Revista Hipocrate România Octombrie 2012

Supliment special Conferin]a Societ`]ii Na]ionale de Oncologie Medical` din România Hipocrate iPadRevista este acum la degetul tău. La propriu

Ediția a XI-aPoiana, Brașov, 11-14 octombrie 2012

Rezumatele lucrărilor

Conferința Societății Naționale de Oncologie Medicală din România

Colecţia de

primăvară

2012

Publicaţie trimestrială pentru sănătatea ta

și a familiei tale

Revista 4P

Învingem cancerul!

O dată-n viaţă

Sănătatea copilului:Sănătatea copilului:

Cum luptăm cu efectele adverse

ale chimioterapiei?

O lecție de autoapărare: vaccinarea

Tulburările de creștere și dezvoltare

Sănătatea adultului:Sănătatea adultului:

Jurnalul unui supraviețuitor de infarct

Să rupem tăcerea din jurul prostatei

Osteoporoza: boala care te fură pe neștiute

Legături periculoase între inimă și creier:

fibrilația atrială și accidentul vascular cerebral

Util: Cele mai active asociaţii ale pacienţilor din România

Povesteamea

Sănătatea vârstei a treia:

Sănătatea vârstei a treia:Iuliana Tudor

Pret: 6,9 RON

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Rezumatele lucrărilor

| Septembrie 20124

l Prof. Dr. Florin B`dulescu1, Dr. Marius Geant`2, dr. Michael Schenker

1 Profesor de oncologie medical`, pre[edinte al Soci­et`]ii Na]ionale de Oncologie Medical` din România

2 National Task Force Romania al Public Health Geno­mics Network Europe

În ciuda faptului c`, în ultimele decade, au fost ob]i ­nute succese semnificative în ceea ce prive[te s`n`tatea uman`, progresele înregistrate au fost neuniforme. Dife­ren]ele se p`streaz` atât între zonele geografice, cât [i în­tre ariile terapeutice. Nu to]i pacien]ii r`spund la cele mai folosite medicamente, iar în rândul celor care r`spund pot exista reac]ii adverse adesea severe, care fac impo­sibil` continuarea tratamentului. Un procent estimat de 5­7% din totalul intern`rilor în spital este din cauza reac]ii­lor medicamentoase adverse, în timp ce o cincime dintre decese apar ca urmare a efectelor adverse ale terapiilor.

90% dintre medicamentele folosite acum sunt efici­ente la numai 40% dintre pacien]i. În timp ce, în prezent, majoritatea pacien]ilor primesc medicamentele mai mult sau mai pu]in în acela[i mod, tratamentul în viitorul nu prea îndep`rtat va fi ajustat la grupurile de pacien]i selec­ta]i, defini]i prin propriile semn`turi moleculare. Aceas­ta este ceea ce definim drept medicin` personalizat`, sau utilizarea aspectelor moleculare [i a testelor diagnostice pentru a ajusta mai bine administrarea medicamentelor [i pentru a gestiona în mod superior boala unui pacient.

Provoc`rile medicinei personalizateMedicina personalizat` implic` numeroase

provoc`ri. Odat` cu maparea genomului uman, au fost ob]inute o multitudine de informa]ii privitoare la modul

în care oamenii difer` unul fa]` de cel`lalt [i la modul în care structura genetic` individual` poate influen]a sus­ceptibilitatea unei persoane pentru o boal` [i r`spunsul la noile tratamente. Genomica nu este singura dintre noi­le discipline, denumite generic „omice“, care încearc` s` defineasc` [i s` explice mecanismele corpului uman. Pro­teomica, sau studiul pe scar` larg` al proteinelor, este o alt` astfel de disciplin`. Exist`, de asemenea, epigenomi­ca, transcriptomica, metabolomica [i metagenomica.

Principala cauz` a e[ecurilor studiilor clinice de faza II [i III nu este reprezentat` de siguran]a sau de profilul de toxicitate al medicamentului, ci de eficacitatea acestu­ia. Acest deficit al dezvolt`rii medicamentelor noi poate fi explicat printr­o în]elegere insuficient` a mecanismului apari]iei bolii la nivelul fiec`rui pacient. Cu alte cuvinte, dac` nu [tim ce se întâmpl` cu adev`rat la nivelul paci­entului individual, [ansele de a­l trata cu succes sunt foar­te mici.

