Encyclopedia of radiation oncology


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Encyclopedia of radiation oncology

  1. 1. CCA-125CHRISTIN A. KNOWLTON1, MICHELLE KOLTONMACKAY21Department of Radiation Oncology, DrexelUniversity, Philadelphia, PA, USA2Department of Radiation Oncology, MarshfieldClinic, Marshfield, WI, USASynonymsCancer antigen 125DefinitionCA-125 is a protein that is considered a tumormarker, or biomarker, found in greater concen-tration in tumor cells than in normal tissues.Ovarian cancer demonstrates a higher concentra-tion of CA-125 in most cases. The role of CA-125is not well understood. This blood test isperformed at diagnosis and can be helpful forfollowing disease status.Cross-References▶ Endometrium▶ OvaryCA 15-3▶ Breast Tumor MarkersCA 27-29▶ Breast Tumor MarkersCAMPEP▶ Commission on Accreditation of MedicalPhysics Education Programs, Inc.Cancer Antigen 125▶ CA-125Cancer Colon▶ Colon CancerCancer ImmunomeTOD W. SPEERDepartment of Human Oncology, University ofWisconsin School of Medicine and Public Health,UW Hospital and Clinics, Madison, WI, USADefinitionComplete set of all known immunogenic tumorantigens. Theoretically it is a infinite challenge.L.W. Brady, T.E. Yaeger (eds.), Encyclopedia of Radiation Oncology, DOI 10.1007/978-3-540-85516-3,# Springer-Verlag Berlin Heidelberg 2013
  2. 2. It is currently under ongoing research anddevelopment.Cross-References▶ Targeted RadioimmunotherapyCancer Intestine▶ Colon CancerCancer of the Breast TisROBYN B. VERA1, DOUGLAS W. ARTHUR2,DAVID E. WAZER3,41Department of Radiation Oncology, Universityof Michigan, Ann Arbor, MI, USA2Department of Radiation Oncology, College ofMedicine,DrexelUniversity, Philadelphia, PA, USA3Radiation Oncology Department, Tufts MedicalCenter, Tufts University School of Medicine,Boston, MA, USA4Radiation Oncology Department, Rhode IslandHospital, Brown University School of Medicine,Providence, RI, USASynonymsCarcinoma in situ; Noninvasive breast cancer;Stage 0 breast cancer; TisN0M0DefinitionsBreast Conservation Therapy. A multidisciplinaryapproach of breast-conserving surgery and adju-vant radiotherapy with the goal of achieving in-breast disease control while preserving breastcosmesis.Paget’s Disease. A clinical presentation of nip-ple eczema and superficial epidermal scaling,which can progress to crusting, erosion, and exu-dates. Histologically characterized by the presenceof Paget’s cells, described as large, round to ovalcells that contain hyperchromatic nuclei andprominent nucleoli, scattered throughout the epi-dermis, this process is often associated with under-lying DCIS or invasive carcinoma.Lobular Carcinoma In Situ (LCIS). Non-infiltrating lobular proliferation of loosely cohe-sive carcinoma cells filling the acinar space.Ductal Carcinoma In Situ (DCIS). A prolifer-ation of ductal carcinoma cells that arise withinand are confined to the ductal lumens of thebreast and that do not infiltrate the basementmembrane.In Situ Carcinoma. A proliferation of malig-nant-appearing cells without evidence of invasionthrough the epithelial basement membrane, var-iants arising from the breast include LCIS, Paget’sdisease, or DCIS.Lumpectomy/Segmental Mastectomy. Theremoval of breast disease with the goal of com-plete excision with negative surgical marginswhile conserving the breast.Simple Mastectomy. The removal of theentire breast tissue, from the clavicle to therectus abdominus muscle, between the sternaledge of the latissimus dorsi muscle, with theremoval of the fascia of the pectoralis majormuscle.Modified Radical Mastectomy. An axillarynodal dissection, levels I and II, in addition tothe removal of the entire breast tissue, from theclavicle to the rectus abdominus muscle, betweenthe sternal edge of the latissimus dorsi muscle,including the removal of the fascia of thepectoralis major muscle.Multicentric Disease. At least two areas ofdiscontinuous disease within the breast that areseparated by more than 4 cm signifying the inabil-ity to remove known disease in one lumpectomyspecimen. Multicentric disease is a contraindica-tion to breast conservation therapy.Multifocal Disease. At least two areas ofdiscontinuous disease that are within 4 cm of78 C Cancer Intestine
  3. 3. one another and removable within in one lump-ectomy specimen. Multifocality is not a contrain-dication to breast conservation therapy.Accelerated Partial Breast Irradiation. Analternative form of adjuvant radiotherapy usedwhen the treatment target is defined as 1–2 cmbeyond the lumpectomy cavity allowing treat-ment to be delivery in an accelerated fashion.Typically, highly conformal treatment techniquesdeliver the intended dose in 5 days.Whole Breast Radiation. Treatment of the allipsilateral breast tissue with external beam irradi-ation utilizing a conventional or hypofrac-tionated treatment scheme.BackgroundLobular Carcinoma In SituHistologically, LCIS is a non-infiltrating lobularproliferation of loosely cohesive epithelial cellsthat fill the acinar space. A distinguishing featureis that LCIS lacks E-cadherin gene expression inover 95% of cases. E-cadherin is a cell–cell adhe-sion molecule that contributes to epithelialorganization and its absence results in the micro-scopic discohesive nature of LCIS. The presenceor absence of E-cadherin positivity aids indistinguishing LCIS from DCIS. LCIS specimensare typically estrogen receptor positive and rarelyHer2Neu positive or p53 mutated.Paget’s DiseaseHistologically, scattered throughout the epider-mis of patients presenting with a crusting, bleed-ing and/or ulcerative nipple, are characteristicPaget’s cells. Paget’s cells are described as large,round to oval cells with hyperchromatic nuclei,prominent nucleoli with frequent mitosis. Inabout half of the cases, an appreciable massis present of which most are invasive carcinoma.Without an associated palpable mass, 66–86%of patients will have an underlying componentof DCIS.DCISOut of the estimated 192,370 new breast cancersdiagnosed in 2009, 62,280 will be noninvasive ofwhich 85% will be DCIS. DCIS representsa continuum of histologic clonal proliferationsthat arise within and are confined to the ductallumens. DCIS lacks the ability to metastasize.Associated axillary nodal metastasis or distantmetastasis are rarely reported and most likelyrepresent undetected invasive carcinoma. Riskfactors associated with the development of DCISare akin to those established for invasive breastcancers and include female gender, older age,benign breast disease, family history, nullparity,and unopposed exposure to estrogen. Historicallyan architectural classification system has beenused, dividing DCIS into five classic histologicsubtypes: comedo, solid, cribiform, papillary,and micropapillary. Often, there are mixed archi-tectural subtypes within one specimen. Limitedprognostic significance has been associated withthese descriptors suggesting limited value in thisarchitectural division. However, alternative fea-tures have been shown to be important andshould be reported: nuclear grade, necrosis,polarization. Additional features that are of prog-nostic and therapeutic significance include mar-gin status, size of the lesion, and a description ofthe relationship of the lesion to any microcalci-fications, specimen x-rays, and mammographyfindings.Initial EvaluationThe incorporation of mammograms as a standardscreening for invasive breast cancers has resultedin the increased diagnosis of in situ breast. Oncedetected, biopsy confirmation of in situ diseaseshould be pursued. Biopsy can be obtained underultrasound or needle-localized guidance usinga fine-needle aspiration, core-cutting needlebiopsy, or excisional biopsy. In addition,a thorough history and physical exam should becompleted with a medical history documentingCancer of the Breast Tis C 79C
  4. 4. family history of associated cancers as well asobstetric and gynecological histories includingthe age at first menarche, age at first pregnancy,number of pregnancies, duration of breast feed-ing, any hormone replacement therapies, and theuse of oral contraceptives. The physical examshould include examination of bilateral breasts,supraclavicular, infraclavicular, and axillary nodalbasins with staging documentation.Once all biopsies have been evaluated and thespecific disease entity is identified, therapeuticoptions that should be considered include obser-vation, breast-conserving therapy, and mastec-tomy. Suitable management recommendationswill depend on details of diagnosis, patient char-acteristics, and patient preferences.Differential DiagnosisThe skin and nipple changes characteristic of theclinical presentation of Paget’s disease can mimicthat of contact dermatitis, eczema, superficial-spreading melanoma, pagetoid squamous cellcarcinoma in situ, and the histologic clear cellsof Toker.Mammographic abnormalities that signalthe presence of DCIS and/or LCIS are not specificto these pathologic entities, and a biopsy isrequired to distinguish from papilloma, atypicalductal hyperplasia, atypical lobular hyperplasia,invasive lobular carcinoma, and invasive ductalcarcinoma.Imaging StudiesMammography plays an essential role in the earlydetection of noninvasive lesions. Patients withsuspected or known Paget’s disease require bilat-eral mammograms to evaluate for evidence ofunderlying disease and to rule out additionalmulticentric and contralateral disease processes.The distinctive mammographic features of DCISand LCIS are the presence of microcalcificationsand the specific character of these calcificationsare suggestive of the pathologic disease process.Linear branching microcalcifications are associ-ated with high-grade DCIS and comedo necrosis.Heterogeneous granular calcifications are associ-ated with moderately differentiated DCIS. Finegranular microcalcifications are found with low-grade, non-comedo DCIS. The mammographicextent of the abnormality guides the plannedextent of surgical excision; however, the imagingsize typically underestimates the pathologic dis-ease spread by 1–2 cm.Increasingly, bilateral breast magnetic reso-nance imaging (MRI) studies are ordered prior tosurgery, yet their role as screening study remainscontroversial.In patients presenting with nipple dischargeand negative mammography, a galactography canbe employed to distinguish the presence ofa papilloma from an underlying DCIS.Laboratory StudiesThere are no specific laboratory studies needed inthe workup and evaluation of noninvasive diseasebut it is anticipated that patients will have theappropriate blood work and metabolic panel ana-lyzed in anticipation of surgery.TreatmentPaget’s DiseaseTreatment for Paget’s disease is started with theresection of the affected nipple-areolar complex,skin, and underlying breast tissue. This canbe accomplished with a total mastectomy ora breast-conserving surgical resection achievingnegative pathologic margins. Breast-conservingsurgery should be followed by whole breast radio-therapy. Further treatment details are dictated bythe presence and characteristics of any underlyinginvasive or noninvasive disease.LCISTypically, LCIS is an incidental biopsy finding.Patients with a diagnosis of LCIS only managed80 C Cancer of the Breast Tis
