytherapy

  • 5 Cryoablations MR guided (iliac, prostate)

  • 1 Biopsy MR guided (penile)

  • 1 Biopsy/Cryoablation combo MR guided

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Table 3.

Monthly block schedule showing the procedures conducted every month.

Monday Tuesday Wednesday Thursday Friday Saturday Sunday
Week 1 Pelvic Neuro Neuro Pelvic/Abdomen Non-clinical Research & Maintenance
Week 2 Open Open/Neuro Open Pelvic/Abdomen
Week 3 Pelvic Neuro Neuro Open
Week 4 Abdomen Open/Neuro Thoracic Pelvic/Abdomen
Week 5 Open Neuro Head/Neck Pelvic/Abdomen
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IMAGE-GUIDED BRAIN TUMOR SURGERY

The National Brain Tumor Society estimates that approximately 210,000 people in the United States are diagnosed with primary or metastatic brain tumors each year. For both low- and high-grade tumors, gross total tumor resection relieves mass effect, decreases risk for seizures, increases time to progression, and lengthens survival.4,5

The goal of intraoperative MRI is to maximize tumor resection without increasing neurologic morbidity.6 The majority of malignant gliomas recur within 2 cm of the enhancing edge of the original tumor,7 making the delineation of the tumor gross margins particularly critical to guiding surgical decision-making. Therefore, the development of techniques capable of accurately depicting tumor margins during surgeries is important for the determination of the optimal resection strategy that maximizes the resected tumor while avoiding injury to adjacent brain tissue.

Advances in pre- and intraoperative imaging are aimed at addressing the two principal challenges of brain tumor surgery: the delineation of tumor margins and the localization of critical brain structures. Harnessing structural and functional imaging can give the surgeon the most complete preoperative map for planning surgery, as shown in Figure 3. The addition of advanced structural and functional data to conventional imaging and neuronavigation can help surgeons with intraoperative decision-making regarding whether or not to resect tissue.

Figure 3.

Figure 3

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Preoperative planning images for image-guided neurosurgery.

Pre-operative brain mapping with functional MRI is increasingly being adopted as a surgical planning tool, allowing more selective deployment of awake surgery and intraoperative mapping. Diffusion tensor imaging, another MRI-based technique, is able to demonstrate, in vivo, the position and trajectory of critical white matter tracts. The addition of presurgical tractography to neuronavigation has been found to increase tumor resection and survival, and decrease neurologic morbidity.8 The use of navigation during surgery can aid the surgeon in integrating those images with the surgical gesture itself.

Optimizing surgical resection is particularly difficult for intrinsic brain tumors due to resemblance of tumor tissue to brain tissue, as shown in Figure 4. In the case of slow-growing tumors such as low-grade gliomas, reorganization and displacement can occur and these tumors can even have functional tissue and tracts within them.9 Thus, brain tumors located near critical brain areas subserving primary motor, sensory, or language functions are difficult to resect maximally while avoiding postoperative neurological deficits.10 It is often difficult to visually distinguish tumor tissue from surrounding white matter (WM) and the location of critical structures is variable, particularly in the presence of mass lesions. This uncertainty leads to two problems: inadequate resection secondary to the surgeon's stopping at what appears to be grossly abnormal tissue (so as to avoid neurological damage) or, neurological damage due to aggressive surgery where resection ends only when clearly normal brain tissue is visualized. The addition of intraoperative imaging is needed to take into account and visualize the effects of resection and retraction and the associated brain shift, as shown in Figure 5. For example, it has been shown that due to craniotomy and resection, the position of WM tracts changes as much as 15 mm during surgery and moreover, this in an unpredictable direction.11,12

Figure 4.

Figure 4

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Neurosurgical intraoperative images showing microscopic view of the target and surrounding structures.

Figure 5.

Figure 5

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(a) Diagnostic MRI showing extent of tumor (b) Intraprocedural MRI prior to resection of the tumor (c) Post-procedural MRI confirming the complete tumor resection.

