Cancer Concepts and Principles: Primer for the Interventional Oncologist—Part I

REVIEW ARTICLE

Cancer Concepts and Principles: Primer for the

Interventional Oncologist—Part II

Ryan Hickey, MD, Michael Vouche, MD, Daniel Y. Sze, MD,Elias Hohlastos, MD, Jeremy Collins, MD, Todd Schirmang, MD,

Khairuddin Memon, MD, Robert K. Ryu, MD, Kent Sato, MD,Richard Chen, DO, Ramona Gupta, MD, Scott Resnick, MD, James Carr, MD,

Howard B. Chrisman, MD, Albert A. Nemcek, Jr, MD,Robert L. Vogelzang, MD, Robert J. Lewandowski, MD, and

Riad Salem, MD, MBA

ABSTRACT

This is the second of a two-part overview of the fundamentals of oncology for interventional radiologists. The first part focusedon clinical trials, basic statistics, assessment of response, and overall concepts in oncology. This second part aims to review themethods of tumor characterization; principles of the oncology specialties, including medical, surgical, radiation, andinterventional oncology; and current treatment paradigms for the most common cancers encountered in interventionaloncology, along with the levels of evidence that guide these treatments.

ABBREVIATIONS

AFP = α-fetoprotein, AJCC = American Joint Committee on Cancer, BCLC = Barcelona Clinic Liver Cancer, CapeOx = capecitabine/

oxaliplatin, CRC = colorectal cancer, DEB = drug-eluting bead, DEBIRI = drug-eluting beads with irinotecan, EASL = European

Association for Study of the Liver, EGFR = epidermal growth factor receptor, 5-FU = 5-fluorouracil, FOLFIRI = irinotecan/5-

fluorouracil/leucovorin, FOLFOX = oxaliplatin/5-fluorouracil/leucovorin, HCC = hepatocellular carcinoma, IRE = irreversible

electroporation, NCCN = National Comprehensive Cancer Network, NCI = National Cancer Institute, NET = neuroendocrine

tumor, NSCLC = non–small-cell lung cancer, PV = portal vein, RF = radiofrequency, RT = radiation therapy, VEGFR = vascular

endothelial growth factor receptor

& SIR, 2013

J Vasc Interv Radiol 2013; 24:1167–1188

http://dx.doi.org/10.1016/j.jvir.2013.04.023

R.S. is supported in part by National Institutes of Health Grant CA126809. D.Y.S.serves on the scientific advisory boards of Jennerex Biotherapeutics(San Francisco, California), Surefire Medical (Westminster, Colorado), TreusMedical (Redwood City, California), Radguard (Los Altos, California), and LunarDesign (San Francisco, California); is a member of the speaker’s bureau of WLGore and Associates (Flagstaff, Arizona); and is a paid consultant for BTG(West Conshohocken, Pennsylvania) and Sirtex (North Sydney, Australia).R.J.L. serves on the scientific advisory boards of Surefire and Nordion(Ottawa, Ontario, Canada). R.S. serves on the scientific advisory board andis a paid consultant for Bristol-Myers Squibb (New York, New York), Abbott(Santa Clara, California), Bayer/Onyx (Leverkusen, Germany), National Com-prehensive Cancer Network, Merit Medical (South Jordan, Utah), BTG,Nordion, Sirtex, and Boston Scientific (Natick, Massachusetts). None of theother authors have identified a conflict of interest.

From the Department of Radiology and Division of Interventional Oncology(R.H., M.V., E.H., J.C., T.S., K.M., R.K.R., K.S., R.C., R.G., S.R., J.C., H.B.C.,A.A.N., R.L.V., R.J.L., R.S.), Northwestern University, 676 N. St. Clair St., Suite800, Chicago, IL 60611; and Department of Radiology (D.Y.S.), StanfordUniversity, Palo Alto, California. Received April 1, 2013; final revision receivedand accepted April 20, 2013. Address correspondence to R.S.; E-mail:[email protected]

This is the second of two parts of a review of theprinciples of oncology for interventional radiologists. Itintends to build upon the fundamentals of clinical trialdesign, statistics, and response assessment discussed inthe first part in order to provide a framework forunderstanding the methods of the different oncologyspecialties, the current treatment paradigms of cancersmost frequently treated in interventional oncology, andan overview of the current levels of evidence that guidethese interventional oncologic treatments.

TUMOR CHARACTERIZATION AND

MANAGEMENT

StagingTumor staging reflects the extent of disease, determinestreatment and therapeutic options, and has specificprognostic implications. Clinical staging refers to non-invasive staging, including physical examination and

dx.doi.org/10.1016/j.jvir.2013.04.023

dx.doi.org/10.1016/j.jvir.2013.04.023

dx.doi.org/10.1016/j.jvir.2013.04.023

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Hickey et al ’ JVIR1168 ’ Cancer Concepts and Principles: An IR Primer, Part II

imaging evaluation, whereas pathologic staging refers tofindings from tissue specimens and allows for the identi-fication of the microscopic extent of disease that may besubclinical, or not apparent, on physical examination orimaging. For this reason, patient populations with clin-ically and pathologically staged disease are not necessarilyidentical and comparable in terms of outcomes.Staging systems vary with tumor types. The Interna-

tional Union Against Cancer (Union InternationaleContre le Cancer) and the American Joint Committeeon Cancer (AJCC) systems were unified into a singlesystem, which is one of the most common stagingsystems used, and characterizes cancers according tothe TNM (tumor, node, metastasis) classification. Can-cers are then divided into stages 0 through IV to guidetreatment and prognosis (1). Additional staging systemsexist, such as for hepatocellular carcinoma (HCC), thatwill be addressed further in this review.

Systemic and Tissue-specific Tumor

MarkersTumor markers generally refer to a variety of substan-ces, including gene mutations, proteins, and metabolites,which can be measured in tumor tissues, blood, or otherbody fluids. Tumor markers can be produced by cancer-ous and normal cells. Certain tumor markers are specificto a type or histology of cancer, whereas others may beincreased in several different cancers. The markers mayplay a role in cancer detection, diagnosis, staging,prognosis, and response assessment. The National Can-cer Institute (NCI) provides a concise summary of themost common tumor markers used in oncology, fromwhich Table 1 is derived (2). Interventional oncologistsshould be well versed with these tumor markers, as theyplay an integral role in cancer management.

METHODS OF TREATMENT: MEDICAL,

SURGICAL, RADIATION, AND

INTERVENTIONAL ONCOLOGY

The anticancer armamentarium includes chemothera-peutic agents, biologic therapies that target specificmolecules in the cell-signaling pathways, radiation, andsurgical and interventional oncology. Although mostcancer treatments use a combination of many, if notall, of these modalities, the timing of administration ofthese treatments can result in synergistic, detrimental, ortoxic clinical outcomes.The Physician Data Query of the NCI and the National

Comprehensive Cancer Network (NCCN) guidelinesprovide up-to-date information on standard treatmentregimens for various cancers of various stages, in additionto references to experimental protocols and clinical trialsas alternatives to standard regimens (3,4).Toxicity is the critical, potentially fatal, limiting factor

of any cancer treatment, including chemotherapy and

radiation. Therapeutic regimens are designed with tox-icity in mind to avoid overlapping or synergistic tox-icities. Consistently evaluating and addressing treatmenttoxicities is inherent to the practice of oncology, andtoxicities should be recognizable to all practitionersinvolved in the care of patients with cancer. The NCI’sCommon Terminology Criteria for Adverse Eventsprovide a standardized classification of toxicities andside effects related to chemotherapy (5). Toxicities aregraded according to severity, whereby grade 1 is mild,grade 2 is moderate, grade 3 is severe, grade 4 is life-threatening, and grade 5 is fatal. In general, onlytoxicities of grade 3 or greater are reported, as grades1 and 2 toxicities related to treatment are consideredclinically acceptable. This lexicon should be used whendescribing toxicities related to any oncologic treatmentor intervention. In addition, there is often a 30-daycutoff point after treatment, after which many adverseevents are not deemed to be treatment-related.

Medical Oncology: ChemotherapyChemotherapy is most frequently delivered as a regimenof multiple chemotherapeutic agents delivered to max-imize tumor cell kill while minimizing toxicity. Thesynergistic effects of multiple agents increase the inter-action between chemotherapy and tumor cells, andreduce the likelihood of tumor cells developing drugresistance. Because bone marrow cells are often the mostsensitive to chemotherapy, standard treatment regimenshave traditionally been designed with regard to bonemarrow recovery to prevent myelosuppression (6).Although chemotherapeutic agents are often adminis-

tered with the intent to cause tumor cell death orcytotoxicity, a number of chemotherapy regimens, par-ticularly those incorporating the molecular-targetedtherapies discussed subsequently in more detail, provideclinical value in terms of cytostasis rather than cytot-oxicity. Effective cytostasis manifests itself as the inhib-ition of tumor cell growth or prevention of meta-stases—namely stable disease—as opposed to tumorshrinkage (7).Classes of chemotherapeutic agents include alkylating

agents, platinum analogues, antimetabolites, topoisomerase-interacting agents, and antimicrotubule agents. Table 2 liststhe most commonly encountered chemotherapeutic agentsin interventional oncology.Chemotherapy use generally occurs in one of four

clinical settings. In primary induction, chemotherapy isadministered as the initial treatment for advancedcancers for which no alternative treatment, such assurgical resection, exists. Neoadjuvant chemotherapyrefers to chemotherapy administered before surgicalresection to reduce the size of the primary tumor orminimize the extent of disease to increase the likelihoodof an R0 resection, which indicates surgical margins freeof tumor. Neoadjuvant chemotherapy can also reduce the

Table 1 . Common Tumor Markers, Source, and Clinical Applications

Marker Cancer Source Clinical Use

ALK gene rearrangement NSCLC, anaplastic large-cell lymphoma Tumor tissue Treatment planning, prognosis

α-Fetoprotein Primary liver cancer, germ cell tumors Blood Response assessment (liver); staging, prognosis,

response assessment (germ cell)

β-Human chorionic

gonadotropin

Choriocarcinoma, ovarian, testicular, gastric, liver, lung Blood Staging, prognosis, response assessment

(choriocarcinoma, testicular cancer)

Cancer antigen 19-9 Cholangiocarcinoma, gallbladder carcinoma, gastric,

pancreatic, adenocarcinoma

Blood Response assessment

Cancer antigen 125 Ovarian cancer Blood Response assessment, monitor for recurrent disease

Carcinoembryonic

antigen

Colorectal, breast, additional adenocarcinomas Blood Prognosis (colorectal), response assessment, monitor for

recurrent disease

Chromogranin A Neuroendocrine tumors, SCLC, prostate Blood Diagnosis, response assessment, monitor for recurrent

disease

c-KIT mutation Gastrointestinal stromal tumors Tumor tissue Treatment planning with molecular-targeted therapy

ERCC1 Gastric, ovarian, NSCLC Tumor tissue Associated with resistance to cisplatin (gastric, ovarian),

treatment planning with docetaxel, cisplatin (NSCLC)

EGFR mutation NSCLC Tumor tissue Treatment planning with molecular-targeted therapy,

prognosis

HER2/neu Breast, gastric, esophageal, ovarian Tumor tissue Treatment with trastuzumab

KRAS Colon, lung, pancreatic Tumor tissue Treatment planning with molecular-targeted therapy

(mutation associated with poor response to cetuximab

and panitumumab, colon) (3,4)

Ki-67 Breast, pancreatic, neuroendocrine tumors Tumor tissue Prognosis

Prostate-specific antigen Prostate Blood Diagnosis, response assessment, monitor for recurrent

disease

EGFR = epidermal growth factor receptor, NSCLC = non–small-cell lung cancer, SCLC = small-cell lung cancer.