  5. 5. with biopsy only have an increased risk for devel-oping invasive ipsilateral and contralateral carci-nomas. The risk for subsequent development ofinvasive disease is less than 15% at 12 years; there-fore, observation alone is the standard manage-ment for pure LCIS. Biopsy evidence of pure LCISshould be followed by lumpectomy to rule outadjacent DCIS or invasive disease. There is nobenefit to achieving pathologically negative mar-gins and thus no role for re-excision to obtainmargins clear of LCIS. Patients should befollowed regularly with routine bilateral mammo-grams and physical exams. If there is an addi-tional histology identified in the tissue, that is,DCIS or invasive carcinoma, the acceptedapproach is to disregard the presence of LCISand accordingly manage the in situ or invasivebreast component. Patients who are young, witha strong family history, and with diffuse diseaseare a subset of the population with LCIS who areconsidered high risk for subsequent developmentof invasive disease. Prophylactic intervention withthe use of tamoxifen or bilateral mastectomies isan appropriate consideration in this group ofpatients.DCISOnce other invasive components of disease havebeen excluded, the primary focus becomes localmanagement of DCIS in the breast. There areseveral approaches ranging from whole breasttherapy to the treatment of a partial breast target.All presentations of DCIS can be successfullymanaged with total mastectomy. Mastectomyseries report disease control rates approaching100% and a cancer-specific mortality rate of lessthan 4%. In cases of multicentric disease presen-tations, diffuse DCIS processes, in patients withcontraindications to radiotherapy, or when antic-ipated cosmetic results are unacceptable, mastec-tomy is the standard of care. There is no phase IIItrial comparing total mastectomy to lumpectomyplus radiation for patients with pure DCIS;however, parallel phase III trials for invasive car-cinomas demonstrate comparable local controlrates and equivalent overall survival betweenbreast conservation treatment with post-lumpectomy radiation and mastectomy. Provid-ing the additional psychological benefit of organpreservation, breast-conserving therapy has beenaccepted as standard of care. There are four ran-domized trials with similar outcomes that aggre-gately demonstrate the locoregional benefit ofadjuvant radiation by comparing surgical exci-sion to surgical excision with the addition ofwhole breast radiation. The role of tamoxifenhas also been established in breast conservationtherapy with several phase III trials (see Table 1).The National Surgical Adjuvant Breast andBowel Project (NSABP) protocol B-17 was the firstprospective randomized trial to evaluate the role ofadjunctive radiotherapy for patients with DCISwhohad undergone a local excision with tumor-freemargins (Fisher et al. 2001). After lumpectomy,814 patients were randomized to either postoper-ative whole breast radiotherapy to 50 Gy, or nofurther therapy. With a median follow-up of12 years, the in-breast tumor recurrence rate withlumpectomy alone was 31.7% and reduced to15.7% with the addition of radiation. The benefitwas realized within patient groups that presentedclinically and mammographically and in those49 years old and >49 years old. Evaluation ofpathologic features that included comedonecrosis,histologic type, margin status, lymphoid infiltrate,nuclear grade, focality, stroma, and tumor sizerevealed only comedonecrosis as a significantpredictor for in-breast recurrence. It should benoted that despite higher failure rates in thosewith comedonecrosis whole breast radiotherapyreduced the risk of in-breast failure and supportingbreast conservation therapy as an appropriateapproach in this group of patients.A randomized phase III trial, contemporaryto the NSABP B-17, was launched by the Euro-pean Organization for Research and Treatment ofCancer of the Breast Tis C 81C
  6. 6. Cancer (EORTC) evaluating the role of radiother-apy after complete local excision of DCIS withhistologically confirmed tumor-free margins(Bijker et al. 2008). The 1,002 patients were ran-domized to local excision with or without wholebreast radiotherapy to 50 Gy. Out of thesepatients, 5% received a boost to the surgical bed.After a median follow-up of 10.5 years, the in-breast recurrence rate of 26% is reported in theexcision alone arm, whole breast radiotherapyreduced this rate to 15%. Subgroup analysisrevealed the benefit of radiation was equivalentfor all entrants. However, two groups with anexceptionally low risk of recurrence, less than10%, were those with well-differentiated DCISwith either a clinging or micropapillary growthpattern. The absolute benefit of radiotherapyremained consistent for these patients but therelative benefit of radiotherapy was less. Thiswas further confirmed in an intergroup trial runby the Eastern Cooperative Oncology Group andNorth Central Cancer Treatment Group ina population of conservatively selected patientswith DCIS and treated with wide excision only.This experience was reported with a median fol-low-up of 6.2 years. Five hundred and sixty-fivepatients were evaluable and the 5 year rate ofipsilateral in-breast failure was 6.1% in the low-intermediate grade group and 15.3% in the high-grade group.From the conclusions drawn from B-17, theNSABP initiated a follow-up trial to determinethe benefit of tamoxifen after postoperativeradiotherapy (Fisher et al. 1999). The criteriawere expanded from B-17 to include womenwith DCIS and LCIS, with one or more massesor calcification clusters, provided that all diseasewas excised. Of note, 15% of the patients hadmicroscopically positive margins on histologicevaluation. After local excision, 1,804 womenwere randomized to whole breast irradiationand placebo or whole breast irradiation followedby tamoxifen for 5 years. Postoperative radiother-apy was delivered with tangential fields to 50 GyCancer of the Breast Tis. Table 1 Results from five randomized trials comparing breast conservationtherapies for DCISNo ofpatients XRT doseMedianfollow-up(months)IBTR afterexcisionaloneIBTR after excision +XRTNSABP B-17(12 year follow-up)818 50 Gy 128 32% 16%EORTC 10853 (10 yearfollow-up)1,010 50 Gy (5%boosted)126 26% 15%NSABP B-24 (7 yearsfollow-up)1,804 50 Gy 87 – 11.1% (7.7% + TAM)UKCCCR (4.4 year follow-up) 1,030 50 Gy 53 14% (11% +TAM)6% (2% + TAM)SweDCIS (8 year follow-up) 1,067 50–54 Gy 96 (mean) 27% 12%XRT radiation, IBRT in-breast tumor recurrence, TAM tamoxifen, NSABP National Surgical Breast and Bowel Project, EORTCEuropean Organization for Research and Treatment of Cancer, UKCCCR United Kingdom Coordinating Committee onCancer Research82 C Cancer of the Breast Tis
  7. 7. in 25 fractions. Patients were administered eitherplacebo or tamoxifen at 10 mg, twice daily for5 years. At 7 years of follow-up, the in-breastfailure rate following lumpectomy, radiotherapyand placebo was 11.1% and reduced to 7.7%when tamoxifen was added to lumpectomy andradiotherapy. The addition of tamoxifen reducedthe contralateral breast occurrence rate from4.9% to 2.3%.To further examine the role of tamoxifen,The United Kingdom Coordinating Committeeon Cancer Research (UKCCCR) DCIS WorkingGroup designed a protocol comparing excisionalone, excision plus tamoxifen, excision plusradiotherapy, and excision plus radiotherapyand tamoxifen (Houghton et al. 2003). Tamoxifenwas prescribed as 20 mg/day, and radiotherapywas delivered through whole breast tangentialfields to a total dose of 50 Gy. Boost was notrecommended. To qualify for enrollment, the1,030 patients underwent an excision with freehistologic margins. Randomization in this 2 Â 2factorial design was optional, and the patient andsurgeon were able to select portions of their adju-vant treatment. When reported with 52.6 monthfollow-up, local recurrence was documented in14% of the patients treated with excision onlyand reduced to 6% when the excision wasfollowed by radiotherapy. The addition of tamox-ifen offered minimal benefit toward overall ipsi-lateral local control rates when added toradiotherapy; however, it did appear to reducethe ipsilateral recurrence rate of DCIS in theabsence of radiotherapy.The SweDCIS study from the Swedish BreastCancer Group randomized 1,067 patientsbetween lumpectomy followed by radiotherapyand lumpectomy alone for the treatment ofDCIS (Holmberg et al. 2008). Patients underwenta sector resection with the goal of achieving a 1cm gross surgical margin, yet microscopic clearresection was not required. The majority ofpatients received 50 Gy in 25 fractions to thewhole breast. In a separate series, a split courseof 54 Gy in 27 fractions, separated by a 2 weekbreak was allowed. No boost dose was delivered.At a mean 8 year follow-up, the in-breast failurerisk reduction was 16.0%. Subgroup analysis byage, lesion size, focality, completeness of excision,and having a screening detected lesion confirmedradiation provided a benefit to all groups.The results from these phase III random-ized trials report relatively similar outcomes.In summary, they demonstrate lumpectomyplus adjuvant radiation durably reduces theipsilateral breast cancer recurrence rates byapproximately 50–60% compared to lumpec-tomy alone. After excision only, one half of thelocal recurrences are DCIS and the other half areinvasive tumors; radiation reduces each of theserecurrence rates by 50%. None of the random-ized trials demonstrate an overall survival ben-efit. The addition of adjuvant radiation reducesthe rate of invasive breast cancer recurrence to0.5–1%/year.Excision Alone for DCISConsiderable effort has been made to identifya subset population within DCIS patients forwhom adjuvant radiation does not offera benefit. The Van Nuys Prognostic Index isa scoring index that was developed through ret-rospective analysis, to select patients for whomlumpectomy alone was sufficient to control localdisease. It is based on tumor grade, size, andsurgical margin. Rigorous obtainment of surgicalmargins greater than 1 cm was an importantpredictor of this index that required meticulousevaluation of the entire surgical specimen. Thisexhaustive pathologic evaluation is not a routinepractice at most facilities. The Van Nuys Prognos-tic Index opens up the possibility of lumpectomyalone to control DCIS once the requisite 1 cmcircumferential pathologic margin are achieved,yet this index has yet to be independentlyvalidated.Cancer of the Breast Tis C 83C
  8. 8. Accelerated Partial BreastIrradiationIn much the same way as excision only, the goal ofAPBI is to treat a limited aspect of the breast;surgical cavity, plus a 1–2 cm margin. Severaltechniques are in use and being evaluated allwith their own pros and cons. The treatmenttime is most frequently 5 days, but shorter coursesand intraoperative treatment is also being evalu-ated. Several small studies have reported goodresults using APBI in the treatment of DCIS;however, definitive data is awaited.In summary, accepted treatment approachesfor DCIS are directed to the whole breast with eithermastectomy or breast conservation therapy withwhole breast radiotherapy. Partial breast treatmentswith wide excision only or lumpectomy followed byAPBI appear to have a role but additional data isawaited. Size, margin status, and grade appear to beimportant factors in determining the needed extentof treatment. The use of tamoxifen is a decisionbalanced between the benefit of reducing recurrenceand the toxicity from taking the medication realiz-ing that no overall survival benefit is associated withreduced recurrence rates.Cross-References▶ Brachytherapy: High Dose Rate (HDR)Implants▶ Conformal Therapy: Treatment Planning,Treatment Delivery, and Clinical Results▶ Stage 0 Breast CancerReferencesBijker N, Meijnen P, Peterse JL et al (2008) Breast-conservingtreatment with or without radiotherapy in ductal car-cinoma-in-situ: ten-year results of European Organi-sation for Research and Treatment of Cancerrandomized phase III trial 10853 – a study by theEORTC breast cancer cooperative group and EORTCradiotherapy group. J Clin Oncol 24:3381–3387Fisher B, Dignam J, Wolmark N et al (1999) Tamoxifen intreatment of intraductal breast cancer: NationalSurgical Adjuvant Breast and Bowel Project B-24randomised controlled trial. Lancet 353:1993–2000Fisher B, Land S, Mamounas E et al (2001) Prevention ofinvasive breast cancer in women with ductal carcinomain situ: an update of the National Surgical AdjuvantBreast and Bowel Project Experience. Semin Oncol28:400–418Holmberg L, Garmo H, Granstrand B et al (2008) Absoluterisk reductions for local recurrence after postoperativeradiotherapy after sector resection for ductal carci-noma in situ of the breast. J Clin Oncol 26:1247–1252Houghton J, George WD, Cuzick J et al (2003) Radiotherapyand tamoxifen in women with completely excised duc-tal carcinoma in situ of the breast in the UK, Australia,and New Zealand: randomized controlled trial. Lancet362:95–102Cancer of the Colon▶ Colon CancerCancer of the Large Intestine▶ Colon CancerCancer of the PancreasRACHELLE LANCIANODepartment of Radiation Oncology, PhiladelphiaCyberknife Center, Delaware County MemorialHospital, Drexel Hill, PA, USASynonymsDuctal adenocarcinoma; Exocrine pancreaticneoplasms; Pancreatic cancerDefinitionCarcinoma arising within the exocrine or endo-crine cells of a centrally located gland in theepigastrum of the abdomen called the Pancreas.84 C Cancer of the Colon