These challenges led to development of the first intraoperative MRI for bringing new information being learned about brain tumors into the OR to guide surgery. The origin of intraoperative MRI can be traced to the Magnetic Resonance Therapy Unit at BWH, which was involved in the development of an open configuration MRI scanner that allowed surgery to be performed with concurrent intraoperative image guidance. In 1994, deployment of the world’s first intraoperative MRI (0.5 Tesla) at BWH enabled performance of various percutaneous, interventional, endoscopic, and open surgical procedures. More than 1000 craniotomies were performed at BWH in the original double donut intraoperative MRI (40% low-grade gliomas, 50% high-grade gliomas, and 10% other intracranial lesions such as metastases, meningiomas, and vascular malformations).13 We have now progressed to the use of our AMIGO with its higher field strength and multimodality capability. Numerous groups around the world have adopted intraoperative MRI systems and use them regularly for neuro-oncologic, epilepsy, functional, and other procedures14. A typical surgical workflow of a neurosurgical procedure in AMIGO is shown in Table 4.

Table 4.

Workflow of the neurosurgery procedure in AMIGO. S surgeon, R radiologist, A anesthesiologist, RS research scientist, MRT MR technologist, N nursing staff.

Step Daily schedule
Start time		 Anticipated
Duration		 Personnel requirement
Patient anesthesized, positioned 7:30am 30 min S, A, N
Coil placement, Initial imaging, Coil removal 8:00am 30 min MRT, R, S
Coregistration, plan approach 8:30am 15 min S, RS
Prep, drape 8:45am 15 min N, A, S
Start surgery. Open craniotomy. 9:45am 1 hour S, N
More intraoperative imaging 10:15am 30 min MRT, R, S
Tumor resection and biopsies. 11:45am (max) 30–90 min S, N
More imaging 12:15pm 30 min MRT, R, S
Possibly further resection. 1:45pm (max) 30–90 min S, N
Closure 2:30pm 45 min S, N
Possibly final imaging 3:00pm 30 min MRT, R, S
Patient transfer 4:00pm 60 min A, N
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The visualization possibilities afforded by intraoperative MRI have also led to the development of minimally invasive approaches for tissue ablation. Both MRI-guided laser interstitial therapy (ILT) and focused ultrasound (FUS) that have been developed in the Brigham IGT program are used to create thermal lesions in the brain15. Early adopters have focused on treatment of brain tumors and epilepsy. Laser-based hyperthermia depends on accurate temperature mapping during ablation that is provided by MRI, either in an MRI-equipped operative suite, or by transporting the patient to a diagnostic MRI scanner. FUS has been used in early clinical studies for the ablation of brain tumors and for functional neurosurgery16. Future applications may include reversible opening of the blood brain barrier for targeted delivery of agents to the CNS.

Efforts are underway to bring some of the last decades’ advances in pre- and intraoperative imaging into a real-time, user friendly, using a cheaper set of tools. For example, efforts to use fluorescent tracers to indicate residual tumors could provide many more patients with the advantages of image-guided therapy.17 Future work envisions comparing intraoperative MRI outcomes with those of intraoperative use of 5-ALA. Advanced MRI and molecular imaging using PET have the potential for more accurately showing the peripheral tumor margin beyond the MRI findings presently used to guide and evaluate brain tumor resection. We will also investigate the use of mass spectrometry (MS) as an intraoperative molecular biomarker for surgical guidance in AMIGO.18

IMAGE GUIDED INTERVENTIONS IN PROSTATE CANCER

The American Cancer Society estimates that approximately 233,000 new cases of prostate cancer will occur in the US in 2014.19 Although prostate cancer is second only to skin cancer in frequency of diagnosed cancer in the US, in recent years, it has been recognized that there has been over-detection and over-diagnosis of prostate cancer with the consequence that many men derive little benefit from Prostate Specific Antigen (PSA) screening. This led to the US Preventive Services Task Force downgrading the utility of PSA screening in 2012.20 Thus, a new approach to detection and diagnosis has become imperative. An important clinical challenge is to determine which men have clinically significant cancers that require active treatment, versus those with clinically insignificant cancer who can be observed or enrolled in active surveillance protocols.21–23