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Table 2 . Common Chemotherapeutic Agents Encountered in Interventional Oncology

Class/Agent(s) Mechanism of Action

Antimetabolite

5-FU Inhibits TS, enzyme that provides the only de novo source

of thymidine for DNA synthesis (10);

leucovorin increases 5-FU toxicity by

optimizing 5-FU metabolite binding to TS

Capecitabine Oral prodrug converted to 5-FU by thymidine

phosphorylase, which is found in higher

concentrations in tumor vs

normal tissue (11)

Gemcitabine Metabolites interfere with DNA polymerase and

are incorporated into DNA strands,

resulting in early strand termination (12)

Platinum-based

Cisplatin, carboplatin, oxaliplatin DNA damage caused by various DNA–DNA and

DNA–protein crosslinks, which inhibit

DNA replication and transcription, cause strand

breaks, and lead to apoptosis (13);

in FOLFOX regimen, oxaliplatin increases

toxicity of 5-FU by inhibiting its intracellular breakdown (14)

Taxane

Paclitaxel, docetaxel Disrupts cell mitosis and progression through

cell cycle by interfering with centrosomes, spindles,

and microtubules required for chromosomal

organization and rearrangement during cell division (15)

Topoisomerase inhibitor

Irinotecan Targets DNA topoisomerase I, which is essential

to reducing natural DNA twisting that occurs during

DNA transcription and replication; causes double-strand

DNA breaks and arrest of DNA replication (16);

FOLFIRI regimen is 5-FU/ folinic acid (leucovorin)/irinotecan

Doxorubicin, epirubicin Targets topoisomerase II, increasing

double-strand DNA breaks, insertions,

deletions, and aberrant recombinations (17)

Antibiotic

Mitomycin C Derived from Streptomyces bacterium;

biologically active in anaerobic conditions

resulting in alkylation and cross-linking of DNA

that inhibits DNA synthesis (18)

5-FU ¼ 5-fluorouracil, FOLFIRI = irinotecan/5-fluorouracil/leucovorin, FOLFOX ¼ 5-fluorouracil/folinic acid (leucovorin)/oxaliplatin, TS

¼ thymidylate synthase.


extent of disease to spare critical organs or tissues thatwould otherwise be included in the surgical resection. Incertain instances, successful neoadjuvant chemotherapycan obviate resection, making the cancer amenable insteadto radiation therapy (RT). Response to neoadjuvanttherapy is an important indicator of tumor sensitivity tothe chemotherapeutic agents and can help guide their usefor postsurgical adjuvant therapy. Adjuvant chemotherapyrefers to chemotherapy used in conjunction with localtreatment, such as surgical resection and RT. Adjuvantchemotherapy addresses micrometastases to reduce therisk of local or distant recurrence. Locoregional chemo-therapy is directly administered to an affected organ or

site, increasing the tumor–to–systemic chemotherapy ratio,such as in chemoembolization of liver tumors or intra-peritoneal chemotherapy for peritoneal carcinomatosis (6).Although not specific to chemotherapy, first-line

therapy refers to the first set of chemotherapeutic,surgical, or radiation treatments provided that is gen-erally accepted as the standard and “best” treatment. Ifthis therapy does not result in a cure, or cannot betolerated because of severe side effects, other treatments,referred to as second-line therapy, may be used instead.Salvage therapy refers to treatment provided aftera failure to respond to other treatments (8). It shouldbe noted that, despite being a commonly used term,

Volume 24 ’ Number 8 ’ August ’ 2013 1171

the definition of a “line” of chemotherapy is nebulous.Chemotherapy regimens for patients may be modified oradjusted in real time. In such cases, this does notnecessarily represent a different line of therapy. As anexample, in colon cancer, chemotherapies received by aspecific patient should be described as exposure to thecytotoxic active agents (eg, 5-fluorouracil [5-FU], oxali-platin, irinotecan) and the biologic agents (as detailedlater).

Medical Oncology: Molecular-targeted

TherapiesMolecular-targeted therapies are designed to interactwith specific molecules in cell signal transduction path-ways to interfere with tumor cell growth or proliferation.Molecular subtyping of cancers has therefore becomeincreasingly important in the era of molecular-targetedtherapies to ensure the cancer has a phenotype that willrespond to the molecular agent. Common molecularsubtyping includes evaluation for the presence of epi-dermal growth factor receptor (EGFR) mutations innon–small-cell lung cancer (NSCLC), KRAS mutationsin colorectal cancer (CRC), and HER2/neu amplifica-tion in breast cancer (9–11). As shown in Table 1, almostall biomarkers used for molecular-targeted therapiesnecessitate tumor samples, often obtained by interven-tional radiologists.EGFRs may be abnormally activated or expressed in

several carcinomas, and the binding of small molecules(ie, ligands) to these receptors initiates a number ofsignaling pathways via tyrosine kinase activation, whichcan ultimately affect cell proliferation, survival, andinvasion (12). Cetuximab is a monoclonal antibodythat binds to a specific domain of the EGFR and hasshown important antitumor activity and clinicalresponses in patients with chemotherapy-refractory or-resistant CRCs (13–17). However, the presence of agenetically mutated KRAS protein, which is a down-stream signaling protein in the EGFR signaling cascade,causes a decreased or absent response to cetuximab,resulting in a worse prognosis compared with patientswith the wild-type KRAS protein (16,18,19).Panitumumab is another monoclonal antibody that

binds to the EGFR to prevent cell signaling, therebyinhibiting proliferation and promoting tumor cell apop-tosis (20). It has shown significant clinical response whenused in patients with chemotherapy-resistant metastaticCRC, or as an addition to first-line treatments ofmetastatic CRC (21,22). The response to panitumumabis also affected by KRAS mutations (23). Therefore,patients with mutant KRAS protein in the setting ofCRC are frequently not candidates for cetuximab orpanitumumab therapies.Physiologic angiogenesis generally only occurs during

embryogenesis, wound healing, and placental development(24). Tumor angiogenesis, required for tumor growth, has

generally lost the physiologic balance between positive andnegative angiogenic controls, resulting in neovasculaturethat is morphologically different from that of normaltissues. Tumor vasculature is leaky, which further affectstumor growth, metastasis, and drug delivery (25).Bevacizumab is a monoclonal antibody that targets

tumor angiogenesis. It binds to one of the vascularendothelial growth factor receptor (VEGFR) ligands,limiting ligand interaction with and activation of thereceptor and ultimately causing regression of tumormicrovessels and inhibiting the formation of new tumorvasculature (26). The addition of bevacizumab to standardfirst- and second-line chemotherapy regimens for meta-static CRC has shown significant improvements in diseaseprogression and overall survival (27–30), and its additionto standard first-line therapy has shown survival benefitsfor patients with stage IIIB and IV NSCLC (31).Aflibercept is another antiangiogenic molecule that

binds to multiple VEGFR ligands (32). The addition toaflibercept to standard second-line chemotherapy regi-mens containing irinotecan for metastatic CRC hasshown significant increases in progression-free and over-all survival (33).Sunitinib is an inhibitor of multiple tyrosine kinases,

including those of the VEGFRs and platelet-derivedgrowth factor receptors. Its use in advanced pancreaticneuroendocrine tumors (NETs) has shown significantincreases in clinical response and overall survival comparedwith placebo (34). Sunitinib has shown favorable outcomesin the treatment of metastatic renal-cell cancer comparedwith standard cytokine therapy, resulting in significantlyprolonged median progression-free survival and a strongtrend toward improved overall survival (35,36).The mammalian receptor of rapamycin is a serine-

threonine kinase that plays an important role in auto-crine stimulation of cell growth, proliferation, andangiogenesis. Everolimus inhibits mammalian receptorof rapamycin and has shown significant improvements inprogression-free survival for patients with progressiveadvanced pancreatic NETs (37).Octreotide is a synthetic analogue of the native

peptide hormone somatostatin. The native hormoneinhibits a number of physiologic functions throughoutthe gastrointestinal tract. Octreotide binds to varioussomatostatin receptors and has been shown to havesignificant antiproliferative effects in NETs (38).Sorafenib is also a multiple kinase inhibitor that causes

inhibition of tumor-cell proliferation and angiogenesis, aswell as increases the rate of apoptosis. Sorafenib hasshown survival benefits for patients with advanced renal-cell carcinoma in whom first-line therapy has failed (39).Its use in advanced HCC has resulted in significantincreases in overall survival and is now the onlystandard systemic therapy for advanced HCC (40,41).Regorafenib is a multiple kinase inhibitor that has

demonstrated significant survival benefits for patientswith gastrointestinal stromal tumors and metastatic


CRC. For patients with metastatic or unresectable gas-trointestinal stromal tumors in whom standard treatmentwith imatinib or sunitinib has failed, regorafenib hasbeen shown to increase progression-free survival com-pared with placebo (42). Regorafenib has also demonst-rated an increased median survival compared withplacebo for patients with metastatic CRC that hasprogressed despite all standard therapies (43).