  9. 9. DescriptionIn the USA, pancreas cancer is the second mostcommon malignant tumor of the gastrointestinaltract and the fourth leading cause of cancer deathsin adults surpassed only by lung, colon, andbreast cancers. Pancreas cancer is difficult to diag-nose in early stages with only 15–20% resectablefor cure at presentation. Even for those patientsable to have surgery with pancreaticoduo-denectomy, long-term survival rate remains poorwith median survival of 13 months and 5-yearsurvivals of 15–30% for node negative and 10%for node positive disease. Forty percent of patientspresent with metastatic disease with median sur-vival of less than 8 months and 30–40% of patientspresent with locally advanced unresectable tumorswith median survival of 8–12 months. Mosttumors arise in the head of the pancreas, oftencausing bile duct obstruction with jaundice.The majority of pancreas cancers (85%) areadenocarcinoma arising from the ductal epithe-lium and more than 95% arise from the exocrineelements including the ductal and acinar cells.Only 5% of pancreatic neoplasms arise from theendocrine pancreas or islet cells.Surgery, if possible, is the first treatmentapproach for pancreatic cancer.Adjuvant treatment with chemotherapyand radiation following surgery has improvedsurvival over surgery alone. If the cancer isunresectable or the patient is medically inopera-ble, local and systemic treatments can providepalliation.AnatomyThe pancreas is a lobulated transverse retroperi-toneal gland located in the upper abdomenextending from the duodenum to the spleendivided into the head, neck, body, and tail. Thetransverse colon passes in front of the pancreaswhile the posterior surface is in contact with theinferior vena cava, common bile duct, right dia-phragm, and aorta (Fig. 1).The head of the pancreas is lodged within thecurve of the duodenum and includes the medialand inferior uncinate process. Tumors of the headSuperiormesentericveinPortalveinAortaHead TailBodyCancer of the Pancreas. Fig. 1 Anatomy of the PancreasCancer of the Pancreas C 85C
  10. 10. of the pancreas are those arising to the right of thesuperior mesenteric-portal vein confluence.Tumors of the body and neck of the pancreas aredefined as those arising between the left edge ofthe superior mesenteric-portal vein confluenceand the left edge of the aorta. The body of thepancreas is in contact with the pylorus and stom-ach anteriorly and the aorta, left adrenal gland,and kidney posteriorly. The tail is narrow andextends to the gastric surface of the spleen andleft colic flexure. Tumors of the tail are thosearising to the left edge of the aorta.The pancreas is intimately related to the ori-gin of the superior mesenteric and celiac arteriesand portal vein posterior. Invasion of these vesselsdetermines resectability. The pancreatic ductpasses from the tail to head emptying the pancre-atic juices through the Ampulla of Vater into theduodenum. Regional drainage is to the superiorand inferior pancreaticoduodenal, portahepatic,celiac, and superior mesenteric and paraaorticlymph nodes. Venous drainage of the pancreas isthrough the portal system to the liver. In additionto the liver, lung and peritoneum are commonsites of metastatic disease.The ductal and acinar cells secrete digestiveenzymes and bicarbonate through the pancreaticduct which helps break down carbohydrates, fats,and acids in the duodenum. In the interstitium ofthe ductal and acinar cells lie the “Islets ofLangerhans” which secrete hormones such asinsulin, glucagon, and somatostatin into the sys-temic circulation for glucose control.EpidemiologyPancreas cancer is rare before age 45, and theincidence increases with age.Studies suggest that a small proportion of pan-creas cancers have a genetic etiology ranging from5% to 10%. Hereditary pancreatitis is associatedwith a markedly increased risk of pancreas cancerand the risk increases with age with a cumulativerisk of 40–50% at age 70 years. Pancreas cancer isassociated with Ashkenazi Jews and BRCA muta-tions, Peutz-Jeghers syndrome (hereditary intestinalpolyposis), atypical multiple-mole melanoma syn-drome, ataxia-telangiectasia, and possibly adeno-matous polyposis and Lynch syndrome (hereditarynon-polyposis colon cancer). Other associationswith pancreas cancer include non-O blood group,nonhereditary chronic pancreatitis and atypical dia-betes mellitus (onset in a thin older patient). Ciga-rette smoking, high body mass, and lack of physicalactivity are considered additional risk factors fordevelopment of pancreas cancer. Spiral CT andendoscopic ultrasound are suggested for patients atsignificant risk of developing pancreas cancer suchas those with a strong family history of pancreascancer and hereditary pancreatitis.Clinical Presentation, InitialEvaluation, and Imaging/Laboratory StudiesMortality rates for pancreas cancer parallel inci-dence because of locally advanced unresectable andmetastatic disease at presentation. Patients presentwith pain, weight loss, and jaundice. On exam,ascites or abdominal mass may be appreciated.Workup includes CT of the abdomen and pelviswhich may detect dilated ducts, pancreatic mass,or evidence of metastatic disease to the liver, peri-toneum, or retroperitoneal lymph nodes. Con-trast-enhanced CT scan with thin sections canalso determine resectability. Many patients requireendoscopic retrograde cholangiopancreatography(ERCP) with stent placement to bypass biliaryobstruction and for cytology. Endoscopic ultra-sound is used to stage the primary tumor, evaluatefor peripancreatic adenopathy, assess vascularinvasion, and obtain biopsy of tumor if ERCPcytology is nondiagnostic. In most patients withpancreas cancer, CA 19-9 serum tumor marker canbe prognostic with values !130 units/ml associ-ated with a higher rate of unresectable disease. CA19-9 can also be used to follow patients after sur-gery if positive preoperatively to detect recurrent86 C Cancer of the Pancreas
  11. 11. disease and for chemotherapy response in patientswho are unresectable. Patients are generally con-sidered unresectable for cure if there is extensiveperipancreatic and distant lymph nodes or metas-tases, encasement of the superior mesenteric vein(SMV), or SMV-portal vein confluence, orinvolvement of the superior mesenteric artery(SMA), inferior vena cava, aorta, celiac axis, orhepatic artery. Small peritoneal and liver metasta-ses can be detected by laparoscopy in high-riskpatients including those with CA 19-9>1,000 units/ml selecting out those who benefitmost from pancreas resection.Clinical staging utilizes all clinical testingincluding CT scans and endoscopic ultrasound,and patients are classified into localized resectable(Stage I and II), locally advanced (Stage III), andmetastatic (Stage IV) pancreas cancers. Pathologicstaging requires resection of the pancreatic cancerwith at least 12 regional lymph nodes assessed. Torecord T stage, tumor size ( 2 cm vs. >2 cm),extra-pancreatic extension, and involvement ofthe celiac axis or superior mesenteric artery mustbe assessed from the surgical specimens.TreatmentSurgery is the standard treatment for pancreascancer if resectable. Approximately one third ofpatients will have positive margins following sur-gery (usually retroperitoneal) and two thirdslymph node metastases. Following surgery alone,more than one half of patients develop locoregionalrecurrence without distant metastases.Adjuvant chemotherapy and chemoradio-therapy have been shown to increase survival inrandomized and uncontrolled trials following sur-gery for pancreas cancer. Two-year survival ratefrom the Gastrointestinal Tumor Study Grouptrial utilizing 40 Gy to the tumor bed with concur-rent and adjuvant 5FU chemotherapy increasedfrom 10% with surgery alone to 20% withcombined modality adjuvant treatment. Ina series of 1,092 patients with pancreas cancertreated with chemotherapy and radiation(50.4 Gy) following surgery at Johns Hopkins Hos-pital and Mayo Clinic between 1985 and 2005, 2-year survival rate increased from 31% with surgeryalone to 45% with adjuvant combined modalitytreatment.An alternative adjuvant approach preferredin Europe is chemotherapy alone with 5FU orGemcitabine regimens since European random-ized trials did not show a benefit to postoperativeradiation. The most recent European trial foundno difference in survival between 5FU andGemcitabine in the adjuvant setting; however,Gemcitabine had less toxicity and is the favoredregimen. The current Radiation Therapy Oncol-ogy Group (RTOG#0848) randomized trial foradenocarcinoma of the pancreas followingpancreaticoduodenectomy randomizes patientswith pancreatic head lesions to Gemcitabine+/-erlotinib for five cycles with a second randomiza-tion to 5FU/radiation 50.4 Gy versus an addi-tional cycle of chemotherapy. This internationalstudy should elucidate the benefit of adjuvantradiation and erlotinib in resected pancreatichead adenocarcinoma.For patients that have marginally or borderlineresectable cancer, preoperative chemoradiotherapyhas been used to improve resectability, identifythose patients who are unlikely to benefit fromsurgery due to development of metastatic disease,and hopefully improve survival by the early andintensive use of chemotherapy. For patients withlocally advanced unresectable disease, radiation andconcurrent 5FU chemotherapy improved survivaland performance status and decreased hospital dayscompared to supportive care alone.Radiation can be delivered with conventionalfractionation (50.4 Gy over 5.5 weeks) with con-formal or intensity-modulated radiation therapy(IMRT) techniques. Treatment planning includesa CT in the treatment position with immobiliza-tion to include the entire liver and kidneys for dosevolume analysis. Bowel contrast may be used toCancer of the Pancreas C 87C