Transrectal ultrasound (TRUS) Biopsy

TRUS-guided biopsies sampling six to twelve cores, one to two for each sextant, has been the diagnostic standard for prostate cancer for many years. The ultrasound images provide guidance to the physician about the size and boundaries of the gland but limited or no information regarding internal glandular tissue or, in particular, focal lesions. The prostate tissue samples are obtained in a directed manner via needles aimed laterally through the rectum to optimize the ability to sample the peripheral zone. Many areas, particularly the anterior gland, frequently are not sampled during TRUS biopsy as they are beyond the range of the needle. As no focal lesion-based targeting efforts are made, the sampling is blinded to focal lesions. The shortcomings of this random sampling biopsy method -- risk of post-biopsy infection (rates 4–10%), upgrading after surgery, based upon whole gland pathology and an inability to detect and diagnose clinically significant cancers24,25 -- have contributed to a search for more optimal methods for prostate cancer diagnosis, precise localization and complete target definition.

MR Guided and Targeted Prostate Biopsy

MR-guided transperineal prostate biopsy (MRGPB) was introduced at BWH in 2001 in the same open-configuration, 0.5 Tesla intraoperative MR scanner mentioned earlier in the neurosurgery discussion. MR-guided, targeted or MR-informed prostate biopsies are now being performed in many centers around the world. In our institution MRGPB biopsies are performed as outpatient procedures under intravenous conscious sedation in the bore of the magnet. A detailed, multiparametric MRI (mpMRI) is acquired pre-biopsy for target identification, and subsequently in-bore transperineal, template-based sampling is performed. Many advances have taken place in the decade since the introduction of the procedure; the current program has migrated to a wide bore MRI, located in the AMIGO facility and is now applied for biopsy and focal therapy for localized prostate cancer. Image navigation and display are provided by 3D-Slicer, free open source software for medical image analysis and visualization.26

Initial analysis of the results for the first cohort of men biopsied in this manner in 3T MRI is promising.27 Based on pre-biopsy mpMRI, there are, on average, fewer than four suspicious targets and locations sampled per biopsy session. Therefore, less rather than more tissue is sampled as is done in TRUS 12–15 or in the template saturation biopsies where 50–80 cores are taken per session. The techniques pioneered at BWH have been adopted, adapted, and used successfully at many hospitals. There are now several different approaches in clinical practice for MR-guided prostate biopsy: they are performed either in or out of the bore of the magnet using real-time MR or real-time US with MR fusions systems.28 It is not surprising that companies have shown significant interest in developing solutions for prostate biopsy that combine the accuracy of MRI and the speed of ultrasound; there are now at least five different vendors providing MR-US fusion products for clinical practice.