Figure. Couinaud segmental anatomy of the liver. Segments

are divided by the hepatic veins and lobar branches of the portal

vein. (Available in color online at www.jvir.org.)

Surgical OncologySurgery has several roles in the diagnosis and treatmentof cancer, including tissue diagnosis, definitive surgicaltreatment for a primary cancer, tumor debulking, resec-tion of metastatic disease with curative intent, treatmentof oncologic emergencies, palliation, and reconstruction.The decision for surgical intervention is not only drivenby technical feasibility (ie, resectability), but also by thepatient’s physical condition and ability to undergosurgery (ie, operability). For instance, suboptimal per-formance status or severe coronary heart disease couldpreclude major surgery; interventional oncology proce-dures play a key role in such cases. Hence, nonoper-ability represents a frequent pathway that leads tointerventional oncology therapies.Curative surgery intends to remove a tumor in its

entirety, including an adequate margin of uninvolvedtissue to eliminate the chance of residual, microinvasivetumor. The definition of adequate margins of tissuevaries from cancer to cancer and is defined by thefindings of clinical trials. An R0 resection indicates thecomplete removal of a tumor and tumor-free margins atsurgical pathologic examination. An R1 resection indi-cates the presence of tumor cells (microscopic) at themargins at surgical pathologic examination. An R2resection indicates that visible (macroscopic) tumor hasremained at the time of surgical resection (44).Resection of a single or few metastases can often be

curative, particularly for metastases of solid tumors tothe liver or lungs. Resection of solitary pulmonarymetastases in certain sarcomas and adenocarcinomascan provide long-term survival rates approaching 30%–

70% depending on the cancer of origin (45,46). Resec-tion of hepatic metastases of CRC in patients withoutadditional extrahepatic metastases can provide 5-yearsurvival rates approaching 60% depending on the extentof liver involvement (47,48). Preoperative scoring beforeresection of hepatic colorectal metastases has beenshown to be highly predictive of outcome. Poor long-term outcome was associated with a node-positive pri-mary lesion, a disease-free interval from primary diseaseto metastasis of less than 12 months, more than onehepatic metastasis, largest hepatic lesion exceeding 5 cmin size, and a carcinoembryonic antigen level greaterthan 200 ng/mL (47).For certain cancers, tumor debulking, or cytoreduc-

tive surgery, which refers to the removal of as much of

the primary or metastatic disease as possible knowingthat viable tumor is left behind, may prolong survival orat least offer significant symptom palliation. Resectionof functional neuroendocrine metastases in the liver, forexample, will not be curative but may prolong survivaland improve quality of life by reducing the biochemicaland hormonal effects of the functional NET cells.Cytoreductive surgery has become standard of care inthe treatment of certain advanced ovarian and uterinecancers. Cytoreductive surgery for advanced ovariancancer, in which successful therapy is defined as removalof all disease greater than 1 cm in size, results in sig-nificant prolongation of progression-free and overallsurvival (49), whereas cytoreductive surgery to eradi-cate gross residual disease in advanced and recurrentendometrial cancer is associated with prolonged overallsurvival (50).Surgical oncologic treatment for cancer prevention

includes prophylactic surgery for the removal of organsbefore evident disease in circumstances of very high risk,such as total proctocolectomy for patients with polyposissyndromes or longstanding ulcerative colitis to preventcolon carcinoma, total thyroidectomy in certain multipleendocrine neoplasia syndromes, and bilateral mastec-tomy and oophorectomy in the setting of BRCA1 andBRCA2 mutations. Palliative surgery in the patient withcancer includes surgery to address intractable pain,bleeding, bowel obstruction, or infection (8).Knowledge of the Couinaud segmental anatomy of

the liver is critical for an understanding of oncologichepatic resections (Fig). The eight hepatic segments havetheir own hepatic arterial, portal venous, and biliarysupplies, with segmental venous drainage to the hepatic

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veins. In a gross specimen, a line along the gallblad-der fossa and inferior vena cava separates the righthepatic and left hepatic lobes, and the falciform ligamentdivides the medial and lateral segments. Anatomi-cally and on imaging, segments are demarcated by theright, middle, and left hepatic veins and the portal vein(PV). The middle hepatic vein separates the right lobefrom the left lobe. Hepatic lobectomies and segmen-tectomies are performed along these divisions and aredefined according to the International Hepato-Pancreato-Biliary Association Brisbane 2000 Terminol-ogy. A right hepatectomy removes segments 5–8 whereasa left hepatectomy removes segments 2–4. A righttrisegmentectomy removes the right lobe plus the medialleft hepatic lobe (segment 4), whereas a left trisegmen-tectomy removes the left hepatic lobe plus the anteriorsector of the right hepatic lobe (segments 5/8). A leftlateral segmentectomy removes the lateral segments ofthe left hepatic lobe (segments 2/3). Wedge resectionrefers to a nonanatomic resection of disease with theextent of resection focused on clean surgical margins (51).Adjunctive modalities to achieve oncologic hepatic

resections include intraoperative ultrasound (US) to helpin the detection of metastases and guide anatomic re-sections, intraoperative radiofrequency (RF) ablation orcryoablation—open or laparoscopic—particularly fordisease that is not amenable to percutaneous therapy,and intraoperative RT for tumors that can be onlypartially resected (52).

Radiation OncologyRadiation oncology relies on the ability of radiation-induced DNA damage to cause cell death. The inter-actions between photons or particle radiation andcellular compounds or water generate ionized moleculesand free radicals that impart damage onto chromosomalDNA, including DNA strand breakage and the forma-tion of abnormal DNA and molecular crosslinks. Themost effective damage to bring about cell death comesfrom double-strand breaks of DNA (53). Cell death mayoccur within few cell divisions or be delayed as a res-ponse to signaling factors released subsequent to radia-tion exposure and damage (54).Cellular oxygen exposure is an important mediator of

radiation-induced cell death, as lower oxygen levels canreduce the lethality of radiation exposure. A higherfraction of cells have been shown to survive radiationexposure in a hypoxic environment compared with anaerobic environment (55). The oxygen enhancement ra-tio is a ratio of the dose required to produce the sametherapeutic effect in hypoxic cells compared with cells ata normal oxygen tension. An oxygen enhancement ratioof 2.5–3 for high-dose radiation indicates that hypoxiccells can require as much as three times the radiationdose as oxygenated cells to bring about the same cellkill (56).

The number of tumor cells killed by ionizing radiationis a function of the radiation dose. The dose required forlocal control, referred to as the tumor control proba-bility, is proportional to the logarithm of the totalnumber of tumor cells. Carcinomas may require 60–80 Gy of radiation, divided into multiple fractionations,whereas more radiation-sensitive cancers, such as lym-phoma, may require a dose of 20–40 Gy (57,58).The effectiveness of an administered radiation dose

depends on the fraction of the dose given at eachtreatment and the duration during which the course ofradiation is delivered. The total radiation dose to beadministered is divided into fractionations, which aredelivered over several treatment sessions. Fractionationdoses are typically in the range of 1.8–2.0 Gy/d for 5days per week (58). Because the repair mechanisms oftumor cells are less effective than the repair mechanismsof normal cells, fractionation relies on the ability ofnormal cells to recover from radiation-induced cellulardamage more quickly and more effectively than tumorcells. Fractionation schemes can be altered depending onthe tumor type and curative or palliative goals oftherapy, such as with accelerated fractionation, hyper-fractionation, or hypofractionation (59). In acceleratedfractionation, the duration of time over which the courseof radiation is delivered is reduced to minimize theopportunity for tumor cell regeneration. In a hyper-fractionation scheme, the dose given at each fraction islower, but the total number of dose fractions is increasedto provide a higher total dose and increase the likelihoodof tumor cells being in a radiation-sensitive phase(58,59).The effects of RT on tumor cells must be carefully

balanced against its effects on uninvolved tissues. Nor-mal tissue responses to radiation exposure can be dividedinto the early effects, which occur within days to weeksof exposure, and late effects, which occur months toyears after the radiation treatment (60). Certain organsmay be more susceptible to acute toxicities and arereferred to as early-responding tissues (61). Late-res-ponding tissues may not manifest toxicities until wellafter the radiation exposure. Radiation effects on tissueare determined by the total radiation dose delivered, themagnitude of the fractionated doses, the duration of thecourse of RT, the time interval between fractionations,and the radiation sensitivity of the tissue exposed(58,62).Radiation sensitization from chemotherapy is an

important concept for patients receiving chemotherapyand RT concomitantly or within short intervals of eachother. Several chemotherapeutic agents, particularly theantimetabolites 5-FU and gemcitabine, platinum agentssuch as cisplatin, and taxanes such as paclitaxel anddocetaxel, augment the effects of chemotherapy andradiation compared with either therapy administeredalone (63–65). The synergistic effects of radiation andradiation-sensitizing chemotherapies have led to their


implementation as standard-of-care treatments for cer-tain head and neck, lung, and gastrointestinal cancers.However, radiation sensitization also increases the riskof chemotherapy- or radiation-associated toxicities.Amifostine may be administered in such circumstancesfor its radiation-protective effects through free radicalscavenging, DNA protection, and acceleration of DNArepair. Its protective effects on nonmalignant as opposedto tumor cells is believed to result from differences in thecells’ pH environment and differential expression of anactivating enzyme (66).In general, external-beam radiation offers the advant-

age of being noninvasive. It is of particular interest invery large, unresectable tumors, or in patients withnonoperable disease as an alternative to best supportivecare. Advances in radiation oncology delivery technolo-gies have allowed external-beam doses to be modifiedaccording to the distribution of viable tumor. Informa-tion on the distribution of tumor metabolic activity, asprovided by positron emission tomography imaging, canmore precisely define the target volume. Multileafcollimators and intensity modulation are devices andalgorithms used to improve the conformability of theradiation beam to the target volume to reduce irradi-ation of uninvolved tissues (67).With three-dimensional conformal RT, the radiation

beam is shaped to match the target volume of the tumorby using multiple beams and multileaf collimators.Intensity-modulated RT further increases radiation pre-cision to optimize radiation doses to an irregularlyshaped tumor volume. Computer algorithms and treat-ment simulations are used to formulate a pattern ofradiation delivery and modulate the energy of theradiation beam to create nonuniform dosing accordingto the tumor dimensions. Radiation beams can bearranged to enter the patient at different locations toconcentrate the beam on the targeted tumor volumewhile minimizing exposure to normal tissue (68,69).As opposed to conformal radiation delivered to a