  12. 12. help identify the stomach and duodenum as wellas large and small bowel within the treatmentfields. IV contrast can be helpful to outline theceliac axis, portal vein, aorta, and superior mesen-teric artery. The tumor volume is contoured if thetumor is not resected and considered gross tumorvolume (GTV). In the postoperative setting thereis no GTV. The location of the pancreatic tumorprior to resection must be contoured based onpreoperative CT with axial images, the operativenote, and pathology report. The most proximal1–1.5 cm of celiac axis, 2.5–3.0 cm of superiormesenteric artery and portal vein segment thatruns anterior to the IVC should be contoured. Inaddition the aorta from the level of the highestcontoured vessel/tumor bed to the bottom of L2and the pancreaticojejunostomy should becontoured separately. The clinical tumor volume(CTV) includes the above structures with variableexpansion depending on the structure contoured.The planning tumor volume (PTV) includes theCTV with 0.5 cm expansion. In addition, normaltissues that should be contoured include liver,right and left kidneys, small and large bowel,stomach, and spinal cord. The goal of radiationtreatment planning is to treat the PTV with theprescribed dose, minimize dose to normal struc-tures, and maximize dose homogeneity.Stereotactic body radiotherapy (SBRT) andintraoperative radiation therapy (IORT) havebeen explored as alternative techniques for radi-ation delivery. Unfortunately the available datahas not shown a survival advantage for thesetechniques over standard fractionated radiation.Chemotherapy for metastatic disease includesgemcitabine, 5-fluorouracil, and oxaliplatin. Radia-tiontherapycanalsobeusefulinpalliationofpainoralternative symptoms related to metastatic disease.Cross-References▶ Colorectal Cancer▶ Hepatic Metastasis▶ Intraoperative Radiation Therapy (IORT)▶ Primary Cancer of The DuodenumReferencesAmerican Joint Committee on Cancer (AJCC) (2010)Exocrine and endocrine pancreas, Chapter 24. In:Edge SB (ed) Cancer staging manual, 7th edn. Springer,New YorkFernandez-del Castillo C (2012) Clinical manifestations,diagnosis and surgical staging of exocrine pancreaticcancer. www.uptodate.comFernandez-del Castillo C, Jimenez R (2012) Epidemiologyand risk factors for exocrine pancreatic cancer. www.uptodate.comJemal A, Siegel R, Xu J et al (2010) Cancer statistics, 2010. CACancer J Clin 60:277Lim JE, Chien MW, Earle CC et al (2003) Prognostic factorsfollowing curative resection for pancreatic adenocarci-noma: a population-based, linked database analysis of396 patients. Ann Surg 237:74Longnecker D (2012) Pathology of exocrine pancreatic neo-plasms. www.uptodate.comNational Comprehensive Cancer Network, Practice guide-lines in oncology. Version 2.2012. Pancreatic adenocar-cinoma. www.nccn.orgPancreatic cancer radiation atlas for treatment planning.www.rtog.org/atlas/pancreasAtlas/main.html. RTOG0848 A phase III trial evaluating both erlotinib andchemoradiation as adjuvant treatment for patientswith resected head of pancreas adenocarcinoma.www.rtog.org/members/protocols/0848/0848.pdfRyan D, Mamon H (2011) Adjuvant and neoadjuvant ther-apy for exocrine pancreatic cancer. www.uptodate.comRyan D, Mamon H (2012) Management of locally advancedand borderline resectable exocrine pancreatic cancer.www.uptodate.comWillett CG, Czito BG, Bendell JC (2008) Cancer of thepancreas, Chapter 56. In: Perez CA, Brady LW(eds) Principles and practice of radiation oncology,5th edn. Lippincott Williams and Wilkins,PhiladelphiaCancer Quality of Life▶ Pain Management▶ Palliation▶ Supportive Care and Quality of Life88 C Cancer Quality of Life
  13. 13. Cancer-Related FatigueJAMES H. BRASHEARS, IIIRadiation Oncologist, Venice, FL, USADefinitionA persistent sense of physical, emotional, cogni-tive, and/or spiritual tiredness or exhaustion thatinterferes with normal functioning of the individ-ual. It is worse than might be expected fromrecent activity, frequently does not improve withrest, and is linked with malignancy or itsmanagement.Cross-References▶ Supportive Care and Quality of LifeCarboplatin (Carboplatinum)CHRISTIN A. KNOWLTON1, MICHELLE KOLTONMACKAY21Department of Radiation Oncology, DrexelUniversity, Philadelphia, PA, USA2Department of Radiation Oncology, MarshfieldClinic, Marshfield, WI, USADefinitionCarboplatin is a chemotherapy agent in the classof platinum medications that works by creatingintra- and interstrand DNA cross-links and DNAto protein cross-links, therefore interfering with celldivision. Carboplatin is commonly administeredin the treatment of ovarian cancer, often in combi-nation with paclitaxel. Side effects of carboplatininclude nausea and vomiting, myelosuppression,brittle hair, and fatigue.Cross-References▶ Ovary▶ Principles of ChemotherapyCarcinoid TumorFILIP T. TROICKI1, JAGANMOHAN POLI21College of Medicine, Drexel University,Philadelphia, PA, USA2Department of Radiation Oncology, Collegeof Medicine, Drexel University, Philadelphia,PA, USADefinitionSlow-growing, hormone-producing tumor thatexists within various sites of the body, most com-monly within the gastrointestinal tract.Cross-References▶ Colon Cancer▶ Lung Cancer▶ Stomach CancerCarcinoma In SituTHEODORE E. YAEGERDepartment Radiation Oncology, Wake ForestUniversity School of Medicine, Winston-Salem,NC, USADefinitionNon-invasive cancers that are typically small andconfined to the primary tissues of commence-ment within the organ of initiation.Carcinoma In Situ C 89C
  14. 14. Cross-References▶ Cancer of the Breast Tis▶ Melanoma▶ Stage 0 Breast Cancer▶ Uterine CervixCarcinoma of LungsTHEODORE E. YAEGERDepartment Radiation Oncology,Wake Forest University School of Medicine,Winston-Salem, NC, USADefinitionMalignancies arising from pulmonary tissues orresultant from metastasis to lung tissue.Cross-References▶ LungCarcinoma of the AdrenalGlandSTEPHAN MOSEDepartment of Radiation Oncology,Schwarzwald-Baar-Klinikum,Villingen-Schwenningen, GermanySynonymsAdrenal carcinoma; Adrenal cancerDescriptionTumors of the adrenal gland are rare tumorswith mostly aggressive local and metastatic spreadand – in case of advanced and metastatic disease –disappointing overall survival rates. They arecharacterized by adrenal gland-specific hormonaldysfunction, which often lead to the diagnosis,and/or non-specific abdominal symptoms. Adre-nal cancer which pathogenesis is largely unknownis found in every age. Treatment of choice is theradical surgical approach which also should bediscussed in an actual inoperable situation toreduce tumor burden and hormone inducedsymptoms. Although literature data provide littleinformation, chemotherapy and radiotherapymay be recommended for adjuvant and palliativetreatment.AnatomyBoth of the adrenal glands are located between thesuperior part of the kidney and the diaphragmaticcrura. The triangular right gland is related tothe inferior vena cava and the liver, whereas thesemilunar left one is placed in the near ofthe spleen, pancreas, and stomach. Embedded byperinephric tissue and still separated from the kid-ney itself, they are enclosed by the renal fascia. Theblood supply is derived from the inferior phrenicartery, the abdominal aorta, and the renal artery(superior, middle, and inferior suprarenal arter-ies). A large central hilar vein drains to the inferiorvena cava (right) and to the renal vein (left). Thelymphatic drainage follows the arterial vessels anddrains predominately to the lumbar nodes (celiacplexus, lateroaortic nodes above the renal pedicle).The adrenal gland is a hormone producingorgan which consists of two functionally separateunits with different embryologic origins. The cen-tral part of the gland (medulla, 10–20% of theorgan) produces catecholamines. The cortex(80–90% of the organ) secrets steroids: mineral-ocorticoids (e.g., aldosterone), glucocorticoids(e.g., cortisol), sex hormones (e.g., androgen).EpidemiologyMost of the adrenal carcinomas are cortextumors. However, the adrenocortical carcinoma(ACC) is a very seldom neoplasia (1–2 per 1million inhabitants), which could occur in every90 C Carcinoma of Lungs
  15. 15. age with a peak before the age <5 years and in thefourth and fifth decades. Bilateral tumors arediscovered in 2.4%. Whereas hormonal inactivetumors are more common in men (3:2 ratio) andin older patients (>30 years of age) hormonalactive carcinomas are more often diagnosed infemale (7:3 ratio) and younger patients.Carcinomas of the adrenal medulla are dividedinto neuroblastoma which is the most commontumor of the adrenal gland in children (90%)originating from the sympathetic nervous system,and malignant pheochromocytoma with an inci-dence of 5–46% of all diagnosed pheochromocy-tomas. Most of the extra-adrenal discoveredpheochromocytomas are malignant as well.There is only little information about the path-ogenesis of adrenal tumors. In case reports, thetransformation from adenomas into carcinomas isdiscussed (“second hit theory”) but the long-termfollow-up of so-called incidentalomas demon-strated no further advices. Most cases present assporadic tumors. However, adrenal carcinomahas been described as a part of hereditary can-cer syndromes (e.g., ▶ Li–Fraumeni syndrome,▶ Beckwith–Wiedemann syndrome, ▶ multipleendocrine neoplasia type I, and ▶ SBLA syn-drome) (Allolio & Fassnacht 2006; Coen 2008).Clinical PresentationTumors of the adrenal gland (Table 1) are verymalignant tumors with aggressive local andmultilocal metastatic spread (liver, lung, bone,lymph nodes). Because of its retroperitoneal loca-tion and – in case of hormonal inactivity – theirnonspecific symptoms (back pain, abdominalfullness, seldom weakness, and fever), they areoften diagnosed at a late date. However, 95% oftumors are hormonal active and in more than60% the patient is diagnosed with a hormonalexcess while these tumors are mostly diagnosedat an earlier stage.In adrenocortical tumors, most frequentlya ▶ Cushing’s syndrome alone or together withvirilization is presented. Virilization is more com-mon in children (adrenogenital syndrome). Inwomen, the overproduction of androgens leadsto hirsutism. The overproduction of aldosteroneis very seldom. Likewise, estrogen producingtumors that are commonly malignant are seldom;in men the tumor leads to testicular atrophy andgynecomastia.In adrenal medulla tumors (pheochromocy-toma), which in 90% occurs in inherited syn-dromes (▶ multiple endocrine neoplasia type II(MEN II A), association with Hippel–Lindau’sdisease, neurofibromatosis, von Recklinghausen’sdisease), patients present with a wide range ofhypertensive disease and associated symptoms(e.g., headache, tachycardia, palpitations, weak-ness) as well as cardiac failure and infarctionwhich are caused by excessive catecholamine pro-duction of the tumor.Macroscopically, carcinomas often showhemorrhage and necrosis. However, to finally dif-ferentiate between benign and malignant tumors,histopathological and immunohistological dis-crimination is necessary (larger nuclear size,numerous and atypical mitotic figures, invasionof vessels, and invasion of the capsule) (Weiss etal. 1989; Saeger 2000; Johanssen et al. 2008).Carcinoma of the Adrenal Gland. Table 1 Classifi-cation of adrenal tumorsAdrenal cortex Adenoma (hormonal active/inactive)Carcinoma (hormonal active/inactive)Adrenal medulla GanglioneuromaPheochromocytoma (benign/malignant)NeuroblastomaMixed type(ganglioneuroblastoma)Connective tissuetumorsMyelolipoma, lipomaMyoma, angiomaFibroma, fibrosarcomaCarcinoma of the Adrenal Gland C 91C