Imaging Prostate Cancer

Initially, prostate MRI, as introduced in the late 1980s29 and early 1990s,30 was developed and applied for loco-regional staging in men with known prostate cancer to assess the extra-prostatic extension, neuro-vascular bundle (NVB) and seminal vesicle invasion along with detection of metastatic lymph nodes and bone lesions. Multi-parametric MRI of the prostate is now recognized as state of the art and the most accurate imaging modality for detecting, characterizing, and staging prostate cancer. By combining three different sequences -- diffusion-weighted imaging (DWI), T2-weighted (T2W), and dynamic intravenous contrast enhanced (DCE) imaging -- MR imaging can detect, characterize, and stage prostate cancer. Diffusion allows assessment of local tissue water motion, so-called “Brownian motion”. The T2W sequences (Figure 6) continue to provide excellent soft tissue contrast, allowing depiction of the sub-structure of the gland and its zonal regions (peripheral, central, and transitional). It can now define 36 sectors of the gland based on anatomical landmarks (apex, base, urethra, anterior fibro-muscular stroma) and T2W image analysis. Focal cancer typically appears as a round, well-defined mass/region of low signal intensity. DWI depicts focal prostate cancer as an area of restricted diffusion with high signal on the DWI and low signal on apparent diffusion coefficient (ADC) images that are derived from the DWI. The ADC value can be measured and, in focal cancer, is inversely related to the Gleason pattern: lower ADC values (<800) are predictive of the presence of higher Gleason 4 pattern disease. DCE sequences will typically show focal cancer with early arterial enhancement and venous wash-out. When all three sequences show these typical features and the ADC is <800, there is a very high probability of a clinically significant (Gleason ≥4) prostate cancer in the patient. Figure 7 shows the mpMRI of a patient with prostate cancer. Currently, most centers performing prostate MRI use this mpMRI approach.31 This combination of sequences is capable of detecting and characterizing intermediate to high-grade cancers with a high degree of accuracy. There are now at least three international efforts in varying stages of development and application to educate, reduce inter-reader variability, and ensure standard approaches and interpretations of prostate MR imaging examinations.32

Figure 6.

Figure 6

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(a) Axial T2W image showing a normal prostate gland (b) Coronal T2W image of the same patient.

Figure 7.

Figure 7

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mpMRI of patient's prostate cancer (a) T2W (b) DWI (c) ADC (d) Subtracted (e) Ktrans (f) ve images. Red arrow indicates the tumor. ADC of 682 for an ROI within the tumor.

Supporting Image Analysis Tools in 3D Slicer

Novel image analysis methods for IGT have been developed and implemented in a free and open source software platform. Tools for visualization of mpMRI, image guidance during biopsy procedures,33 and non-rigid registration of prostate MRI across time-points34 are in active clinical use. MR/US (ultrasound) registration methodology35 and characterization of registration uncertainty are in active research.36,37 Further, MRI has also been used to confirm the needle position prior to obtaining biopsy samples, as shown in Figure 8.

Figure 8.

Figure 8

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(a) T2W imaging showing needle artifact (black dot) within tumor (b) DWI image confirming needle position (c) Reformatted T2W Coronal image (d) Reformatted DWI coronal image.

MR Guided Focal Therapy For Localized Prostate Cancer

Focal therapy for prostate cancer is gaining increasing attention in clinical trials and clinical applications.38 The definition of what constitutes “focal therapy” is variable: it may depict therapy that is acutely localized to the image-defined tumor, to larger sub-gland volumes or, hemi-gland therapy. The other large group of men undergoing focal thermal therapies is those presenting for salvage therapy. In these patients, local control and avoidance of further side effects are critical. MR guided cryotherapy has been used39 with initial results demonstrating its feasibility. Long-term follow up is pending. Using a set-up similar to MRGPB, a new MR guided cryotherapy program has recently been established at BWH in AMIGO. The cryoprobes are placed inside the gland under MR guidance and directed directly into focal MR defined lesions. The MR imaging (Figure 9) depicts temperature change in the gland, surrounds the tumor, and enables avoidance of iceball extension into normal structures such as urethra or NVBs. Using mpMRI with a combination of the sequences, the 3D volume can be well defined,40,41 as shown in Figure 10.

Figure 9.

Figure 9

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MRI used for monitoring the progression of the iceball during cryotherapy.

(a) Pre-treatment (b) 2 mins (c) 4 mins (d) 10 mins (e) 15 mins after the start of cryotherapy.

Figure 10.

Figure 10

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3D Slicer-based planning and monitoring for cryotherapy. 3D models of iceball and tumor show complete eclipsing of the tumor by iceball, ensuring adequate tumor treatment.