specific target volume over the course of multiplesessions, such as with three-dimensional conformal RTand intensity-modulated RT, stereotactic radiosurgerygenerally refers to the use of high-dose conformalradiation delivered to a tumor volume in a single session.Stereotactic RT, also called stereotactic body RT orstereotactic ablative RT, refers to the delivery of high-dose focused radiation in one to five fractions, withindividual doses typically exceeding 5 Gy (70). The totaldose and fractionation range from 30 Gy delivered inone fraction of as much as 60 Gy delivered in three tofive fractions; however, the biologic effective dose of theradiation delivered is greater than the absolute valueof the dose. A dose of 60 Gy delivered in three fractionshas approximately the same effective dose as 150 Gydelivered in conventional 2-Gy fractions (71). Stereo-tactic radiosurgery and stereotactic body RT techno-logies include Gamma knife, CyberKnife, and proton

beam therapies. Gamma knife stereotactic radiosurgeryemploys an array of precisely collimated beams to createa spherical treatment volume of variable diameters andis specific to intracranial lesions (67). CyberKnife andother similar linear accelerator–based stereotacticradiosurgery technologies rely on modifications of thestandard linear accelerator devices to achieve capabilitiessuch as real-time target volume tracking, as well as ra-diation beam shaping and intensity modulation. Ortho-gonal radiographs obtained immediately before radiationdelivery are cross-referenced with stereotactic trackingsoftware to establish the radiation beam alignment (72).Proton-beam radiosurgery uses protons instead of

photons to deliver a radiation dose and relies on theprinciple that a proton beam will stop at a depthproportional to the energy of the beam, thereby elimi-nating a dose to the tissues beyond the targeted volume(73,74). Because the Bragg peak of protons, which is thepoint of maximum energy transfer and therefore dosedeposition, occurs in the last few millimeters of theproton beam’s range, tumor volume can be targeted withhigh radiation doses while minimizing doses to thedeeper normal tissues (58).Brachytherapy refers to an altogether different mode

of radiation delivery in which a radioactive source,usually with a short radius of cytotoxic activity, is placedclose to or within the tumor, allowing very high localtumor doses that decline rapidly with distance accordingto the inverse-square law (75).Intracavitary brachytherapy applicators may be

placed within a body cavity or surgical site. Forexample, in the balloon-based brachytherapy systemsused to provide accelerated partial breast irradiation, aballoon catheter is implanted in the lumpectomy cavityat the time of surgery and afterloaded with a radio-isotope (76). Permanent low–dose-rate brachytherapyseeds implanted in the prostate gland for the treatmentof localized prostate cancer are a form of interstitialbrachytherapy (77). A line source of radioactivity withinthe lumen or duct of an organ, such as those placedwithin transhepatic biliary stents for the treatment ofunresectable cholangiocarcinoma, are referred to astransluminal or intraluminal brachytherapy (78).Intraoperative RT refers to the administration of a

single dose of external-beam radiation at the time ofopen surgery as opposed to multiple fractionations ofexternal beam radiation. It is most commonly describedin head and neck, breast, pelvic, and unresectable biliarymalignancies (52,79,80).

Interventional OncologyInterventional oncology offers a broad scope of percuta-neous and transcatheter endovascular cancer therapiesthat provide unequivocal clinical benefits and are clearlyunique from medical, surgical, and radiation oncologic


treatments, thereby establishing interventional oncologyas the fourth pillar of cancer care.Percutaneous therapies consist of nonthermal and

thermal ablative technologies. Nonthermal technologiesinclude chemical ablation and irreversible electropora-tion (IRE), whereas thermal ablative technologies in-clude RF ablation, cryoablation, and microwave abla-tion. In a manner analogous to achieving an R0 resectionin surgical oncology, ablative therapies aim to ablate acircumferential margin of healthy tissue measuringapproximately 0.5–1.0 cm, often referred to as an A0ablation.Chemical ablative therapies, including percutaneous

ethanol injection and percutaneous acetic acid injection,cause protein denaturation and thrombosis of the tumormicrovasculature. This treatment is primarily used forHCC, as the soft nature of the tumor compared with thesurrounding cirrhotic liver favors diffusion confined tothe tumor itself. Although inexpensive and efficacious,chemical ablative techniques may be limited by thepredictability of their response and the smaller upperlimit of tumor sizes (≤ 2 cm) that can be adequatelytreated.IRE is a nonthermal ablation technique that induces

cell death by disrupting the electric potential gradientacross cell membranes, leading to the formation ofpermanent nanopores through the plasma membrane,altering cellular transport and ultimately cell homeo-stasis (81). The effects of IRE are dependent on anumber of tissue and electrical field parameters, whichallow for precise mathematical modeling and treatmentplanning (82). In addition, IRE appears to be free fromperfusion-mediated tissue cooling and heating issues thataffect the thermal ablative therapies, and has beenshown to be safe for use on hepatic tumors adjacent tohepatic veins and portal pedicles (83,84).RF ablation causes tissue heating as a result of the

frictional energy generated by polar molecules, partic-ularly water, that vibrate in attempt to remain alignedwith the direction of an alternating current, as well asresistive heating generated as an electric current passesthrough ionic tissue (85). Microwave ablation causestissue heating by causing polar water molecules tocontinuously realign with an oscillating electromagneticfield that emanates from the microwave antenna. Thepropagation of microwaves is not limited by lowelectrical conductivity, high tissue impedance, or lowthermal conductivity, as can be the case with RFablation (86). With both technologies, tissue heatinginduces coagulation necrosis and subsequent cell death.Cryoablation causes rapid cooling of the target tissue,resulting in intracellular ice crystal formation that dest-roys organelle and cell membranes and induces mem-brane pore formation that disrupts the electrochemicalgradient. Cellular tonicity is also disturbed, causing lethaltransmembrane fluid shifts. If these changes do not causeimmediate cell death, they often initiate apoptosis (87).

The ability to visualize ice ball formation, the edge ofwhich marks the 01C isotherm, in cryoablation on severalimaging modalities is a particular benefit.High-intensity focused US is a noninvasive ablative

modality that can cause coagulation necrosis of tumorsat a specific focal length as a result of controlled localheating. Although data are limited, favorable outcomeshave been reported for US-guided high-intensity focusedUS in the treatment of hepatic, pancreatic, renal, breast,and bone tumors (88). High-intensity focused US hasbeen reported to cause complete necrosis for tumorsadjacent to major blood vessels without damage to thevessels (89).Intraarterial chemoinfusion therapy traditionally

required surgical placement of chemotherapy ports, butadvances in technology have now allowed for minimallyinvasive port placement by interventional radiologists(90,91). Intraarterial chemoinfusion allows for increasedlocal concentration and therapeutic response for chemo-therapeutic agents with first-order kinetics and a steepdose–response curve (92).Transcatheter endovascular therapies of interventional

oncology rely on embolization in its various manifes-tations. Embolization may be used to selectively treat atumor via its nutrient arterial supply with bland embo-lization, chemoembolization, or radioembolization, or toinduce liver hypertrophy to increase the functional liverremnant before tumor resection in PV embolization.Transarterial embolization procedures are locore-

gional therapies for the treatment of primary andmetastatic hepatic malignancies. Bland embolizationrefers to the infusion of embolic materials via thenutrient artery to cause occlusion of the tumor arterioles.Chemoembolization involves selective infusion of che-motherapeutic agents via the nutrient arterial supply,followed by an embolic agent, to attain higher intra-tumoral chemotherapy concentrations by preventingchemotherapy washout, in addition to inducing ischemictumor necrosis. Transarterial chemoembolization withdrug-eluting beads (DEBs) is an adaptation of thisconcept in which biocompatible, nonresorbable beadsare loaded with a chemotherapeutic agent and thenadministered through selective catheterization of thetumor’s nutrient arterial supply. The beads are intendedto deliver higher and more sustained doses of thechemotherapeutic agent to the tumor and reduce sys-temic exposure to maximize tumor cell kill whileminimizing systemic toxicities (93).Transarterial radioembolization refers to the selective

intraarterial delivery of glass or resin microspheresloaded with the radioisotope yttrium-90 (90Y). Deposi-tion of the radioactive microspheres within the tumorallows for the safe administration of radiation doses thatmay exceed 150 Gy, whereas the likelihood of develop-ing severe radiation-induced liver disease may exceed50% for external-beam radiation doses greater than40 Gy (94,95). Radiation segmentectomy further builds


on the concept of selective radiation administration inthat high doses of radiation are delivered to an evensmaller volume of one or two hepatic segments tomaximize tumor irradiation and minimize exposure ofthe normal liver parenchyma. Indeed, calculated seg-mental radiation doses have been reported in excess of500 Gy, with calculated tumoral doses greater than1,200 Gy, with a very low incidence of biochemicaltoxicities (96).PV embolization involves selective embolization of a

portion of the liver before partial hepatic resection toredirect portal venous flow to the intended future liverremnant. This causes hypertrophy of the nonembolizedportion of the liver and improves functional hepaticreserve. Patients with normal livers with a plannedresection of more than 80% of their functional livermass, or patients with existing liver disease in addition tothe resectable tumor with a planned resection of morethan 60% of their functional liver mass, are at highestrisk for postoperative complications. By inducing pre-operative hypertrophy of the future liver remnant, PVembolization allows otherwise unsuitable patients tobecome surgical candidates by reducing the postopera-tive morbidity and mortality associated with majorhepatic resections (97). Changes similar to PV embo-lization have also been observed during long-termfollow-up of patients who received unilobar 90Y radio-embolization, with significant volumetric decreases inthe treated hepatic lobe and concomitant significantvolumetric increases in the untreated lobe. This atro-phy–hypertrophy complex, termed radiation lobectomy,has resulted in a volumetric increase of the untreatedlobe of approximately 40%, which compares to 30%hypertrophy of the liver remnant seen following ex-tensive hepatic resection and approximately 15% hy-pertrophy of the future liver remnant following PVembolization (98).