  16. 16. Differential DiagnosisBenign tumors of the adrenal gland (e.g., adeno-mas, ganglioneuromas) are more common(1–8% of the general population). Most of themare incidentally diagnosed. Laboratory and imag-ing studies are very important with regard to thetherapeutic procedure to differentiate thesebenign tumors from carcinoma.A rare tumor of the adrenal medulla isthe benign pheochromocytoma, which producescatecholamines causing hypertension (prevalenceof 0.1% of hypertensive patients) and maybe associated with various endocrine- andnonendocrine-inherited disorders. The minimallyinvasive adrenalectomy by the transperitoneal orretroperitoneal lateral approach has become thetreatment of choice.Imaging StudiesTumors larger than 6 cm are suspected to bemalignant (NIH-consensus). Carcinomas areoften irregularly shaped with potential invasioninto local structures and demonstrate inhomo-geneous contrast enhancement in imagingstudies. However, although there may be nosymptoms, with modern imaging studies moretumors of the adrenal gland tend to be inciden-tally discovered in an earlier stage (<3–6 cm).Computed tomography (CT) and the magneticresonance imaging (MRI) are quite equivalentwith an advantage for the MRI (T2-weightedimages) toward the diagnosis of venous invasion.This may be completed by an angiography. Theevaluation of the fat content as well as the washout of contrast media after 10 min could helpto discriminate tumors. It has to be evaluatedif the fluorodeoxyglucose positron emissiontomography is helpful to better differentiatebetween benign and malignant lesions. Further-more, CT (chest, abdomen) and bone scanare useful regarding the diagnosis of metastases(see Tables 2 and 3) (Coen 2008; Johanssenet al. 2008).Laboratory StudiesThe evaluation of hormonal changes is manda-tory in all patients with an adrenal mass. Theresults could give strong advices and could leadto the diagnosis of cancer (e.g., estrogen produc-tion in men, secretion of steroid precursor). Fur-thermore, the evaluation before therapy may haveinfluence on the extent of surgery (open versusminimal invasive surgery) as well as on postoper-ative strategies (e.g., postoperative insufficiencyof the adrenal gland in case of Cushing’s syn-drome). However, the evaluation before therapyis important to enable the early diagnosis ofrecurrence during the follow-up of patients.Besides taking the history and doing thephysical examination, preoperative hormonaldiagnostic studies are recommended (Table 3).TreatmentNowadays, approximately two-thirds of patientsare diagnosed in tumor stages in which surgery isthe treatment of choice (stage I 5%, stage II 39%,stage III 27%). In the other patients, a metastaticdisease has to be treated. The overall 5-year-survival of all stages ranges from 16% to 47%(stage I 80%, stage II 57%, stage III 40%, stageIV 15%). The median survival in metastatic dis-ease is less than 12 months. However, despiteCarcinoma of the Adrenal Gland. Table 2 TNM-staging (WHO 2004)Stage T N MI(T1 N0 M0)5 cm withoutinvasionÀ ÀII(T2 N0 M0)>5 cm withoutinvasionÀ ÀIII(T3 N0 M0, T1–2 N1M0)Outside adrenal fat + ÀIV(T3–4 N1 M0, T1–4N0–1 M1)Invading adjacentorgans+ +92 C Carcinoma of the Adrenal Gland
  17. 17. radical surgery 70–85% of patients develop bothlocal recurrent and/or metastatic disease, whichgives rise to the evaluation of adjuvant therapies.SurgerySurgery is the treatment of choice in adrenal tumorsgiving the best chance to cure the patient. Hereby,a margin-free resection is a strong prognostic fac-tor; if there is macroscopic tumor left, a secondsurgical approach has to be discussed. Even ifthe tumor seems to be inoperable predominatelyin hormone active tumors as well as in metastatictumors, surgery could be performed to reduce thetumor mass and its associated symptoms, and tocontrol the excessive production of hormones.Likewise, in case of local recurrence, surgery shouldbe discussed for the same reason. Especially inpheochromocytoma, the surgical approach is ahigh-risk procedure because of possible catechol-amine excess during surgery. Therefore, the patientshave to be monitored very carefully.Beyond studies, the open radical adrenalec-tomy is the standard procedure that is often com-bined with a lymphadenectomy. In case ofinvasion of adjacent organs, these organs have tobe (partially) removed. To reduce peri- and post-operative complications, tumor spillage has to beavoided. The lateral retroperitoneal approachrepresents the standard procedure in localizedadrenal tumors whereas the transabdominal ante-rior approach is usually performed in tumorswith invasion of adjacent organs and/or lymphnodes (Allolio et al. 2006; Johanssen et al. 2008).ChemotherapyIn advanced and/or metastastic disease, theadrenolytic agent mitotane is clearly effectivewith objective response rates of 14–36%. Unfor-tunately, most studies failed to demonstratea survival benefit and despite a response tomitotane approximately 50% of patients hada recurrence within 5 years. Nevertheless, becauseof the results in metatastic disease and despitelimiting data mitotane is recommended in theadjuvant setting.To reduce the hormonal excess serum, levelsof 10–14(À20) mg/L have to be obtained basedon the knowledge that higher levels are associatedwith better tumor response. Because of theincreased metabolic clearance of glucocorticoidsduring the mitotane therapy, the patient has to besubstituted with cortisol. Unfortunately, therapyis often limited by the side effects of mitotane(e.g., gastrointestinal symptoms, diarrhea, andnausea, less often: lethargy, somnolence, ataxia,dizziness). Therefore, besides an evaluation ofCarcinoma of the Adrenal Gland. Table 3 Preop-erative hormonal diagnostic studies in suspicion ofcancer of the adrenal gland (Recommendations ofthe “European Network for the Study of AdrenalTumors,” ENSAT)Laboratory studiesGlucocorticoids Dexamethason suppressiontest (24 h)Twenty-four hour urinarycortisolBasal level of serum cortisolBasal level of plasma ACTH(adrenocorticotrophichormone)Mineralocorticoids Serum potassiumQuotient of aldosterone/renin (in case ofhypertension and/orhypokaliemia)Sex hormones,steroid precursorsDehydroepiandrosterone(DHEA) (serum)17-hydroxyprosterone(serum)Androstendione (serum)Testosterone (serum)Estradiole (in men andpostmenopausal women)Evaluation ofpheochromocytomaTwenty-four hour urinarycontrol of catecholamineMetanephrine (plasma)Carcinoma of the Adrenal Gland C 93C
  18. 18. ACTH, aldosterone, and rennin, a strong moni-toring (blood count, cholesterol, triglyceride,transaminases) is mandatory.A lot of other chemotherapeutic agents werestudied in ACC but only a few patients respondedto those treatments. A regimen with a promisingpotential might be the combination of mitotane,etoposide, cisplatin, and doxorubicin; in the firstworldwide phase III trial (FIRM-ACT-study),this regimen will be actually compared toa combination of mitotane and streptomycin inmetastatic disease. Furthermore, efforts are madeto evaluate the efficiency of monoclonal anti-bodies and tyrosine kinase inhibitors (Terzolo &Berruti 2008; Veytsman et al. 2009).RadiotherapyThe role of radiotherapy in the treatment of thecarcinoma of the adrenocortical gland is contro-versial because the tumor was formerly consid-ered to be radioresistant. However, some smalltrials reported some objective local tumorresponses especially in a palliative setting (40–57%). Likewise, there is only little informationabout the role of radiotherapy in an adjuvantsituation where in 25–86% a local control wasobtained. Unfortunately, the number of patientslocally treated in the primary tumor area is smalland details about the delivered dose and the targetvolume definition are mostly missing. On theother hand, there are some reports demonstratingthat radiotherapy is effective regarding symptomreduction in case of bone and brain metastases aswell as in vena cava obstruction (50–77%). Inmalignant pheochromocytoma, it may beassumed that radiotherapy is limited to palliativetreatment (Coen 2008).After reviewing literature data and taking intoaccount the limited number of retrospectivelypublished trials, the European Network for theStudy of Adrenal Tumors (ENSAT) actually statedthat the role of radiotherapy should not beneglected regarding the prevention of a localrecurrence (Cerquetti et al. 2008; Polat et al.2009). The following recommendations are given:1. In patients with localized tumors and micro-scopically complete resection (R0 resection)postoperative radiotherapy does not seem tobe beneficial and may be only discussed intumors larger than 8 cm with histopathologicevidence of invasion in blood vessels anda Ki-67 index >10%.2. Postoperative radiotherapy is recommendedin all patients in whom a microscopicallyincomplete resection (R1 resection) wasperformed. If there is doubt about the resec-tion status, radiotherapy should be consideredas well. Furthermore, patients with a stage IIItumor may have a benefit from postoperativelocal treatment as long as there is no tumorthrombus in the vena cava.3. If the tumor capsule is intraoperativelyharmed or if tumor spillage into the abdom-inal cavity could not be avoided, the effective-ness of radiotherapy is questionable andshould not be indicated.4. Palliative radiotherapy of symptomatic meta-static lesions is well known. As literature datademonstrate, ACC is not radioresistant; there-fore, radiotherapy is an option in both localsymptomatic tumor and metastatic lesions(e.g., bone lesions, cerebral metastases, venacava obstruction).5. Because of the new promising results ofmitotane in cell culture models as well as inthe adjuvant setting, a combined treatment isrecommended whereas there are no data aboutthe combination with other cytotoxic drugs.When mitotane is simultaneously given, thedaily dose should not be higher than 3 g/daybecause of limiting liver toxicities.6. Radiotherapy should be started within 6–12weeks after surgery. Of course, an individualizedthree-dimensional planning using modern tech-nique has to be used to shield organs at risk94 C Carcinoma of the Adrenal Gland
  19. 19. (especially kidney, liver, small bowel). Therecommended target volume includes (a) thediaphragm and – in case of invasion – the partof the thoracic wall, (b) the para-aortic/paracaval lymph nodes (if involved or at highrisk to be involved), (c) the anterior border ofthe tumor, (d) the border of the diaphragm crus,and (e) caudally at least the kidney hilum. Adoseof 40 Gy (1.8–2.0 Gy, 5Â/week) should beadministered and followed by a boost to thetumor region with 10–20 Gy (1.8–2.0 Gy, 5Â/week). In palliative treatment, the well-knowndose schedules should be used based on an indi-vidualized decision (e.g., 1Â8, 5Â4, 10Â3 Gy).Based on literature data as well as on theserecommendations, acute and late side effectsinduced by radiotherapy should be only mildwith a low incidence of grade III and IV toxicities.Kidney and liver functions have to be monitoredduring therapy as well as during follow-up. Veryseldom, a ▶ Budd–Chiari syndrome is diagnosed.It has to be taken into account that in ACC per sea high incidence of secondary malignancies (12–24%) is reported. Restaging is recommendedevery 3 months for the first 2 years; afterwardsthe intervals could be prolonged.The results of treatment depend on the earlydiagnosis followed by excellent surgery. The lim-ited data including our knowledge about adjuvanttherapies lead to the actual recommendation that –if indicated – the combination of radiotherapy andmitotane could gain a better local control as well asa lower incidence of metastases. This might possi-bly cause a survival benefit. In palliative treatment,radiotherapy is a helpful option in most patientswith a metastatic adrenal gland carcinoma. Fur-ther efforts are needed to transfer these recom-mendations into evidence-based therapy.Cross-References▶ Neuroblastoma▶ Thyroid CancerReferencesAllolio B, Fassnacht M (2006) Clinical review: adrenocorticalcarcinoma: clinical update. J Clin Endocrinol Metab91:2027–2037Cerquetti L, Bucci B, Marchese R, Misiti S, De Paula U,Miceli R, Muleti A, Amendola D, Piergrossi P,Brunetti E, Toscano V, Stigliano A (2008) Mitotaneincreases the radiotherapy inhibitory effect andinduces G2-arrest in combined treatment on bothH295R and SW13 adrenocortcal cell lines. EndocrRelat Cancer 15:623–634Coen JJ (2008) Adrenal Gland. In: Halperin EC, Perez CA,Brady LW (eds) Principles and practice of radiationoncology, 5th edn. Wolters Kluwer/Lippincott Wiliams& Wilkens, PhiladelphiaJohanssen S, Fassnacht M, Brix D, Koschker AC, Hahner S,Riedmiller H, Allolio B (2008) Das Nebennieren-karzinom – Diagnostik und Therapie. Urologe47:172–181Polat B, Fassnacht M, Pfreudner L, Guckenberger M,Bratengeier K, Johanssen S, Kenn W, Hahner S, AllolioB, Flentje M (2009) Radiotherapy in adrenocorticalcarcinoma. Cancer 115:2816–2823Saeger W (2000) Histopathological classification of adrenaltumours. Eur J Clin Invest 30(Suppl 3):58–62Terzolo M, Berruti A (2008) Adjunctive treatment of adre-nocortical carcinoma. Curr Opin Endocrinol DiabetesObes 15:221–226Veytsman I, Nieman L, Fojo T (2009) Management of endo-crine manifestation and the use of Mitotane as a che-motherapeutic agent for adrenocortical carcinoma. JClin Oncol 27:4619–4629Weiss LM, Medeiros LJ, Vickery AL Jr (1989)Pathologic features of prognostic significance inadrenocortical carcinoma. Am J Surg Pathol 13:202–206Carcinoma of the Colon▶ Colon CancerCarcinoma of the MaleUrethra▶ Male UrethraCarcinoma of the Male Urethra C 95C
