Cancer

Imaging
Mukund Seshadri DDS, PhD

Mukund.Seshadri@roswellpark.org 716-845-1552

Cancer Imaging

CT -- ? X-ray -- ? PET --? MRI --? US--? Op3cal Imaging?

Clinical Paradigm in Oncology

Diagnosis/staging Management

Presenta(on

SCC tongue

Radiology
In Medicine/Oncology
Diagnose and stage disease at the 3me of presenta3on Assess response to therapy (chemo/RT) Surveillance tool (wait and watch) Screening tool for clinically occult cancers

Kundra V et al. AJR 2007

Grin N et al. AJR 2007

Dong Q et al. Radiographics 1999

Radiology
In Radia<on Oncology
Treatment planning Iden3fy volumes to compute op3mal radia3on treatment strategy Delinea3on of pa3ent anatomy - Desired radia3on target - Organs at risk

Durante & Loeer, Nat Rev Clin Oncol

Radiology
In Drug Discovery and Development

Rudin and Weissleder, Nature Rev 2003

Medicine has gone molecular..

Hanahan and Weinberg, Cell 2011

And so has radiology

Molecular Imaging

Padhani, Radiology 2010

Mul<-modal/Mul<-parametric Imaging

Padhani, Radiology 2010

Sessa, NCP Oncology 2008

Evolu<on of Radiology

Weissleder, Nature 2008

Imaging systems

Weissleder, Nature 2008

Magne<c Resonance Imaging

E-MRI.org

Factors inuencing image contrast

Sprawls-Medical Imaging

Factors inuencing image contrast

Elster, Q&A in MRI

Mitchell et al, AJR 1987

T1- and T2-weighted MRI

T1W T2W

Ca - Floor of the Mouth (Axial) M soO 3ssue mass; Arrow - genioglossus

Simple anatomic imaging Extent of tumor (delineaZon of margins)

Rumboldt et al.,Oral Oncol 2006

Dynamic contrast-enhanced MRI

Typically involves repeated (dynamic) T1/T2-weighted imaging of 3ssues before and aOer administra3on of the contrast agent. Relates enhancement paUern of 3ssues to underlying physiological parameters (perfusion, permeability) by analyzing 3me-dependent tracer concentra3on.
Jackson, Medicamundi 2003

Dynamic contrast-enhanced MRI

Enhancement (E)
Maximum increase in signal intensity normalized to baseline signal intensity

St signal intensity at 3me t, S0 baseline signal intensity

Early

Late

Padhani, BJR 2003

DCE-MRI of Tumor Angiogenesis

Pharmacokine<c model of CA kine<cs
T2W Subtrac<on

Ktrans

Ve

Kine3cs of low MW CAs in 3ssues is determined by 3 factors 1. Blood perfusion 2. Transendothelial transport (across the vessel wall) 3. Diusion of the CA into the inters33al space
Padhani, JMRI 2002

DCE-MRI of Tumor Angiogenesis

Mul<parametric MRI of breast cancer

(Le^ to right) T1-weighted subtracZon image IAUGC for 60 seconds (IAUGC60) Maps of relaZve blood ow (rBF) Transfer constant (K trans ),
Padhani, Radiology 2012

SPIO-enhanced MRI of Lymph nodes

Non-enhanced Iron-oxide enhanced

Darkening on T2W images due to suscep3bility ar3facts from iron

Kircher et al, Radiology 2012

Diusion Weighted Imaging

Diusion-weighted MRI to monitor tumor response to therapy

Hofstra et al., JCO 2007

Parametric Response Mapping

Complete responder (top) >63% of the tumor volume was found to have a signicant increase in ADC (depicted as red voxels), sugges3ng massive cell kill in the tumor mass. Par<al responder In 46% of the tumor volume producing a signicant increase in ADC.