DISEASE-SPECIFIC REVIEW AND LEVELS

OF EVIDENCE

Hepatocellular CarcinomaHCC is the second most common cause of cancer-relateddeaths in the world (99), and most often occurs inpatients with chronic liver disease as a result of viralhepatitis, alcohol-induced liver disease, or nonalcoholicsteatohepatitis. Several organizations, including the Am-erican Association for the Study of Liver Disease, theUnited States Veterans Administration, and the Euro-pean Association for the Study of the Liver (EASL),recommend screening for HCC in all patients withcirrhosis and certain patients with hepatitis B infectioneven in the absence of cirrhosis. Screening includes aliver US and serum α-fetoprotein (AFP) level measure-ment every 6–12 months (100–102).

According to the EASL and American Association forthe Study of Liver Disease practice guidelines, the diag-nosis of HCC is based on imaging or pathologic exami-nation. In patients with cirrhosis, the presence of a lesionmeasuring greater than 1 cm with hallmark features onfour-phase computed tomography (CT) or dynamiccontrast-enhanced magnetic resonance imaging is diag-nostic of HCC (level IID evidence). Hallmark features arehypervascularity on the arterial phase with washout onportal venous or delayed phases. If hallmark features arenot seen on one modality, imaging with the secondmodality is recommended. Biopsy is reserved for suspi-cious lesions that do not exhibit typical imaging character-istics of HCC. Serum AFP level is no longer part of thediagnostic criteria of HCC, and is an imperfect indicatorof HCC because approximately 40% of HCCs less than2 cm in size and 28% of HCCs 2–5 cm in size will not havean increased AFP level (102,103).The Barcelona Clinic Liver Cancer (BCLC) staging

system for HCC is the most widely accepted stagingsystem in clinical practice and clinical trials, and it is therecommended staging system for prognosis predictionand treatment allocation (level IIA evidence). BCLCcriteria divide patients into very early (0), early (A),intermediate (B), advanced (C), and terminal (D) stagesbased on performance status, Child–Pugh scoring, andtumor characteristics. Treatment recommendations arebased on the BCLC stage, including curative treatmentsfor very early and early-stage HCC (BCLC stages 0 andA), palliative treatments for intermediate-stage andadvanced HCC (BCLC stages B and C), and sympto-matic treatment for terminal HCC (BCLC stage D). Asreflected in the BCLC staging system, the natural historyof HCC depends heavily on tumor liver function, func-tional status, and tumor characteristics. Patients withuntreated intermediate-stage disease have a 1-year sur-vival rate of approximately 50%, whereas those withadvanced-stage and terminal HCC have 1-year survivalrates of 25% and 11%, respectively (104). BCLC is theonly system that associates a stage with a recommendedtreatment strategy.Surgical resection is the first-line treatment for patients

with solitary tumors and preserved liver function (levelIIA evidence). Resections should be anatomic anddelineated by the Couinaud hepatic segments (level IIIAevidence). There is no consensus on the necessary widthof a negative surgical margin, and recurrence andsurvival analyses have reported acceptable outcomesfor margins ranging from 0.5 cm to more than 2 cm(105–107). Preserved liver function is indicated by anormal bilirubin level and a hepatoportal venous pres-sure gradient no greater than 10 mm Hg or a plateletcount of at least 100,000 with associated splenomegaly.However, fewer than 10% of patients with HCC areeligible for resection according to these criteria (102).For patients who are not candidates for surgical

resection, liver transplantation is the first-line treatment


if the tumor characteristics are within transplant criteria(level IIA evidence). The Milan criteria are the mostcommonly used criteria worldwide, and limit eligibilityto a single tumor measuring 5 cm or smaller or thepresence of no more than three tumors, each no largerthan 3 cm (108). In the United States, the OrganProcurement and Transplantation Network and UnitedNetwork for Organ Sharing define transplant-eligibleHCC as T2 disease, with tumor size and number criteriaidentical to those in the Milan criteria (109). TheUniversity of California, San Francisco, has expandedcriteria to include a solitary tumor no larger than 6.5 cmor a maximum of three tumors no larger than 4.5 cmwith a total tumor diameter no larger than 8 cm (110).The Model for End-stage Liver Disease model uses thevalues of total bilirubin, International NormalizedRatio, and creatinine to calculate a score that predictssurvival probability for patients with end-stage liverdisease. Liver transplant candidates with HCC receivea Model for End-stage Liver Disease score increase(“exception points”) as well as an additional 10%increase every 3 months until they receive a transplantor are no longer eligible for transplantation because ofdisease progression (109).For patients with early-stage HCC who are not

surgical candidates, ablative treatments, both nonther-mal and thermal, are options with very favorableresponse profiles. Percutaneous ethanol injection andRF ablation have been shown to be equally effective fortumors smaller than 2 cm, but the effects of RF ablationare more predictable (level I evidence) (103). RFablation has demonstrated 5-year survival rates inearly-stage HCC ranging from 50% to 64%. RF ablationresults are most favorable for tumors smaller than 3 cm,with rates of successful ablation decreasing as tumorsexceed 3 cm. For patients with tumors no larger than2 cm, complete sustained response has been shown in97% of patients, with a 5-year survival rate approaching70%, which is comparable to survival rates followingsurgical resection (111). Indeed, data suggest that, forsmall, solitary, early-stage HCC, RF ablation offerssimilar survival rates to surgical resection and mayarguably represent an equivalent alternative to surgicalresection as first-line treatment (111,112).Recent data indicate that tumor necrosis following RF

ablation initiates a T-cell–mediated immune responsethat provides prolonged immune response and protec-tion against recurrent HCC (113).The zone of ablation should include a circumferential

ablative margin of 0.5–1 cm (114). However, even withsmall tumors, tumor location has a substantial impacton the ability to achieve complete tumor necrosis. Thepresence of a large vessel (≥ 3 mm) abutting the tumordecreases the rate of complete tumor necrosis to less than50% as a result of a “heat-sink” effect (115). In addition,a subcapsular location is associated with an increasedrisk of incomplete ablation and tumor progression (116).

Recurrence after surgical resection or ablation occursin approximately 80% of patients by 5 years. Approx-imately half of these recurrences are early recurrences,occurring within 2 years, and are considered recurrencesas a result of primary tumor dissemination. Late re-currences are considered de novo tumors arising in anoncogenic liver (117,118).Preoperative “bridging” therapies such as ablation

and embolization can be considered if the wait onthe transplant list is expected to exceed 6 months (levelIID evidence) (103,119). Ablation of HCC in trans-plantation-eligible patients must be undertaken withcaution because, at follow-up imaging, the zone ofablation, which includes the ablative margin, will exceedthe original tumor size. As transplantation criteria oftentake absolute lesion size into account rather than tumorviability, a complete necrotic response may nonethelesspush a lesion beyond the size limitations for transplanteligibility. Bland embolization, chemoembolization, andradioembolization also provide acceptable bridging ordown-staging strategies for patients on the transplantwaiting list.Conventional transarterial chemoembolization, specif-

ically emulsified chemotherapeutic agent and Lipiodolfollowed by embolization, is the recommended first-linetherapy in intermediate-stage disease (BCLC stage B)without vascular invasion, cancer-related symptoms, orextrahepatic spread, and is now considered the standardof care (102). Two landmark prospective randomizedtrials (120,121) have demonstrated improved overallsurvival for transarterial chemoembolization comparedwith best supportive care in patients with HCC and pre-served liver function (level IA evidence). In one study(120), patients treated with transarterial chemoem-bolization had 1-, 2-, and 3-year survival rates of 57%,31%, and 26%, respectively, compared with 32%, 11%,and 3% in the control group. In a second study (121), thetrial was stopped early when sequential inspectiondemonstrated that transarterial chemoembolization hada significantly improved survival compared withconservative treatment. One- and 2-year survival ratesfor chemoembolization were 75% and 50%, respectively,compared with 63% and 27% for the control group. Themedian survival for untreated intermediate-stage HCC isapproximately 16 months, whereas survival after chemo-embolization has been shown to be approximately 20months (102). Chemoembolization with doxorubicin-loaded DEBs has been shown in a randomized trial(93) to have similar results to conventionalchemoembolization, but with higher administered dosesof doxorubicin and significantly reduced serious livertoxicity and doxorubicin-related adverse events (level IDevidence).Radioembolization is an alternative transarterial

treatment option for intermediate-stage HCC and hasbeen shown to be safe and efficacious for patients withPV invasion (122). In this treatment, 90Y-loaded glass or


resin beads are infused via selective hepatic arterialcatheterization. Because of the hypervascular nature ofHCC, which derives the vast majority of its blood supplyfrom the hepatic arteries, there is preferential depositionof the radioactive microspheres within the tumor. Thereare no randomized controlled trials comparing survivalafter radioembolization versus transarterial chemoembo-lization, but studies have shown median survival times ofapproximately 17 months in patients with intermediate-stage HCC and 12 months for advanced HCC with PVinvasion (level IIA evidence) (122–124). A comparativeeffectiveness analysis of more than 200 patients treatedat the same institution with radioembolization andchemoembolization (125) indicated similar survivaltimes for the two therapies, with a significantly reducedtoxicity profile for radioembolization. The authorsconcluded that more than 1,000 patients would have tobe enrolled in a randomized controlled trial to achievesufficient statistical power to demonstrate equivalence ofsurvival times for the two therapies (125).Sorafenib, a multiple–tyrosine kinase inhibitor, is an

oral, molecular-targeted therapy for HCC and is the onlysystemic therapy that has demonstrated a survival advant-age for advanced HCC. A randomized, double-blind,placebo-controlled phase III trial (Sorafenib Hepatocel-lular Carcinoma Assessment Randomized Protocol[SHARP]) by Llovet et al (40) of patients with advancedHCC demonstrated a median overall survival of 10.7months in the sorafenib group compared with 7.9 monthsfor the placebo group, as well as a significantly longer timeto tumor progression for the sorafenib group (5.5 mo vs2.8 mo) (40). In the Asia–Pacific trial (41), in which themajority of patients had hepatitis B infection, medianoverall survival was 6.5 months for the sorafenib groupcompared with 4.2 months for the placebo group. Shortermedian survival times in the Asia–Pacific trial (41)compared with the trial of Llovet et al (40) reflect themore advanced stage of disease for patients included inthe Asia–Pacific trial (41). Sorafenib is therefore re-commended as standard systemic therapy for patientswith preserved liver function (Child–Pugh class A) butadvanced tumor (BCLC stage C), or for patients withprogression following locoregional therapy (level IAevidence) (102).Response assessment for HCC should follow necrosis

methodologies, ie, the EASL or modified ResponseEvaluation In Solid Tumors criteria, which measureviable tumor as indicated by enhancing tissue (levelIIB evidence). Multiphase CT or dynamic contrast-enhanced MR imaging should be performed 1 monthafter surgical resection, ablation, locoregional therapy,or initiation of systemic therapy (level IA evidence). Toevaluate for time to progression, cross-sectional imagingis recommended every 6–8 weeks. To evaluate forrecurrence, repeat cross-sectional imaging should occurevery 3 months for the first year and every 6 months forthe second year (102).