Medicina modern` a oferit suficient de multe infor­ma]ii despre entit`]i patologice individuale, dar în acest moment cunoa[tem destul de pu]ine lucruri despre cone­xiunile dintre acestea. Bolile reprezint` o re]ea complex`, în ochiurile c`reia se afl` componente moleculare, celu­lare [i fiziologice, toate acestea alc`tuind sistemul biolo­gic uman, unic pentru fiecare individ. De aceea, esen]ial este s` privim în ansamblu, nu doar izolat, o boal`, un tra­tament [i efectele acestuia, pentru fiecare pacient care ne intr` în cabinet.

Rolul tehnologiei informa]iei [i comunica]iilor

Sub umbrela medicinei personalizate, se dezvolt` din ce în ce mai multe tehnologii care s` ajute la oferi­

În loc de introducere

Medicina viitorului începe de ast`zi. Cu medicina

personalizat`, în oncologie

www.revista-hipocrate.ro REZUMAT

Supliment special Conferin]a Societ`]ii Na]ionale de Oncologie Medical` din România

Septembrie 2012 | 5

rea unui tratament individualizat. Cum genomul pare a fi elementul cheie în acest demers, studii recente au ar`tat c` pot fi combinate diverse profile genomice într­un pro­fil integrativ personal, individual, pentru a monitoriza schimb`rile survenite în c`ile biologice, atât la persoana s`n`toas`, cât [i la cea bolnav`, cu scopul de a evalua ris­cul medical.

Utilizând tehnologia informa]iei [i a comunica]iilor pentru a sus]ine integrarea la scar` larg` a informa]iei, este posibil, într­un viitor nu prea îndep`rtat, s` avem acces la o în]elegere la nivel de sistem a s`n`t`]ii fiec`rui om, o abordare care acum lipse[te în multe arii terapeutice [i, în final, s` identific`m solu]iile de asisten]` medical` per­sonalizat`.

Demersul reprezint` o provocare major` nu doar pen­tru cercetarea medical`, ci [i pentru industria IT, care tre­buie s` identifice solu]ii pentru stocarea unui volum uria[ de date. De exemplu, pentru a integra informa]ia con]inut` în corpul unui singur individ, cu mijloacele cunoscu­te la acest moment, este necesar` o energie de 100.000 de ori mai mare decât cea generat` de Soare!

Fenomenul de îmb`trânire a popula]iei [i presiunea asupra bugetelor

Demografia joac`, de asemenea, un rol din ce în ce mai important în contextul social actual [i din viitorul apropiat. Persoanele vârstnice constituie o propor]ie din ce în ce mai mare din popula]ie, iar costul asisten]ei me­dicale este în cre[tere, punând în discu]ie sustenabilitatea pe termen lung a sistemului de asigur`ri de s`n`tate.

Cheltuielile în sistemele de s`n`tate sunt din ce în ce mai mari. Omenirea s­a bucurat de un succes enorm ­ în prezent existând aproximativ 7.500 de medicamente dis­ponibile pentru pacien]i în întreaga lume – [i totu[i acest succes este o barier` în calea progresului. Vor exista foar­te pu]ine medicamente noi pân` când vom putea în]elege mai bine cum putem reclasifica bolile la nivel molecular.

Educarea medicilor [i a pacien]ilor în direc]ia personaliz`rii

O alt` problem` important` o constituie instruirea me­dicilor [i informarea pacien]ilor. Medicii vor trebui instrui]i într­un num`r de discipline, pentru a în]elege [i a putea utiliza toate instumentele sofisticate pe care le vor avea la dispozi]ie pentru medicamentele personalizate. Odat` in­strui]i, ace[tia vor trebui s` aib` acces la facilit`]ile de dia­gnostic [i de tratament, pentru a asigura aceast` asisten]` în conformitate cu principiul UE al egalit`]ii accesului la sistemele de s`n`tate [i cu cel al accesului universal la me­dicamente.

Modul în care este practicat` meseria de medic se afl` într­o transformare rapid`. Timp de mii de ani, diagnosti­cul [i tratamentul s­au bazat pe ceea ce se putea vedea, mi­rosi, gusta [i intui. În ultimii 100 de ani, diagnosticul a evo­luat, ajungând s` includ` cuno[tin]e ale proceselor biochi­mice [i celulare. În prezent, diagnosticul [i tratamentul in­clud elemente de biologie molecular` [i de genetic`. În vi­itor, managementul pacien]ilor va trebui s` se bazeze pe analiza computerizat` a informa]iilor moleculare pentru a

identifica tratamentele optime sau necesare pentru pacien]i, la nivel individual.