Hofstra et al., JCO 2007

Galban et al., 2009

Positron Emission Tomography

A compound labeled with a positron- emicng radionuclide is introduced into the body, usually by intravenous injec3on. When one of the radionuclide atoms decays, a positron is emiUed, travels a very short distance in 3ssue (typically 01-100 mm for radionuclides of interest), and annihilates with an electron in the 3ssue. The mass of the two par3cles is converted into energy, which is emiUed in the form of two back-to-back 511 keV gamma rays

Cherry and Gambhir, ILAR 2001

PET scanner

A positron emission tomography scanner consists of a ring, or mul3ple rings, of gamma ray detectors that register simultaneous gamma ray hits and their loca3on, thus dening the line along which the positron-emission took place. By collec3ng large numbers of gamma-ray pair events (typically 106 to 107) and using computed tomography methods, cross-sec3onal images reec3ng the concentra3on of the positron-emicng radionuclide can be generated.

Cherry and Gambhir, ILAR 2001

PET in oncology

18FFDG is taken up in facilitated transport by metabolically ac3ve cells via

glucose transporters (Glut) in cell membrane. In cell cytoplasm, 18FFDG undergoes phosphoryla3on to form FDG-6-phosphate (FDG-6-P) that, unlike glucose, cannot undergo further metabolism and becomes trapped in cell with only negligible amount of FDG-6P diusing from cells.
Rosen et al.,Radiographics Kapoor et al AJR 2005

Computed Axial Tomography (CAT/CT)

Limita<ons of conven<onal radiography - Inecient X-ray absorp3on
- Low contrast - High scaUer to primary x-ray ra3os - Compresses 3D into 2D (superimposi3on, reduced conspicuity) To overcome these drawbacks, - Limit irradia3on and visualiza3on to individual slices - Display as 2D images without overlap - Reconstruct from projec3ons - minimize scaUer and exposure
Goldman, J Nucl Med Tech 2007

Computed Axial Tomography (CAT/CT)

CT gantry/terminology - X-ray tube, detectors - AUenua3on coecient - 2D views projec3ons at all angles - Reconstruc3on by back projec3on (ltered back projec3on) - Contrast is inuenced by 3ssue density

Goldman 2007

PET-CT and MRI of Head and Neck Cancer

(A) coronal fused PET/CT image of the tumor mass without FDG uptake within the marrow cavity of the mandible. (B) The corresponding non-contrast- enhanced CT image (B) demonstrated the presence of cor3cal bone erosion only. (C) Coronal T2-weighted MRI (D) Contrast-enhanced T1W-MRI

Hafez et al., Oral Oncology 2011

PET/CT imaging of Therapeu<c Response

18F-30deoxy-30-uorothymidine (FLT), which can measure tumor cell prolifera<on noninvasively. FLT is retained inside the cell by thymidine kinase 1 and is considered a marker of the S-phase.

PET imaging of Androgen Signaling

Androgens repress PSMA expression in mul3ple prostate cancer models, whereas an3-androgens upregulate expression
Evans, Cancer Discovery 2012

Nanotechnology and Cancer

Molecular Basis for Nanotherapeu<cs

Normal Normal Tumor

Tumor

Enhanced permeability and reten<on (EPR)

Tumor vessels are usually hyperpermeable to macromolecular plasma solutes (widened EJs, fenestrae, transendothelial channels, discon3nuous basement membrane) and lack lympha3cs.
Rao, ACS Nano 2008

Nanocarriers for Cancer Imaging and Therapy

Peer, Nat Nano 2008; ConZ, Invivo 2006

Rao, ACS Nano 2008

Nanopar<cle-mediated drug delivery

PSMA-targeted Docetaxel nanopar<cle

Hrkach et al, Science Transl Med 2012

Op<cal imaging-guided surgery

Folate receptor targe<ng in ovarian cancer

Van Dam et al., 2011

The Future of Cancer Imaging

Cancer Imaging

CT -- ? X-ray -- ? PET --? MRI --? US--? Op3cal Imaging?

Photodynamic Therapy

Photodynamic Therapy (PDT)

Food and Drug Administra3on (FDA) approved treatment for a variety of oncologic and non-oncologic condi3ons originally developed at Roswell Park (Dougherty, 1974). Involves photoac3va3on of a 3ssue-localized drug by light of a specic wavelength.