In summary, the BCLC staging system is currently themost widely accepted staging system for HCC andprovides an algorithm to guide treatments; however,there is significant variability in treatment paradigms indifferent parts of the world and throughout the UnitedStates. The use of chemoembolization for intermediate-stage HCC (BCLC stage B) without vascular invasion,cancer-related symptoms, or extrahepatic spread, andthe use of sorafenib for advanced HCC, are based onlevel IA evidence. Surgical resection, ablation, andtransplantation are primarily based on nonrandomizedcohort analyses, whereas the use of bland embolizationand radioembolization are based on phase II cohortstudies. Other HCC staging systems to be familiarwith include the Cancer of the Liver Italian Program,Okuda, Chinese University Prognostic Index, JapaneseIntegrated Score, Taiwanese scoring, as well as UnitedNetwork for Organ Sharing system.

Colorectal CancerCRC is the second leading cause of cancer death in theUnited States. When localized to the bowel, the cancer ishighly treatable and often curable. Penetration throughthe bowel wall, involvement of regional lymph nodes,and distant metastases determine prognosis and arereflected in the staging systems. Elevated serum carci-noembryonic antigen levels carry a negative prognosticsignificance (126).Patients at the highest risk for the development of

CRC include those with hereditary conditions such asfamilial adenomatous polyposis and hereditary nonpo-lyposis CRC (also known as Lynch syndrome) orinflammatory bowel diseases such as ulcerative colitisor Crohn disease (127). A personal history of adenomas,first-degree relatives with CRC or adenomas, and apersonal history of breast, ovarian, or endometrialcancer also increase risk (128). However, these riskfactors account for fewer than 40% of incident CRCs.CRC is staged according to the AJCC TNM classi-

fication. To confirm the absence of nodal involvement,at least 12 lymph nodes should be included in thesurgical pathologic examination. Stage I disease doesnot extend beyond the muscularis propria, and stage IIdisease extends beyond the colon and may be locallyinvasive. The presence of regional lymph node meta-stases indicates stage III disease, and distant metastasescharacterize stage IV disease.Without evidence of distant metastatic disease, surgi-

cal resection of the primary tumor and en bloc removalof regional lymph nodes is the standard of care (NCCNcategory 2A recommendation), with laparoscopic-as-sisted colectomy having been shown to be as effectiveas open colectomy (NCI level IA evidence) (129). Theuse of adjuvant chemotherapy for stage II disease iscontroversial and may be limited to stage II disease athigh risk for recurrence (130). RT may be considered forlocally invasive disease (131).


Metastatic disease confined to regional lymph nodesdenotes stage III disease, and patients with fewer thanfour lymph nodes involved have a better prognosis thanpatients with four or more lymph nodes involved (132).Stage III disease should be treated with 5-FU–basedchemotherapy combined with oxaliplatin (NCCNcategory 1 recommendation; NCI level IA evidence). 5-FU, given concomitantly with leucovorin (folinic acid),is administered intravenously; capecitabine, an oralfluoropyrimidine, is enzymatically converted to 5-FUwithin tumor cells. Disease-free survival is equivalentfor patients who receive oxaliplatin with intravenous5-FU/leucovorin (ie, FOLFOX) or oral capecitabine (ie,CapeOx; NCI level ID evidence) (133).Distant metastases characterize stage IV disease and

will occur in 50% of patients with CRC, either at thetime of initial presentation or as a result of diseaserecurrence (134). Isolated hepatic metastases that arelimited in number and have no major vascularinvolvement may be candidates for surgical resection,resulting in 5-year survival rates from 40% to 60% (NCIlevel IIID evidence) (47,48). Similar survival rates maybe achieved with resection following neoadjuvant che-motherapy (135). For patients who are not surgicalcandidates, 5-year survival rates following percutaneousRF ablation approach but do not equate to or exceedthose of surgical resection for tumors 4 cm or smaller(level IIID evidence) (136). In a randomized phase IItrial (137), RF ablation added to systemic chemotherapyfor unresectable colorectal metastases increased medianprogression-free survival by nearly 7 months (16.8 vs 9.9mo; level ID evidence). The study was not powered toevaluate for differences in overall survival.First-line treatment for stage IV disease includes

FOLFOX or 5-FU/leucovorin/irinotecan (FOLFIRI;NCI level ID evidence) with or without the addition ofmolecular-targeted therapies. Capecitabine is an accept-able alternative to infused 5-FU for oxaliplatin-basedtherapy (level ID evidence) (138). First-line treatmentregimens with molecular-targeted therapies include theaddition of bevacizumab to FOLFOX (or CapeOx) orFOLFIRI, the addition of panitumumab to FOLFOXor FOLFIRI, or the addition of cetuximab to FOLFIRI(NCCN category 2A recommendation; NCI level Ievidence) (131). Patients who receive panitumumab orcetuximab must have wild-type KRAS, as carriers ofmutant KRAS have worse outcomes (22,139). Second-line therapy for patients who start with FOLFOX orCapeOx regimens generally includes switching to anirinotecan-based regimen with bevacizumab, ziv-afliber-cept, cetuximab, or panitumumab. Second-line therapyfor patients who start with FOLFIRI regimens includescetuximab or panitumumab with irinotecan only, orFOLFOX (or CapeOx) with bevacizumab (NCCNcategory 2A). The molecular-targeted drug regorafenibmay be considered in patients with mutant KRAS whosedisease has progressed with second-line therapy or

patients with wild-type KRAS whose disease has pro-gressed with second- and third-line therapies.Radioembolization has shown favorable outcomes in

patients with unresectable hepatic metastases of CRC.The use of radioembolization for the treatment ofchemotherapy-resistant or -refractory disease remains acategory 3 recommendation according to the NCCNguidelines. The addition of 90Y radioembolization tochemotherapy has shown significantly prolonged timesto tumor progression compared with chemotherapyalone (15.9 mo vs 9.7 mo; P o .001 [140]; 18.6 mo vs3.6 mo; P o .0005 [141]), with a trend toward prolonged2-year survival in one study (39% vs. 29%; P ¼ .06 [140])and a significantly longer median survival in a secondstudy (29.4 mo vs 12.8 mo; P ¼ .02 [141]; level I andlevel II evidence). A randomized phase III trial ofchemotherapy with and without radioembolization(142) demonstrated a significantly prolonged time toliver progression (5.5 mo vs 2.1 mo; P ¼ .003) and timeto tumor progression (4.5 mo vs 2.1 mo; P ¼ .03), but nosignificant difference in median overall survival (10.0 movs 7.3 mo; P ¼ .80), even though more than 40% of thepatients in the control arm crossed over to receiveradioembolization after disease progression (level IDevidence) (142). A matched-pair study of radioemboliza-tion for patients with chemotherapy-refractory disease(143) showed a prolonged median survival (8.3 mo vs 3.5mo; P o .001) compared with best supportive care (levelIIIA evidence).Hepatic arterial embolization with the use of DEBs

preloaded with irinotecan (ie, DEBIRI) has shownfavorable outcomes compared with systemic FOLFIRI.Results of a randomized trial comparing DEBIRI versussystemic FOLFIRI demonstrated significantly prolongedoverall survival, median survival (22 mo vs 15 mo; P ¼.006), progression-free survival, and duration of qualityof life improvement (8 mo vs 3 mo; P ¼ .00002) forpatients who received DEBIRI (level IA evidence) (144).Direct hepatic arterial chemoinfusion has been most

often reported for the treatment of metastatic CRC.Many randomized trials (145–150) have compared out-comes of hepatic arterial versus systemic intravenousadministration of 5-fluorodeoxyuridine (floxuridine),and more recently infusional 5-FU with leucovorin.Several of these studies have demonstrated significantlyand markedly improved response rates for patients whoreceive the arterial infusion. However, survival analyseswere limited by substantial patient crossover (145–147),the inclusion of patients with extrahepatic metastases inthe hepatic infusion group (147), or a majority of pa-tients not receiving or prematurely terminating arterialinfusion as a result of catheter malfunction (148). Twoadditional studies did not show a survival advantage forpatients receiving hepatic arterial chemoinfusion (147,148),and another demonstrated a survival advantage only insubgroups analysis of patients with hepatic tumor burdenof less than 25% (149). One of the most recent studies


comparing hepatic arterial versus systemic 5-FU withleucovorin (150) did demonstrate significant increases inoverall survival, hepatic response rate, and physicalfunctioning for patients who received hepatic arterialchemoinfusion, although time to extrahepatic progressionin this group was significantly shorter.In summary, the use of chemotherapy and molecular-

targeted therapies in the treatment of metastatic CRC isbased on level IA evidence. There is level I evidence tosupport the use of transarterial therapies in the treatmentof metastatic CRC. Surgical metastasectomy and abla-tive therapy and RT are based on nonrandomized cohortanalyses. It should be noted that, although surgicalresection may provide survival benefit compared withother available treatments for hepatic metastases, the useof survival after metastatic resection as a benchmarkagainst which other therapies are compared is inherentlyflawed, given that surgical resectability, particularly inCRC, reflects a selection bias of early detection.