  20. 20. Carcinoma of the Penis▶ Penile CancerCarcinoma of the UpperUrinary Tract▶ Renal Pelvis and UreterCarcinoma of the UterineCervix▶ Brachytherapy-GyN▶ Uterine CervixCarcinomas: Basal CellCarcinoma▶ Skin CancerCardia of StomachFILIP T. TROICKI1, JAGANMOHAN POLI21College of Medicine, Drexel University,Philadelphia, PA, USA2Department of Radiation Oncology, Collegeof Medicine, Drexel University, Philadelphia,PA, USADefinitionMost proximal section of the stomach which isattached to the esophagus.Cross-References▶ Stomach CancerCardiac ToxicityANTHONY E. DRAGUNDepartment of Radiation Oncology, JamesGraham Brown Cancer Center, University ofLouisville School of Medicine, Louisville,KY, USADefinitionThe risk of cardiotoxicity due to radiation ther-apy is mainly a historical phenomenon, corre-lated to the use of crude radiotherapy planningand delivery techniques. Modern radiationplanning techniques allow exclusion of themajority of cardiac tissue and, thus, this isexceedingly rare in the modern era. In multidis-ciplinary management, increased risks of pre-mature cardiac disease including decreased leftventricular ejection fraction, congestive heartfailure, cardiomyopathy, and acute myocardialinfarction are mainly incurred by the increaseduse of cardiotoxic systemic therapies, suchas anthracycline, taxane, and trastuzimab-containing chemotherapeutic regimens. Radia-tion techniques that exclude treatment of theinternal mammary chain and utilize novelmethods such as forward planning, respiratorygaiting, and deep inspiration breath hold tech-niques are all useful in reducing the irradiatedheart volume and reducing overall risk.Cross-References▶ Stage 0 Breast Cancer96 C Carcinoma of the Penis
  21. 21. Carney ComplexRAMESH RENGAN1, CHARLES R. THOMAS, JR.21Department of Radiation Oncology, Hospital ofthe University of Pennsylvania, Philadelphia,PA, USA2Department of Radiation Medicine, OregonHealth Sciences University, Portland, OR, USADefinitionAn autosomal dominant syndrome with varyingpenetrance characterized by cardiac myxomas,cutaneous myxomas, spotty pigmentation of theskin, endocrinopathy, and both endocrine andnonendocrine tumors.Cross-References▶ Primary Cardiac TumorscARTBERNADINE R. DONAHUE1, JAY S. COOPER21Department of Radiation Oncology,Maimonides Cancer Center, Brooklyn, NY, USA2Maimonides Cancer Center, New York, NY, USASynonymsARTDefinitionCombined antiretroviral therapy (also called ARTor HAART)Cross-References▶ HAART▶ Malignant Neoplasms Associated withAcquired Immunodeficiency SyndromeCD20 Surface AntigenTOD W. SPEERDepartment of Human Oncology, Universityof Wisconsin School of Medicine and PublicHealth, UW Hospital and Clinics, Madison,WI, USADefinitionIt is an activated-glycosylated phosphoproteinthat is expressed as a cell surface antigen onmature B lymphocytes. It has no known naturalligand and its function is not fully elucidated. It isthe antigenic target for anti-lymphoma TRIT.Cross-References▶ Targeted RadioimmunotherapyCeliac AxisFILIP T. TROICKI1, JAGANMOHAN POLI21College of Medicine, Drexel University,Philadelphia, PA, USA2Department of Radiation Oncology, Collegeof Medicine, Drexel University, Philadelphia,PA, USADefinitionBranch of vessels originating from the aorta justbelow the diaphragm that supply the liver, stom-ach, part of the esophagus, spleen, part of theduodenum, and the pancreas.Cross-References▶ Cancer of the Pancreas▶ Esophageal Cancer▶ Hodgkin’s Lymphoma▶ Stomach Cancer▶ TestesCeliac Axis C 97C
  22. 22. Centigray (cGy)TOD W. SPEERDepartment of Human Oncology, University ofWisconsin School of Medicine and Public Health,UW Hospital and Clinics, Madison, WI, USADefinitionGray is the SI unit of absorbed dose for ionizingradiation. It represents the energy (joule; J)absorbed by one kilogram (kg) of matter. Onehundred cGy is equal to one Gy.1Gy ¼ 1J=kgCross-References▶ Radiation Oncology PhysicsCervical Cancer▶ Brachytherapy-Gyn▶ Uterine CervixCervical IntraepithelialNeoplasia (CIN)PATRIZIA GUERRIERI, PAOLO MONTEMAGGIDepartment of Radiation Oncology, RegionalCancer Center “M. Ascoli”, University of PalermoMedical School, Palermo, ItalyDefinitionThe term “cervical intraepithelial neoplasia”(CIN) was introduced by Richart (1973) topresent the concept of cervical neoplasia asa disease continuum. Dysplasia and CIS, ratherthan representing separate diseases, were part ofthe spectrum of disease progression to invasivesquamous cell carcinoma. In Richart’s system,CIN 1 corresponds to mild dysplasia, and CIN2 to moderate dysplasia. CIN 3 encompassesboth severe dysplasia and carcinoma in situ(CIS). The National Cancer Institute in 1988worked on developing a uniform terminologysystem that could be reproducible, wouldcorrelate with the histology of the lesion,and would facilitate communication betweenthe laboratory and the clinician. The resultwas the Bethesda Nomenclature system forcervicovaginal cytology (National Cancer Insti-tute Workshop 1989). By this time, the role ofhuman papilloma virus (HPV) as an etiologicagent in the development of cervical intraepithelialneoplasia and cervical carcinoma was wellestablished. The data, coupled with the lack ofreproducibility in assigning lesions to the categoriesof CIN 1, CIN 2, CIN 3, and CIS led theintroduction of only two categories: low-gradesquamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL).The classification LSIL encompassed HPV,mild dysplasia, and CIN 1; HSIL encompassedmoderate dysplasia, severe dysplasia, CIS, CIN 2,and CIN 3.Cross-References▶ VaginaReferencesNational Cancer Institute Workshop (1989) The 1988Bethesda System for reporting cervical/vaginalcytological diagnoses. J Am Med Assoc 262:931–934Richart RM (1973) Cervical intraepithelial neoplasia. PatholAnnu 8:301–32898 C Centigray (cGy)
  23. 23. Cervical Malignancy▶ Uterine CervixCetuximabCARSTEN NIEDER1, TOD W. SPEER21Radiation Oncology Unit, NordlandssykehusetHF, Bodoe, Norway2Department of Human Oncology, University ofWisconsin School of Medicine and Public Health,UW Hospital and Clinics, Madison, WI, USASynonymsErbituxDefinitionMonoclonal antibody interfering with the epider-mal growth factor receptor (EGFR) pathway.Many tumors overexpress EGFR, and in headand neck cancer, administration of cetuximabplus radiotherapy has been shown to be superiorto radiotherapy alone.Cross-References▶ Monoclonal Antibodies▶ Targeted Radioimmunotherapy▶ Total Body Irradiation (TBI)Chemoradiation▶ Bladder▶ Esophageal Cancer▶ Lung▶ Sarcomas of the Head and NeckChernobyl Nuclear ReactorAccidentJOHN P. CHRISTODOULEASThe Perelman Cancer Center,Department of Radiation Oncology, University ofPennsylvania Hospital, Philadelphia, PA, USADefinitionThe Chernobyl nuclear reactor accident whichoccurred on April 26, 1986, in what is now theUkraine, is widely considered the worst power-plant accident in history. The power plant at Cher-nobyl lacked many safety features including anadequate containment structure.Cross-References▶ Short-Term and Long-Term Health Risk ofNuclear Power Plant AccidentChest, Abdominal, and PelvicTumor Metastases▶ Palliation of Visceral Recurrences andMetastasesChiropractic▶ Complementary MedicineChiropractic C 99C
  24. 24. ChloromaCASPIAN OLIAI1, THEODORE E. YAEGER21Department of Radiation Oncology, Collegeof Medicine, Drexel University, Philadelphia,PA, USA2Department Radiation Oncology, Wake ForestUniversity School of Medicine, Winston-SalemNC, USADefinitionA chloroma is also known as a granulocytic sar-coma or myeloblastoma, as it is usually a solid butextramedullary tumor that is mainly comprisedof myeloid precursors.Solid collection of leukemic cells composedmostly of myeloblasts occurring outside ofthe bone marrow. Simply stated, it is anextramedually manifestation of AML, but canalso be found in MDS and MPD. Also known asmyeloid sarcoma or granulocytic sarcoma.Chloromas are usually associated withacute myelocytic leukemia mostly presenting inthe orbit and extracranial bone structures(Chapman 1980). The term “Chloroma” isderived from the Greek root of “Chloros” (simi-larly chlorophyll) because the cells producea myeloperoxidase that can cause a greenish hueto the tumor. The alternate term “granulocyticsarcoma” (GS) is often applied when the tint isnot produced. As such, a GS only representsabout 3% of patients actually seen witha diagnosis of acute or chronic granulocytic, poly-cythemia vera, hypereosinophilia, and myeloidmetaplasia. Without these associated hemopoi-etic events, the presentation of GS alone is typi-cally a precursor to acute myelocytic leukemiaand blast crisis (Neiman 1986). Interestingly,increased survival of the acute leukemias areallowing increasing numbers of patients thatdevelop GS (Neiman 1981).GS is usually found in the first decade of lifeand is associated with M4 and M5 acute myeloidsubtypes and 8:21 translocations.Cross-References▶ Hodgkin’s Lymphoma▶ Leukemia in General▶ Sarcoma▶ Sarcomas of the Head and NeckReferencesChapman P (1980) Johnson S Mastoid chloroma relapse inacute myeloid leukemia. J Laryngol Otol 94:1423–1427Neiman RS (1986) The peripheral cell lymphomas come ofage. Mayo Clin Proc 61:504–506Neiman RS et al (1981) Granulocytic sarcoma: a clinico-pathologic study of 61 biopsied cases. Cancer 48:1426–1437Cholangiocarcinoma▶ Liver and Hepatobiliary TractCHOPCURT HEESEDepartment of Radiation Oncology, EasternRegional Cancer Treatment Centers of America,Philadelphia, PA, USADefinitionMultidrug chemotherapy regimen consistingof Cyclophosphamide (brand names cytoxan,neosar), Adriamycin (doxorubicin/hydroxydox-orubicin), Vincristine (Oncovin), Prednisone(sometimes called Deltasone or Orasone).Cross-References▶ Cutaneous T-Cell Lymphoma100 C Chloroma
  25. 25. ChordomasCARLOS A. PEREZ, WADE L. THORSTADDepartment of Radiation Oncology, SitemanCancer Center, Washington University MedicalCenter, St. Louis, MO, USADefinitionA tumor arising from the primitive notochord(chorda dorsalis) that typically involves the clivusand notochord along the cervical vertebrae in thehead and neck region.EpidemiologyChordomas are more common in patients in thefifth to sixth decade.Although slowly growing, they are locallyinvasive. Basisphenoidal chordomas tend tocause symptoms earlier and may be difficult todifferentiate histologically from chondromas andchondrosarcomas and radiographically fromcraniopharyngiomas, pineal tumors, and hypo-physeal and pontine gliomas. The incidence ofmetastasis has been reported to be as high as25%. Lymphatic spread is uncommon.Clinical PresentationChordomas tend to originate from the clivus andchondrosarcomas from the temporal bone.In the head, extension may be intracranial orextracranial, into the sphenoid sinus, nasophar-ynx, clivus, and sellar and parasellar areas,with a resultant mass effect. In chordomasof the sphenooccipital region, the mostcommon presenting symptom is headache.Other presentations include symptoms of pitui-tary insufficiency, nasal stuffiness, bitemporalhemianopsia, diplopia, and other cranial nervedeficits.Diagnostic WorkupMost patients have significant bony destruction,and some may have calcifications in the tumor;hence, plain films and, specifically, CT scans orMRI are very useful. In most cases, the soft tissuecomponent is much more extensive than initiallyappreciated, and a CTscan with contrast enhance-ment is required. MRI is inferior to CT todemonstrate bony destruction and intratumoralcalcification, but MRI is superior to CT regardingthe delineation of the exact extent of the tumor,which allows for better treatment planning.Because of availability and lower cost, CT appearsto be the technique of choice for routine follow-upof previously treated patients (Perez and Thorstad2008).General ManagementThe management of the patient, which is chal-lenging, is dictated by the anatomic location ofthe tumor, the direction, and extent of spread.A surgical approach is recommended (when fea-sible) but complete surgical extirpation alone isunusual. Intracranial spread usually requires ste-roid coverage and therapy directed to correction ofneurologic deficits, which may be present. Becauseof the high incidence of local recurrence, com-bined surgical excision and irradiation is fre-quently used. No effective chemotherapeuticagent or combination of drugs has been identified.Radiation TherapyIrradiation techniques vary, depending on thelocation of the tumor. Basisphenoidal tumorswere treated by a combination of parallel-opposed lateral fields, anterior wedges, and pho-ton and electron beam combinations, dependingon the extent of the neoplasm. Precision radiationtherapy planning, using CT and MRI, is requiredbecause high doses of external-beam radiationtherapy are needed. 3D CRT or IMRT provideoptimal dose distributions, with sparing of nor-mal tissues (Fig. 1).Chordomas C 101C