History of PDT
- Oscar Raab (1900) medical student in Munich
Certain wavelengths of light were lethal to paramecia that were exposed to acridine orange.

- Professor Hermann Von Tappeiner

photodynamic ac3on Used eosin for treatment of skin lesions

Tappeiner and Jesionek, 1903

Before A[er
hgp://www.magicray.ru/ENG/lecture/L2/2.html

hgp://www.photobiology.info/HistPhotosens.html

History of PDT
- Lipson and colleagues (1960s)
Tumor-localizing agent was not Hp Synthesis of Hp-deriva3ve (HpD)

- T.J. Dougherty (1974)@Roswell

Photodestruc3on of cells in vitro by uorescein Ac3ve frac3ons of HpD

Bualo Physician, Autumn 2004

PDT Basic principles

Administra3on of a drug (sensi3zer) Localized ac3va3on (excita3on) of the sensi3zer in 3ssue by light of a specic wavelength Genera3on of highly reac3ve free radicals Oxidiza3on of biological substrates causing cytotoxic eects within the illuminated 3ssue.
Adapted from Lasers in Surgery and Medicine, 2006

Photodynamic Triad
Photophysics
Light
Wavelength Light sources Fluence/Fluence rate

Sensi<zer
AdministraZon Tissue concentraZon LocalizaZon

Oxygena<on
Tissue distribuZon Vascular perfusion Rate of diusion

Photochemistry

Photobiology

Photophysics
Laser source is used to deliver monochroma3c light through op3cal bers Wavelength of ac3va3on generally corresponds to the absorbance maxima of the sensi3zer used Longer wavelengths are preferred due to their ability to penetrate deeper into the 3ssues
Tang et al, 2004

Light Delivery
Spherical Inters<<al

Cylindrical

Lens ber

Choice of light diusing 3p depends on the size and type of 3ssue to be illuminated
hgp://www.biospec.ru/

Biophysical basis of PDT

A simplied Jablonski diagram

The biological eects of PDT are a consequence of a dynamic interac3on between the photosensi3zer, 3ssue/ molecular oxygen and light

PDT Dosimetry - terminology

Dened by the uence and uence rate Fluence: Total amount of light dose delivered (J/cm2). Fluence rate: Rate at which the light dose is delivered (mW/cm2). The photochemical process associated with singlet oxygen genera3on is also oxygen-consuming. Biological response to PDT is cri3cally dependent on the regimen employed

Photochemistry - Sensi<zers
Guidelines for ideal photosensi<zers - Toxicity - Ac3va3on - High singlet oxygen yield - Ease of administra3on - Elimina3on - Cost-eec3ve

Allison et al, 2004

Photochemistry - Sensi<zers

AgosZnis et al., 2011

Photosensi<zers
Porphyrins - Useful sensi3zers, high singlet oxygen yield, absorp3on in the visible spectrum
Photofrin - combina3on of monomers, dimers & oligomers derived from chemical manipula3on of Hp, 630 nm absorp3on

Allison et al, 2004

Photofrin
1st photosensi3zer to be approved by the FDA Approved indica3ons in endobronchial and lung cancers, BarreUs esophagus Limita<on: Prolonged cutaneous sensi3vity

Photochlor
Photosensi<zer: HPPH
2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) (665 nm)
Chlorin-based sensi3zer - Pandey et al., (1991) Signicantly decreased photosensi3vity than Photofrin in pa3ents Currently undergoing clinical evalua3on in head and neck and lung cancers

Biological response to PDT

Complex; Combina3on of direct cytotoxicity, vascular damage and the induc3on of immune/inammatory responses. Dependent on several parameters: - Sensi3zer used, injected dose, PK-PD. - Tissue oxygena3on - Light treatment condi3ons
Unlike (ssue factors such as vascularity or oxygena(on, light treatment condi(ons are under the direct control of the clinician or the experimenter.