Neuroendocrine TumorsNETs arise from the neuroendocrine cells of the embryo-logic fore-, mid-, and hindgut, the most common ofwhich are carcinoid and pancreatic NETs. PancreaticNETs arise from the endocrine tissues of the pancreas,whereas carcinoid tumors most frequently arise in thelungs, small intestine, appendix, or rectum. Except whenassociated with genetic syndromes such as multipleendocrine neoplasia types 1 and 2, NETs are relativelyrare, with sporadic incidence.NETs are classified based on tumor histology, speci-

fically differentiation and grade, and are generallyseparated into three different categories: G1 (well differ-entiated, low-grade), G2 (well differentiated, intermedi-ate-grade), and G3 (poorly differentiated, high-grade).Cancers are staged according to the AJCC TNM stagingsystem (151). Pancreatic NET staging follows the TNMstaging system for pancreatic exocrine carcinoma,whereas carcinoid tumor staging differs according tothe organ of involvement.Pancreatic NETs represent 1% of incident pancreatic

cancers (152). The majority (70%) of functioning pan-creatic NETs are insulinomas, but nearly 90% of theseare benign. Gastrinomas and somatostatinomas repre-sent 10% of the functioning NETs but have the highestrisk for metastases. Survival rates for metastatic pan-creatic NETs are approximately 20%–25% in popu-lation-based studies (153), but have been reported ashigh as 57% at a dedicated cancer institute (154). The5-year survival rate for metastatic carcinoid tumors atdedicated cancer centers is approximately 75% (155).Cross-sectional multiphase imaging is important for

the diagnosis of primary and metastatic NETs. Becausemany NETs express high-affinity receptors for somatos-tatin, nuclear medicine imaging with the use of a soma-tostatin analogue (indium-111–diethylene triamine

pentaacetic acid–octreotide) can be an important imag-ing tool for tumor localization and indicates the abilityto treat with octreotide, a somatostatin analogue thatinhibits tumor growth. Chromogranin A is a serummarker that may be increased with NETs, allowing itsuse as a tumor marker (NCCN category 3), but mayalso be increased in patients taking proton-pump inhib-itors and those with gastritis, hypertension, and renalor liver failure (151). The serotonin metabolite 5-hy-droxyindoleacetic acid may be used as a tumor markerfor some cases of carcinoid tumor.Excision or surgical resection with curative intent is

generally recommended for NETs (NCCN category 2A;NCI level IIID evidence). Depending on the location ofthe primary tumor and its size, with 2 cm frequentlybeing the cutoff, surgical resection with local lymphnode dissection should be performed.For NETs with limited hepatic disease, surgical

resection of the primary tumor as well as hepaticmetastases is an option (NCI level IIID evidence).Nearly all patients will have recurrence within 5 yearsfollowing hepatic resection, but 5- and 10-year survivalrates exceed 70% and 50%, respectively (156). Non-etheless, most patients with metastatic disease are notcandidates for surgical resection. For patients withunresectable but asymptomatic disease with a lowtumor burden, observation is recommended, withclinical and imaging assessment every 3–12 monthsuntil there is evidence of significant disease progression.For patients with symptomatic but unresectable disease,

clinically significant tumor burden, or clinically significantprogressive disease, several treatment options exist. Formetastatic carcinoid tumor, patients should receive octreo-tide (NCCN category 2A) (157). Octreotide may beconsidered in patients with pancreatic NETs expressingsomatostatin receptors (NCCN category 2B). Additionaltreatment options include systemic treatment withmolecular-targeted therapies, such as everolimus or suniti-nib (NCCN category 2A, NCI level ID evidence forpancreatic NET) (34,37); cytotoxic chemotherapy (NCCNcategory 2A for pancreatic NET; category 3 for carcinoidtumor), thermal ablative therapy (NCCN category 2B); orhepatic arterial therapies including bland embolization,chemoembolization, or radioembolization (NCCN cate-gory 2B recommendation, NCI level IIID evidence). Thereare no prospective randomized trials comparing blandembolization, chemoembolization, and radioembolizationfor the treatment of progressive, unresectable carcinoidtumor or NETs. Bland embolization and chemoemboliza-tion of hepatic metastases have been shown to providesignificant symptomatic and radiologic responses in amajority of patients, with encouraging progression-freesurvival (158). Radioembolization has been reported toprovide a complete response in as many as 18% of patients,although survival times do not differ significantly fromthose seen following bland embolization or chemoem-bolization (159,160).


Liver transplantation has been performed for patientswith metastatic NETs confined to the liver; however,liver transplantation in this setting is still consideredinvestigational and not part of the standard treatmentalgorithm (151).In summary, the use of chemotherapy with systemic

agents for the treatment of metastatic NETs is based onrandomized studies with surrogate markers for overallsurvival. Surgical resection, ablative therapies, andtranscatheter arterial therapies are based on nonrandom-ized cohort studies.

Intrahepatic CholangiocarcinomaIntrahepatic cholangiocarcinoma arises from the bileduct epithelium peripheral to the confluence of the rightand left hepatic ducts and is a relatively rare malignancy,but with an increasing incidence. Most patients presentwith advanced disease, and disease usually recurs despitesurgery in patients who are surgical candidates. Riskfactors include chronic biliary inflammation, includingprimary sclerosing cholangitis, liver fluke infestation,hepatolithiasis, and cirrhosis (161). There is recentevidence that hepatitis C infection may also increasethe risk of cholangiocarcinoma (162).Staging of intrahepatic cholangiocarcinoma used to be

identical to the staging of HCC; however, modificationsto the most recent (ie, seventh) edition of the AJCCTNM staging system have distinguished intrahepaticcholangiocarcinoma from HCC and focus on the num-ber of tumors and the presence of vascular invasion andlymph node metastases. Tumor size has not been shownto have an independent effect on survival (163). Surgicalresection is the only curative therapy for intrahepaticcholangiocarcinoma, with 5-year survival rates ofapproximately 20%–30%, but most patients are notsurgical candidates at presentation (164). In general,multiple tumors and lymph node metastases precludesurgical resection.Patients with R0 resection may receive observation

alone or adjuvant chemotherapy in the setting of a clinicaltrial. Patients with R1 or R2 surgical resections mayreceive additional resection when feasible, locoregionaltherapy, chemoradiation with a radiation-sensitizing fluo-ropyrimidine agent, or a fluoropyrimidine- or gem-citabine-based chemotherapy. Combination therapy withgemcitabine and cisplatin has been shown to increaseprogression-free and overall survival compared withgemcitabine alone, and is now the recommended chemo-therapy for unresectable or advanced cholangiocarcinoma(165).Locoregional therapies for intrahepatic cholangiocar-

cinoma have been shown to be safe and effective in smallseries, but there have been no randomized clinical trials.RF ablation has been reported to provide good localtumor control in patients with unresectable cholangio-carcinoma, with the optimal results in tumors smaller

than 5 cm. Reports of median overall survival followingRF ablation range from 20 to 38.5 months (166,167).RF ablation for recurrent tumors, also smaller than 5cm, following curative resection has also been reported,with median overall survival after ablation of 27.4months (level III evidence) (168). In a study of 24patients treated with 90Y radioembolization (169), sixpatients (27%) had partial response and 15 patients(68%) had stable disease, with a median survival of14.9 months. Seventeen patients (77%) in this cohort hadmore than 50% tumor necrosis and two patients (9%)had complete tumor necrosis (level III evidence) (169).In a report of 25 patients with unresectable intrahepaticcholangiocarcinoma treated with 90Y radioembolization(170), six patients (24%) showed a partial response and11 patients (48%) had stable disease, with a mediansurvival after treatment of 9.3 months (level IIIevidence). In a study of 62 patients treated withchemoembolization with a combination of cisplatin,doxorubicin, and mitomycin-C (171), 11% had apartial response and 64% had stable disease, with amedian overall survival after treatment of 15 months(level III evidence).In summary, the evidence for resection of localized,

resectable cholangiocarcinoma is based on nonrandom-ized cohort studies. For unresectable cholangiocarci-noma with or without metastatic disease, gemcitabine/cisplatin is the standard of care based on randomizeddata that show improvement in survival.

Lung CancerLung cancer is the leading cause of cancer death in theUnited States and comprises several histologic subtypes,including small-cell lung cancer and NSCLCs such assquamous cell carcinoma, large-cell carcinoma, adeno-carcinoma, and NETs of the lung. Classifications foradenocarcinoma have recently been updated, eliminatingthe use of “bronchioloalveolar cell carcinoma” and“mixed-subtype adenocarcinoma” from the classificationsystem. The new categories include adenocarcinomain situ (formerly bronchioloalveolar cell carcinoma),minimally invasive adenocarcinoma, invasive adenocar-cinoma (formerly nonmucinous bronchioloalveolar cellcarcinoma), and variants of invasive adenocarcinoma.Immunohistochemical staining is used to differentiatesmall-cell lung cancer from NSCLC, primary frommetastatic adenocarcinomas, and adenocarcinoma frommalignant mesothelioma, as well as to determine theneuroendocrine status of lung tumors (172).Stage I disease includes tumors smaller than 5 cm.

Stage IIA disease includes tumors no larger than 7 cmwithout lymph node involvement and smaller than 5 cmwith ipsilateral peribronchial or hilar lymph nodeinvolvement, whereas stage IIB disease includes tumors5–7 cm with ipsilateral peribronchial or hilar lymphnode involvement, tumors larger than 7 cm without


lymph node involvement, or tumors with local invasion.Stage IIIA disease includes tumors of any size withipsilateral mediastinal or subcarinal lymph node involve-ment, or invasion of critical structures with lymph nodeinvolvement limited to the ipsilateral peribronchial orhilar regions. Any nodal involvement of the supra-clavicular lymph nodes or contralateral lymph nodesdenotes stage IIIB disease. Stage IV disease includes aseparate tumor in a contralateral lobe, pleural nodules,malignant effusion, and distant metastases (173).Molecular analysis has an important role in guiding

the treatment of lung cancers. The two most commonEGFR mutations found in NSCLC are associated withsensitivity to molecular-targeted therapy with the tyro-sine kinase inhibitors erlotinib and gefitinib. The pres-ence of an EML4-ALK gene rearrangement mayrepresent an indication for the use of the tyrosine kinaseinhibitor crizotinib. Levels of expression of ERCC1 canhelp predict sensitivity to platinum-based chemothera-pies. KRAS mutations are associated with shortersurvival than wild-type KRAS, and the use of erlotinibin patients with KRAS mutations may reduce theefficacy of chemotherapy (174,175).Chemotherapy, surgery, and RT are the mainstays of