  26. 26. Chordomas. Fig. 1 Chordoma of clivus in 81-year-old man treated with 70 Gy in 2 Gy fractions. Example ofIMRT plan: (a) cross section in upper portion of PTV demonstrating coverage of target volume (PTV) withsparing of ocular structures. (b) Sagittal plane dose distribution with excellent coverage of PTV. (c) Dose-volume histogram:Structure Dose range (Gy) Mean dose (Gy)PTV (including left neck) 60–75 70Optic nerves/chiasm 25–50 41Ocular globe 3–30 12Source: Reproduced with permission from LeVay J, O’Sullivan B, Catton C, et al (1994)102 C Chordomas
  27. 27. The tumor usually surrounds the spinal cordand infiltrates vertebral bones. A combined tech-nique using protons or electrons to boost theinitial photon fields has been generally applied.In the treatment of chordomas surrounding thespinal cord, IMRT can provide high-dose homo-geneity and PTV coverage. Frequent digital portalimage-based setup control reduces random posi-tioning errors for head and neck cancer patientsimmobilized with conventional thermoplasticmasks (Gabriele et al. 2003). Image-guided radi-ation therapy with daily setup correction andverification using megavoltage or kilovoltage CTimaging may be useful as well.Because of the slow proliferative nature ofchordomas, high linear energy transfer (LET)may prove useful in their management. Rutzet al. (2007) reported a 77% 3-year progression-free survival in 26 patients treated with spot-scanning proton irradiation (median dose 72▶ Co Gray Equivalent. Four grade 2–5 late effectswere observed. Brachytherapy can be used forrecurrent tumors of the base of skull or adjacentto the spine when a more aggressive surgicalexposure is offered.Results of TherapyPhotonsForsyth and colleagues (1993) reported on 51patients with intracranial chordomas (19 classi-fied as chondroid) treated surgically (biopsy in 11patients and subtotal removal or greater in 40); 39patients received postoperative irradiation. The5- and 10-year survival rates were 51% and 35%,respectively; 5-year survival was 36% for biopsypatients and 55% for those who had resection. Taiand associates (1995) reviewed the results of irra-diation combined with surgery, irradiation alone,and surgery alone in 159 patients reported in theliterature. Analysis of the optimal biologicallyequivalent dose was performed using the linear-quadratic formula on 47 patients treated withphotons; no dose–response relationship wasshown. Keisch and coworkers (1991) reportedon 21 patients with chordoma treated at our med-ical center. The 5- and 10-year actuarial survivalwas significantly better in patients treated withsurgery alone or surgery and irradiation than inthose treated with radiation therapy alone (52%,32%, and 0%, respectively) (P = 0.02).ProtonsThe best results in the treatment of chordomashave been obtained with radical surgical proce-dures followed by high-dose proton irradiation.Berson et al. (1988) described 45 patients withchordomas or chondrosarcomas at the base of theskull or cervical spine treated by subtotal resec-tion and postoperative irradiation. Twenty-threepatients were treated definitively by charged par-ticles, 13 patients with photons and particles, andnine were treated for recurrent disease. Dosesranged from 36 to 80 Gy equivalent. Patientswith smaller tumor volumes had better survivalrate at 5 years (80% vs. 33% for larger tumors).Patients treated for primary disease had a 78%actuarial local control rate at 2 years, versus 33%for patients with recurrent disease.Fagundes and colleagues (1995) updated theMassachusetts General Hospital experience with204 patients treated for chordoma of the base ofthe skull or cervical spine. Sixty-three patients(31%) had treatment failures, which were localin 60 patients (29%) and the only site of failure in49 patients. Two patients had regional lymphnode relapse, and three developed surgical path-way recurrence. Thirteen patients relapsed in dis-tant sites (especially lungs and bones). The 5-yearactuarial survival rate after any relapse was 7%.Two patients (1.4%) with local tumor controldeveloped distant metastases in contrast with 10of 60 (16%) who failed locally and distantly.Terahara et al. (1999) reported on 132patients with skull base chordoma treated withcombined photon and proton irradiation; in 115Chordomas C 103C
  28. 28. patients dose-volume data and follow-up wereavailable. Doses ranged from 66.6 to 79.2▶ CGE (median 68.9 ▶ CGE). The dose to theoptic structures (optic nerves and chiasm), thebrain stem surface, and the brain stem centerwas limited to 60, 64, and 53 ▶ CGE, respectively.Local failure developed in 42 of 115 patients36%), with actuarial local tumor control rates at5 and 10 years being 59% and 44%, respectively.A report on proton therapy for base of skullchordoma was published by the Royal College ofRadiologists (2000). They concluded that out-come after proton therapy is superior to conven-tional photon irradiation.Cross-References▶ Conformal Therapy: Treatment Planning,Treatment Delivery, and Clinical Results▶ Image-Guided Radiation Therapy (IGRT): kVImaging▶ Image-Guided Radiation Therapy (IGRT): MVImaging▶ IMRT▶ Pediatric Ovarian Cancer▶ Proton Therapy▶ Renal Pelvis and Ureter▶ Sarcomas of the Head and NeckReferencesBerson AM, Castro JR, Petti P et al (1988) Charged particleirradiation of chordoma and chondrosarcoma of thebase of skull and cervical spine: the Lawrence BerkeleyLaboratory experience. Int J Radiat Oncol Biol Phys15:559–565Fagundes MA, Hug EB, Liebsch NJ et al (1995) Radiationtherapy for chordomas of the base of skull and cervicalspine: patterns of failure and outcome after relapse. IntJ Radiat Oncol Biol Phys 33:579–584Forsyth PA, Cascino TL, Shaw EG et al (1993) Intracranialchordomas: a clinicopathological and prognostic studyof 51 cases. J Neurosurg 78:741–747Gabriele P, Macias V, Stasi M et al (2003) Feasibility ofintensity-modulated radiation therapy in the treatmentof advanced cervical chordoma. Tumori 89:298–304Keisch ME, Garcia DM, Shibuya RB (1991) Retrospectivelong-term follow-up analysis in 21 patients withchordomas of various sites treated at a single institu-tion. J Neurosurg 75:374–377LeVay J, O’Sullivan B, Catton C et al (1994) An assessment ofprognostic factors in soft tissue sarcoma of thehead and neck. Arch Otolaryngol Head Neck Surg120:981–986Perez CA, Thorstad WL (2008) Unusual non-epithelialtumors of the head and neck. In: Halperin EC, PerezCA, Brady LW (eds) Perez and Brady’s principles andpractice of radiation oncology, 5th edn. Wolters KluwerLippincott Williams & Wilkins, Philadelphia, p 996Royal College of Radiologists Proton Therapy Working Party(2000) Proton therapy for base of skull chordoma:a report for the Royal College of Radiologists. Theproton therapy working party. Clin Oncol (R CollRadiol) 12:75–79Rutz HP, Weber DC, Sugahara S et al (2007) Extracranialchordoma: outcome in patients treated with function-preserving surgery followed by spot-scanning protonbeam irradiation. Int J Radiat Oncol Bio Phys67:512–520Tai PT, Craighead P, Bagdon F (1995) Optimization ofradiotherapy for patients with cranial chordoma:a review of dose–response ratios for photon tech-niques. Cancer 75:749–756Terahara A, Niemierko A, Goitein M et al (1999) Analysis ofthe relationship between tumor dose inhomogeneityand local control in patients with skull base chordoma.Int J Radiat Oncol Biol Phys 45:351–358Chronic LymphocyticLeukemia▶ Leukemia in GeneralChronic MyelogenousLeukemia (CML)DefinitionAlso known as chronic granulocytic leukemia is awhite blood cell line malignancy of predomi-nately a myeloid stem cell line. It characteristicallyexhibits a chromosome translocation commonlycalled ‘The Philadelphia Syndrome’ which has a 9and 22 translocation. CML can evolve into an104 C Chronic Lymphocytic Leukemia
  29. 29. acute phase or blast phase which represents abone marrow crisis with shortened survival.Cross-References▶ Leukemia in GeneralCine CTDAREK MICHALSKI1, M. SAIFUL HUQ21Division of Medical Physics, Department ofRadiation Oncology, University of PittsburghCancer Centers, Pittsburgh, PA, USA2Department of Radiation Oncology, Universityof Pittsburgh Medical Center Cancer Pavilion,Pittsburgh, PA, USADefinitionA stationary volume scanning mode in planargeometry with patient being consecutivelyscanned in space and continuously in time.Cross-References▶ Four-Dimensional (4D) Treatment Planning/Respiratory GatingCisplatinCHRISTIN A. KNOWLTON1, MICHELLE KOLTONMACKAY21Department of Radiation Oncology, DrexelUniversity, Philadelphia, PA, USA2Department of Radiation Oncology, MarshfieldClinic, Marshfield, WI, USASynonymsCisplatinumDefinitionCisplatin is a platinum-based chemotherapyagent frequently used in cervical cancer. Its mech-anism of action is to cross-link strands of DNAand thereby interfere with mitotic cell division. Itis frequently administered on a weekly basis withradiation therapy as a definitive treatment foradvanced cervical cancer or as postoperativetreatment with concurrent radiation. Possibleside effects of cisplatin include nausea,nephrotoxicity, neurotoxicity, ototoxicity, alope-cia, and electrolyte disturbances.Cross-References▶ Principles of Chemotherapy▶ Uterine CervixCisplatinum▶ CisplatinClark LevelBRANDON J. FISHERDepartment of Radiation Oncology, Collegeof Medicine, Drexel University, Philadelphia,PA, USADefinitionThe Clark level is a measure of depth of invasioninto the skin used as a prognostic indicator forskin cancers: level I: confined to the outermostlayer of the skin, epidermis; level II: penetrationinto the dermis; level III to IV: invasion throughthe dermis into deeper dermal layers, yet stillconfined to the skin; level V: penetrationthrough the dermis and into the fat andhypodermis.Clark Level C 105C