Biological response to PDT

Castano et al, Nature Reviews Cancer 2006

Vascular response to PDT

Increased vascular permeability Hemorrhaging Loss of perfusion (shutdown) Depending on sensi(zer and treatment condi(ons
Chen et al, 2006

Immune/inammatory response to PDT

Prostaglandins Cytokines Chemokines Inammatory cell inltra3on (neutrophils and macrophages)

Castano et al, Nature Reviews Cancer 2006

Clinical-PDT in Oncology
Emerging as a viable clinical treatment for nearly every histological type/site. * Head and neck cancers (Biel et al.,1998)
* Skin cancers (Osero et al.,2005). * Intra-abdominal sarcomas (Hahn et al., 2006).

O-label use Brain, bladder, head and neck, prostate, breast.

Brown et al, 2004

Advantages
Equivalent or greater ecacy compared to standard therapies Reduced morbidity/disgurement Can be repeated for large bulky tumors inters33al PDT Use of PDT is not precluded by prior/subsequent surgery or chemotherapy Excellent cosme3c outcome skin lesions, HNC PDT as an adjunct could eliminate residual disease

Clinical PDT

hgp://www.roswellpark.org/PaZent_Care/What_Is_a_Clinical_Trial/ClinicalTrialsOnlineSearch

Lung cancer
Endobronchial Lung Cancer Advanced disease, pallia3ve intent (airway obstruc3on)

Loewen et al, Lasers in Surgery and Medicine 2006

Clinical PDT for Early Stage Lung Cancer

Before A[er

Slides courtesy of Adam Sumlin

Loewen, Dougherty

Oral Cancer
Pretreatment 1 week post

Pretreatment

3 weeks post
Slides courtesy of Nestor Rigual, MD

Photofrin-PDT (75 J@150 mW)

Limita<ons of PDT?? How can we make it beIer?

Limita<ons of PDT
X The FDA-approved sensi3zer Photofrin is associated with prolonged and some3mes severe cutaneous sensi3vity in pa3ents las3ng for 1-2 months. X Improve therapeu3c ecacy X Develop methods for detec3on/monitoring ecacy or ac3vity

Cutaneous phototoxicity

Bellnier et al., 2006

Clinical PDT Skin phototoxicity (HPPH)

Study 45 pa3ents 3,4,5 or 6 mg/m2 HPPH Up to 133 J/cm2 solar- spectrum light (SSL) on 3 consecu3ve days aOer HPPH Results 18% had no reac(on to SSL 16% had strongest reac3on obtained in the study- erythema w/o edema or blistering Response appears to be related to HPPH-dose
Bellnier et al., 2006

Clinical PDT Skin phototoxicity (HPPH)

Conclusions 90% of the subjects exposed to SSL 3 days aOer Photochlor infusion had responses that were less severe than those obtained with either the 1- or 2-day sensi3zer-SSL interval. Photochlor, at clinically eec3ve an3tumor doses, causes only mild skin photosensi3vity that declines rapidly over a few days.

Bellnier et al., 2006

Combina<on strategies with PDT

Well-designed adjuvant or combina3on therapies can result in maintaining or increasing the potency of the an3tumor eect while abroga3ng toxicity. Previous work:

* PDT + Hyperthermia (Henderson et al., 1985). * PDT + Chemotherapy (Can( et al., 1998). * PDT + Surgery (Delaney et al., 1993). * PDT + Radia3on (Imamura et al.,1994) * PDT + MMPs (Ferrario et al., 2002) * PDT + Doxorubicin (Snyder et al.,2003)

Combina<on strategies with PDT

AgosZnis et al., 2011

Imaging-guided inters<<al PDT

Jerges et al.,2008

MRI-guided inters<<al PDT

Jerges et al.,2008

CT-guided inters<<al PDT

Imaging-guided inters<<al PDT

Vogl et al, 2004

Imaging-guided inters<<al PDT

Vogl et al, 2004

Conclusions/Take home message

Understand basic principles Basic components: Photo-physics/chemistry Biological response Clinical indica3ons/applica3ons

PDT is a mul3disciplinary endeavor (scien3sts, physicists, surgeons, radiologists, nurses)

Vogl et al, 2004