NSCLC treatment. Surgery offers the best chance ofcure, and lung cancer resection with complete ipsilateralmediastinal lymph node dissection is indicated forpatients with stage I, II, and IIIA disease (NCCNcategory 2A, NCI level IA evidence) (175,176).Chemotherapy may be used for neoadjuvant and

adjuvant therapy, or for advanced or metastatic disease.Platinum-based chemotherapies are the foundation oflung cancer care, but the ultimate chemotherapeuticregimen is determined by tumor histology and clinicalparameters. Patients with resected stage II and IIIAdisease benefit from cisplatin-based adjuvant chemo-therapy (NCI level IA evidence) (176). Chemotherapywith radiation is the standard treatment algorithm forpatients with unresectable stage III disease (NCI level IAevidence), and combination chemotherapy for patientswith stage IV disease improves survival and palliatesdisease-related symptoms (NCI level IA evidence).The addition of bevacizumab to standard first-line

chemotherapy has shown benefits in certain patients withadvanced stage IIIB or stage IV NSCLC (NCCNcategory 2A, NCI level IA evidence). The EFGRinhibitors gefitinib and erlotinib in place of platinum-based therapies have shown improved progression-freesurvival for patients with advanced-stage disease andcorresponding gene mutations (NCI level ID evidence)(177–180).RT is used as adjuvant therapy for resectable disease,

primary local treatment for patients with inoperable orunresectable disease, or palliative therapy in incurabledisease (NCCN category 2A, NCI level I evidence).For patients with inoperable or unresectable disease,

stereotactic ablative RT, in which high-dose radiation

(4 5 Gy) is delivered in few fractions, is an option (175).For medically inoperable stage I NSCLC (tumor o5 cm), tumor and local (tumor and involved lobe)control rates approaching 98% and 91%, respectively,at 3 years have been reported, with 3-year disease-freeand overall survival rates of 48% and 56%, respectively(181).RF ablation is an option for treatment of localized,

node-negative lung cancers in patients who refuse sur-gery or would not tolerate surgery as a result of poorperformance status, limited cardiopulmonary reserve, orother comorbidities. RF ablation is also an option forthe treatment of tumors arising in previously irradiatedtissue. A large, multicenter, prospective study of RFablation for primary and metastatic lung cancers meas-uring no more than 3.5 cm in patients who were notcandidates for surgery, chemotherapy, or RT showedcomplete responses lasting at least 1 year in 88% ofpatients, without a significant difference in primaryversus metastatic lung cancers. Overall 1-year and2-year survival rates for patients with NSCLC were70% and 48%, respectively. One- and 2-year overallsurvival rates were 89%–92% and 64%–66%, respec-tively, for patients with colorectal and other metastasesto the lungs (level III evidence). A different study (182)compared outcomes for patients with stage I NSCLCwho were unable to undergo lobectomy and insteadreceived sublobar resection, RF ablation, orcryoablation. There was no significant difference in theprobability of 3-year survival based on therapy received,with 3-year cancer-specific survival rates ranging from87% to 91% and cancer-free survival rates ranging from46% to 61% (level III evidence) (182). Although theseresults are not directly comparable to outcomes fromsurgical or radiation therapies because these patients hadcomorbidities precluding such treatments, the outcomesdo compare well to reported outcomes of external-beamRT and stereotactic RT in similar populations (183).In summary, the evidence for resection of early-stage

lung cancer is based on nonrandomized phase II data(level II evidence). For more advanced disease inpatients with metastatic disease, treatment with chemo-therapy is based on randomized evidence with survivalas the endpoint (level I evidence). Stereotactic ablativeRT and ablative therapies for inoperable lung cancer arebased on level III data.

Renal CancerRenal cancer represents approximately 2%–3% of allmalignancies in the United States and has an increasingincidence. The vast majority of renal cancers are renalcell carcinomas. Stage I disease includes renal massesno larger than 7 cm confined to the kidney. Renalmasses larger than 7 cm but still confined to the kidneyare considered stage II disease. Extension into themajor veins or perinephric tissue, or nodal involvement,


indicates stage III disease. Stage IV disease includestumors extending beyond the Gerota fascia or into theipsilateral adrenal gland (184).Surgical resection, which includes radical nephrectomy

and nephron-sparing partial nephrectomy, is the mainstayof treatment of early-stage renal cancer, with significantlong-term survival benefits. Stage II and III renal cancersare treated with radical nephrectomy, whereas stage IVdisease may be treated with molecular-targeted therapies(NCCN category 1, NCI level ID evidence), cytokineimmunotherapy (NCCN category 2A, NCI level IAevidence), or the combination of cytokine immunotherapyand bevacizumab (NCCN category 1, NCI level IDevidence). Systemic chemotherapy for unresectable orstage IV disease, with the choice of agents depending onthe histologic subtype of the renal cell carcinoma, hasshown modest responses and remains an NCCN category3 recommendation (184,185).For patients with T1 renal tumors (≤ 7 cm) but

substantial medical comorbidities or limited life expect-ancy, active surveillance or thermal ablation are alter-natives to surgical resection. With active surveillance ofT1 renal cancers, patients are monitored and treated inthe event of disease progression (185). The AmericanUrological Association includes thermal ablation asan acceptable treatment option for T1 renal masses(≤ 7 cm) in surgical candidates at high risk with theunderstanding that, although thermal ablative therapieshave shown similar distant recurrence-free survival ratesas surgery, there may be an increased risk of localrecurrence, particularly for T1b tumors (4–7 cm; levelIII evidence) (186,187). Tumor size and location are thecritical factors in choosing which thermal ablationmodality to use. Although a metaanalysis comparingRF ablation versus cryoablation (188) appears toindicate that RF ablation is associated with higherrates of local recurrence compared with cryoablation(12.9% vs 5.2%; P o .0001), resulting in a higher rate ofrepeat ablation (8.5% vs 1.3%; P o .0001), the study hasbeen criticized for the heterogeneity of the patientcohorts. For tumors smaller than 3 cm, RF ablationand cryoablation are highly effective. A large retros-pective review at a single institution (189) reports nosignificant difference in outcomes between RF ablationand cryoablation for renal tumors 3.0 cm or smaller withregard to technical success, local recurrence, andcomplications. Specifically, local recurrence followingRF ablation occurred in 3.2% of treated lesions,whereas local recurrence following cryoablationoccurred in 2.8% of treated lesions (189). However,rates of effective local tumor control with RF ablationdo decrease as tumor size exceeds 3 cm. In a study of100 tumor RF ablations (190), RF ablation resulted incomplete tumor necrosis for all tumors smaller than3 cm, whereas 44% of tumors larger than 3 cm requiredrepeat ablation. In a study of 125 tumor RF ablations(191), RF ablation provided complete tumor necrosis

for all tumors smaller than 3.7 cm, whereas 30% of thelarger tumors had residual viable tumor on follow-up.Cryoablation, on the contrary, has demonstratedeffective local tumor control for tumors larger than3 cm (192). In addition to size greater than 3 cm, acentral location near the renal hilum can result inincomplete tumor necrosis with RF ablation as a resultof the heat-sink effect of the hilar vessel, whereascryoablation has been shown to be safe and effectivefor tumors in this location (190,193–195).Arterial embolization of renal cell tumors may be used

for palliation of symptoms resulting from the primarytumor or caused by ectopic hormone or cytokineproduction. Preoperative arterial embolization may alsobe used to decrease blood loss during partial nephrec-tomy or facilitate surgery in cases of limited access to therenal hilar vessels (184,196).In summary, the evidence for resection of early-stage

RCC treated with resection is based on nonrandomizedlong-term cohort analyses. For the treatment of meta-static disease, the majority of evidence is based onrandomized evidence with progression-free survival asthe endpoint. The only exception to this is temsirolimus,for which a survival advantage has been demonstrated inrandomized studies (197).

Osseous Metastatic DiseaseThe skeleton is the third most common site of metastaticdisease and affects 30%–95% of patients with breast,prostate, lung, bladder, and thyroid cancers (198).Although external-beam radiation is the standard ofcare for the treatment of painful osseus metastases,symptom relief can be delayed or transient (199).Limitations of radiation dose exposure to thesurrounding normal tissue may also preclude repeatradiation for persistent or recurrent pain (200). RFablation and cryoablation of painful osseus metastaseshave been shown to consistently provide significant andprolonged pain improvement (201–203). Multiple probescan be used to treat large tumors, and ice-ball visual-ization with cryoablation provides an important benefitwhen treating tumors adjacent to critical structures(200).Cementoplasty, including vertebroplasty and kypho-

plasty, plays an important role in treating painfulvertebral compression fractures in patients with cancer.Metastatic disease, in addition to previous RT, hormoneand steroid treatments, and poor nutritional status, in-crease the risk of development of painful vertebral com-pression fractures (204). A prospective, multicenter,randomized trial by Berenson et al (205) (CancerPatient Fracture Evaluation trial) demonstrated that,compared with nonsurgical management, balloonkyphoplasty provided a significant reduction in pain,analgesic agent use, and disability, as well as significantimprovement in quality of life (level IC evidence).


Combining RF ablation with vertebroplasty or kypho-plasty can provide local tumor control and may reduce therisk of procedure-related complications. In addition totumor necrosis, thermal effects can change the tumorconsistency to optimize cement distribution within thelesion, and vessel thrombosis within the ablation zone mayreduce the risk of venous cement leakage that can result inradiculopathy (epidural and neural foraminal veins) orpulmonary embolism (206,207). When combined withkyphoplasty, RF ablation may reduce the likelihood ofcement leakage by allowing for a low-pressure infusion ofcement into a preformed cavity, particularly in circum-stances in which the lesion is close to critical structures orin the presence of vertebral body cortical defects (207).Cementoplasty is contraindicated in patients with spinalcord compression, spinal instability as evidenced by asevere kyphotic deformity or vertebral body subluxation,or osteomyelitis. Posterior wall defects and epidural tumorspread are relative contraindications that require carefulconsideration (208,209).

CONCLUSIONS

Cancer treatment comprises the broadest range ofmedical disciplines and requires the collaboration ofnumerous specialists to provide patients with optimalcare and outcomes. Such effective collaborationdemands a precise understanding of the disease entitiesand their standard-of-care treatments, as well as anexpert comprehension of the rationale, levels of evi-dence, and controversies that underlie the treatmentdecisions. A mastery of the fundamentals of oncologyis the foundation of such knowledge and the necessaryfirst step in further advancing the specialty of interven-tional oncology. We hope these fundamentals are pro-vided in this review.

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Cancer Concepts and Principles: Primer for the Interventional Oncologist—Part I

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