  30. 30. Cross-References▶ Skin CancerClark’s Nevus▶ Atypical (Dysplastic) NeviClass I Hysterectomy▶ Total Abdominal HysterectomyClass II Hysterectomy▶ Modified Radical HysterectomyClass III Hysterectomy▶ Radical HysterectomyClass IV Hysterectomy▶ Extended Radical HysterectomyClinical Aspects ofBrachytherapy (BT)ERIK VAN LIMBERGENDepartment of Radiation Oncology, UniversityHospital Gasthuisberg, Leuven, BelgiumSynonymsCurietherapyDefinition/DescriptionBrachytherapy (BT) is a technique of radiationtherapy delivery where the radioactive sources areplaced very close or even inside the target volume.The name is derived from the Greek wordbrawus which means short as this is opposed toother techniques of radiotherapy: teletherapy orexternal beam radiation therapy.BackgroundBrachytherapy is the earliest method of radiother-apy which was developed soon after the discoveryof radioactivity by Becquerel in 1896 and devel-opment of radium sources by Marie Curie. Dur-ing the first decade of the twentieth century, thefirst treatments with radium were performed byDanlos and Bloc (1901) in Paris and Abbe(1905) in the USA.Modern brachytherapy uses artificial iso-topes (Iridium-192, Cobalt-60, Iodine-125, Palla-dium-103), remote control afterloading machineswith stepping source facilities, 3D dose planningbased on 3D imaging (ultrasound, CT, MRI) tooptimize dose distribution and deliver high dosesmore and more conformal to the planning targetvolume (PTV) and low doses to the surroundingorgans at risk.Basic CharacteristicsBrachytherapy is able to deliver a verylocalized radiation, since sources have a very steepfall off of the doses and are applied very close tothe target volume (intracavitary, endoluminal,endovascular, or surface contact brachytherapy)or implanted in the target (▶ interstitial brachy-therapy). In most cases when adequate tech-niques are applied, uncertainties in dose deliveryare small and no or no large PTV to CTV marginshave to be taken. This reduces significantly thetreated volume and thus also the side effects ofhigh radiation doses.Since the doses are delivered in small vol-umes, radiation can be delivered in a short overall106 C Clark’s Nevus
  31. 31. treatment duration which reduces the risk oftumor repopulation (Joiner and van der Kogel2009).The dose can be delivered by temporary orpermanent implants.▶ Temporary implants can deliver the doseat classical low dose rate, but with stepping sourcetechnology ▶ High Dose Rate (HDR) brachyther-apy and more recently ▶ Pulsed Dose Rate (PDR)brachytherapy has been developed. PDR brachy-therapy like HDR brachytherapy utilizes a singleminiaturized source which moves step by stepthrough implanted afterloading devices toachieve the desired dose distribution. In PDRsuch a sequence of steps, also called a pulse, isrepeated a number of times to obtain the pre-scribed total dose. By choosing an appropriatenumber of pulses one can simulate, froma radiobiological point of view, a continuouslow dose rate treatment (Fowler and VanLimbergen 1997). This and other newly devel-oped techniques allow brachytherapy to be usedin a very wide variety of tumor types and sites(Gerbaulet Poetter et al. 2002 and Devlin 2007).▶ Permanent implants: The most commonradionuclides used for permanent implants areiodine-125, palladium-103, and gold-198 encap-sulated in seeds. These sources have a relativelyshort half-life and are left implanted in the tissuefor gradually delivering the dose while the activitydecays. The photon energy used in permanentseed implants is low so that radiation protectioncan be achieved with relatively simple measures(Fig. 1).Different Dose Rates inBrachytherapyDepending on the source strength, brachytherapycan deliver the target dose at classical low doserate, high dose rate, medium dose rate, or pulseddose rate (Joiner and van der Kogel 2009).At low dose rate (LDR) the dose is delivered at0.4–1 Gy/h (+/À10 Gy/day). The sourcescommonly used for LDR are cesium-137 (LDRafterloaders), or iridium-192 as LDR wires. Irra-diation is continuous and can take 1–6 daysdepending on the dose.At ▶ medium dose rate (MDR) the dose isdelivered at 1–12 Gy/h usually by cesium-137sources in 1–3 days depending on the dose.At high dose rate (HDR) the dose is deliveredby a stepping source afterloader (iridium-192 orcobalt-60) at >12 Gy/h (>10 Gy/min) in one orseveral fractions. As in external beam irradiation,enough time is kept in between fractions (>6 h)to allow for full repair.At pulsed dose rate (PDR) the dose is deliv-ered by a stepping source afterloader iridium-192at >12 Gy/h (>10 Gy/min) in hyperfractionatedhourly or two hourly pulses with incompleterepair in between fractions (Fowler and VanLimbergen 1997).At very low dose rate (VLDR) the dose isdelivered by low-activity, low-energy seed sources(iodine-125, palladium-103, gold-198) which areimplanted permanently in the clinical targetvolume.▶ Afterloading technique implies implanta-tion of nonradioactive source carriers: dedicatedClinical Aspects of Brachytherapy (BT). Fig. 1Permanent seed implant with I-125 sources for thecurative treatment of early prostate cancerClinical Aspects of Brachytherapy (BT) C 107C
  32. 32. applicators such as gynecological (Fig. 2) orendobronchial or endoesophageal (Fig. 3) brachy-therapy, guide needles (Figs. 4 and 5), catheters ortubes (Fig. 6) which later after dosimetric studyare loaded with radioactive sources. Because theapplication itself is with nonradioactive materiala meticulous and very precise positioning of thesource carriers allows a high geometric quality ofapplication, and an effective radioprotection.Manual afterloading is possible with plastictubes, guide gutters, hypodermic and guideneedles, plastic needles, silk threads (for intersti-tial brachytherapy); applicators (for intracavitaryor surface brachytherapy); and catheters (forintraluminal applications).Remote afterloading machines: these projec-tors can be used with interstitial, intracavitary,intraluminal as well as with contact brachyther-apy (Fig. 7). Afterloading equipment is connectedto various types of applicators and catheters.Remote afterloading is mandatory for MDR,HDR, as well as PDR brachytherapy for reasonsof radiation protection.Stepping source afterloaders contain a highactivity source mounted on a cable. Dwell posi-tions and dwell times are calculated in 3D plan-ning systems and allow for optimization of thedose distribution (Fig. 8). They can be used forHDR (with a 10 Ci source) as well as PDR (with a0.5–1 Ci source) brachytherapy (Fig. 9).Clinical Aspects of Brachytherapy (BT). Fig. 2 (a) Fletcher-type applicator for intrauterine–intravaginalbrachytherapy for cervix cancer. (b) Chassagne–Pierquin individually designed mold applicator. (c) MRI-compatible IU-IV applicator for MR image-guided BT. (d) Different MRI compatible applicators for intracavitarybrachtherapy: Stockholm-type ring IU-IV applicator, Norman Simon capsules for endometrial cancercombined intrauterine and vaginal applicator108 C Clinical Aspects of Brachytherapy (BT)
  33. 33. Indications for BrachytherapyOver the past two decades, technical develop-ments, new radioactive sources, modernafterloading machines using different dose ratesand 3D dose distribution optimization, and greatprogress in imaging have opened new fields forbrachytherapy.The target volumes to be implanted shouldbe relatively small and accessible, and the targetlimits should be well defined.Brachytherapy AloneIt is used for small tumors of the skin in smallareas of the skin such as eyelids, nose, ear, lip, oralcavity, as an alternative to mutilating surgery. It isalso an established treatment technique used forearly low-risk prostate cancer.Brachytherapy as Boost AfterExternal Beam IrradiationFor larger tumors which measure 40 mm or more,frequently because of poorly defined tumorlimits, radiation treatment should start withexternal beam radiation, delivering 45–50 Gy inClinical Aspects of Brachytherapy (BT). Fig. 3Endoesophageal brachytherapy with a dedicatedendoesophageal applicator of appropriate diameterClinical Aspects of Brachytherapy (BT). Fig. 4 Hypodermic needles: small (length 20–80 mm, externaldiameter 0.8 mm) hypodermic needles are used in small-size implants in sensitive structures like lip (Fig. 4a),inner canthus and eyelids (Fig. 4b), nose vestibulum and penis. These small needles have to be afterloadedmanually with Iridium 192 wiresClinical Aspects of Brachytherapy (BT) C 109C
  34. 34. 5 weeks. Brachytherapy is used as a boost for doseescalation following as soon as possible after theend of the external beam therapy.Brachytherapy in Combinationwith SurgeryPerioperative or postoperative implants can beindicated after surgery with positive or doubtfulmargins. This strategy is used as barrier brachy-therapy in oral cavity cancers, bladder cancers,soft tissue sarcomas (especially in children forgynecological, urological, or intraorbital localiza-tions) or as ▶ accelerated partial breastirradiation (APBI) as alternative to whole breastirradiation after breast conservative surgery inselected small and low-risk breast cancer (Polga´ret al. 2010).Brachytherapy for Reirradiation inPreviously Irradiated AreaBecause the treatment volumes are small andconformal to the clinical target volume, brachy-therapy is also used as retreatment technique forrecurrences or new secondary tumors in irradi-ated areas in head and neck, breast or prostatecancer.Clinical Aspects of Brachytherapy (BT). Fig. 5 Larger (100–200 mm, external diameter 1.6–2 mm) guideneedles are used in breast (a), prostate, anus, interstitial pelvis (b). When made of titanium they arecompatible with CT and MRI imaging and can be connected to a remote control afterloaderClinical Aspects of Brachytherapy (BT). Fig. 6 Semiflexible to rigid plastic needles and tubes with anexternal diameter of 1.6–2 mm, which are compatible with CT and MRI imaging, are used in prostate, anus,rectum, gynecology, brain, head and neck, and soft tissue sarcomas. They can be connected via transfer tubesto a HDR or PDR remote control afterloading machine110 C Clinical Aspects of Brachytherapy (BT)
  35. 35. Many technical innovations have made thischange possible, based on a more frequent use ofnew dose rates: high dose rate, medium doserate, and pulsed dose rate brachytherapy. Thetechnological aspects of brachytherapy aremore and more sophisticated, allowing the inte-gration of 3D imaging data and 3D dose distri-butions. Examples are: 3D navigation forinterstitial stereotactic brachytherapy, scannersimulation and 3D virtual planning, MRI- andultrasound-assisted brachytherapy treatmentplanning, and CT-based software for clinicalevaluation.Other technologies are developed foradapted and effective brachytherapy whencombined with other treatment modalities,such as radiosensitizers, hyperthermia, exter-nal beam irradiation, chemotherapy, andsurgery.Contraindications toBrachytherapyBrachytherapy is not indicated in targetvolumes that are not accessible enough toperform a geometrically correct source posi-tioning in order to obtain a good dosedistribution.Since the lower energy radiation of thebrachytherapy sources is absorbed by photoelec-tric absorption, which is proportional to Z3,positioning of sources close to bone, for instance,the mandibula in head and neck cancer, shouldbe avoided, and use of leaded mandibularprotectors is advocated. If this is not feasiblewithout compromising target covering, BT iscontraindicated.LDR or PDR BT is contraindicatedin patients who are mentally unfit or tooconfused to stay alone in a treatment roomfor a longer time to avoid displacementor removal of the source carriers by thepatient.Clinical Aspects of Brachytherapy (BT). Fig. 8 TheIr-192 stepping source mounted on a cable allowsdwell position and dwell time optimization by theprogrammed stepping motorClinical Aspects of Brachytherapy (BT). Fig. 7Treatment with a remote control afterloader securesradioprotectionClinical Aspects of Brachytherapy (BT) C 111C
  36. 36. Cross-References▶ Anal Cancer▶ Brachytherapy▶ Carcinoma of the Uterine Cervix▶ Endometrium▶ Esophageal Cancer▶ Female Urethra▶ Male Urethraa b cd eClinical Aspects of Brachytherapy (BT). Fig. 9 Modern stepping source afterloaders: (a) NucletronMicroselectron (PDR or HDR), (b) Varian GammaMed (HDR or PDR), (c) Varian Varisource (HDR), (d) BebigMultisource (HDR), and (e) Nucletron Flexitron (HDR or PDR)112 C Clinical Aspects of Brachytherapy (BT)