All of the ablative techniques -- laser therapy, cryotherapy, photodynamic therapy, high-intensity focused ultrasound42, and interstitial electroporation -- are being applied to prostate cancer using real-time US or MR guidance. Clinical trials of MR-guided focused ultrasound for localized prostate cancer with the goal similar to that of ablating focal lesions in a non-invasive manner have been in progress in recent years.

IMAGE-GUIDED WEDGE RESECTION SURGERY

The American Cancer Society estimates that approximately 224,210 new cases of lung cancer will occur in the US in 2014.19 CT is the primary imaging modality for lung cancer detection and significant improvements in CT technology in recent years have enabled the detection of increasingly small lung lesions. Cancer screening trials indicate longer-term survival for patients whose cancers are detected early.43,44 Segmentectomy is now becoming the preferred surgical method for early and small Stage I tumors (less than 2 cm across), traditional lobectomy for larger tumors.45,46 However, localizing the tumor in a deformed lung is difficult due to significant tissue deformation, minimally invasive access to the tissue during Video-assisted Thoracic Surgery (VATS) and lack of air-tissue contrast on CT or C-arm CT imaging. Failure to localize the tumor -- based on the size of the tumor, its depth from the pleural surface, and whether it is semi-solid or ground-glass opacity -- can necessitate a conversion of the minimally invasive procedure to the more invasive thoracotomy in up to half to two-thirds of the patients.47 Although Wedge resection surgery compared to lobectomy has resulted in better lung function, local tumor recurrence rate can be as much as double that of lobectomy (16% vs. 8%) and five-year survival rate can be significantly lower (59% vs. 80%).48 The higher tumor recurrence rate is likely due to lack of accurate localization of the tumor and difficulty in assessing its extent intraoperatively.

Seeking to improve localization, the preoperative and intraoperative localization and labeling of tumors has been investigated by many research groups. It has been shown that ultrasound -- intraoperative transthoracic ultrasonography for occult lung lesions49 and thoracoscopic ultrasound for solitary pulmonary nodules50 -- can be used to localize lesions prior to resection. However, using ultrasound in the lung can be problematic due to the presence of air pockets creating significant air-tissue boundary artifacts. Marking and contrast agents such as Lipiodol, colored collagen, and barium sulfate can be used prior to surgery to mark the pleural surface close to the lesion or the lesion itself, and portable fluoroscopy used to image the marking agent and localize the lesion on the day of the surgery.51,52

A different method of marking lung cancer lesions involves the percutaneous placement of hardware such as hook-wires53 or microcoils into the lesion, and following them during the procedure for guidance. Placement of microcoils under CT guidance can be performed very accurately (up to 97% success rate).54

Building upon these concepts, preliminary results55 from a Phase I/II trial in progress in the AMIGO suite demonstrates the safety and feasibility of an integrated workflow of localizing the lesion using hardware fiducials under C-arm CT imaging followed by conventional video-assisted thoracic surgery in a hybrid OR. By performing the procedure in a single session, the risk of lung injury, dislodging of the fiducial and contamination is minimized. Considering the anticipated widespread use of CT-based lung cancer screening and, as a consequence, the significant increase of lung cancer patients, the introduction of an image-guided, minimally invasive tumor resection method into routine clinical practice is very desirable.

SUMMARY AND FUTURE PERSPECTIVES

With the introduction of advanced multimodal image-guided therapies, cancer diagnosis and treatment has moved from dependence on the limitations of human visualization and dexterity to an enhanced ability to localize and target an individual’s diseased tissue based upon his/her own images, assess tissue temperature, perfusion, and metabolism that can be used for monitoring and controlling therapy. In AMIGO, novel innovative IGT technologies are being developed and tested that improve localization, target definition and targeting, which forms the essence of focused and personalized molecular image-guided cancer therapy.

Acknowledgments

Funding sources: Authors were supported by NIH grants: P41EB015898, R01CA111288, R21CA156943, R01CA120528, R25CA089017

Footnotes

Financial disclosure statement: There are no financial disclosures by any of the authors.

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