Un model pentru autorit`]iOferind pacien]ilor medicamente personalizate, furni­

zorii de asisten]` de s`n`tate pot evita încerc`rile [i erorile [i pot reduce reac]iile adverse. Aceasta asigur` un poten ­ ]ial de beneficii majore pentru pacien]i [i pentru sistemul sanitar ca întreg. În prezent, acest poten]ial este în mare m`sur` neexploatat. De exemplu, 640 de milioane de euro s­ar economisi anual, la nivel mondial, prin introducerea test`rii pentru mutat]ia KRAS în cancerul de colon, urmat` de instituirea unui tratament t]intit.

Autorit`]ile franceze au instituit un program na]ional pentru pacien]ii cu cancer, în cadrul c`ruia ace[tia pot fi testa]i, gratuit, în privin]a caracteristicilor moleculare ale tumorilor lor. Aceste teste sunt efectuate în oricare dintre cele 28 de centre regionale. Odat` testa]i, pacien]ilor li se pot prescrie cele mai adecvate medicamente, imediat ce acest lucru este posibil. Programul a fost ini]iat în 2006, ca r`spuns la cererea pacien]ilor de acces la cele mai noi te­rapii ]intite pentru cancer. Programul este derulat de c`tre Institutul Na]ional pentru Cancer (Institut National du Can­cer) [i de c`tre Ministerul S`n`t`]ii. Laboratoarele din cele 28 de centre regionale administreaz` teste, pe baza c`rora mostrele tumorilor pacien]ilor sunt analizate, iar cancere­le definite. Abordarea privitoare la clasificarea tumorilor s­a modificat, odat` cu introducerea diagnosticelor mole­culare; se cunoa[te acum, de exemplu, c` tumorile malig­ne colorectale constau din cel pu]in patru subseturi patolo­gice, fiecare corespunzând unei anumite muta]ii genetice. La fel se întâmpl` [i în cazul cancerului pulmonar f`r` ce­lule mici, care poate fi caracterizat de [apte muta]ii diferite sau transloca]ii cromozomiale.

De la “evidence based medicine” la “value based medicine”

În concluzie, anii care urmeaz` vor consemna trans­la]ia de la prescript]ie la prevent]ie, de la pacientul mediu la pacientul individual, de la abordarea reduct]ionista` a dezvolta`rii medicamentelor la o abordare care prives]te boala în ansamblu, nu doar un fragment, de la sistemul centrat pe medic la sistemul centrat pe pacient. [i, nu în ul­timul rând, de la “evidence based medicine” la “value ba­sed medicine”. Iar oncologia se afl` în avangarda acestei revolu]ii care a început în medicin`.

România: unde suntem [i unde putem ajunge?Pentru România, însu[irea profund` a principiilor me­

dicinei personalizate poate reprezenta o cale scurt` pen­tru recuperarea decalajelor care ne separ` de statele oc­cidentale. Dup` ani de zile în care reforma ghidurilor de practic` pe modelul vestic în oncologie a fost blocat`, ca [i constituirea Registrului Na]ional de Cancer, în anul în care criza oncologicelor ieftine a ]inut prima pagin` a mass­me­diei, a discuta despre medicina personalizat` reprezint` o sacr` obliga]ie, nicidecum o curiozitate. Ea deriv` din prin­cipiul fundamental al lui Hipocrate, p`rintele medicinei: “Primum non noncere (în primul rând, s` nu faci r`u)”.

| Septembrie 20126

l Dr. G. Ionescu, Dr. C. Mazilu, Dr. C. Stan, Fiz. C. PopescuPET­CT Department Euromedic Fundeni

FDG PET­CT is an important imaging tool in the no­ninvasive evaluation and monitoring of children with known or suspected malignant diseases. In this presenta­tion, we discuss the preparation of children undergoing PET studies and review radiation dosimetry and its impli­cations for family and caregivers, normal 18F­FDG distri­bution in children, and various artifacts that may arise.

We explore the use of FDG­PET in the study of chil­dren with the more common malignancies, such as brain neoplasms and lymphomas, and the less­common tumors, including neuroblastomas, bone and soft­tissue sarcomas, Wilms’ tumors, hepatoblastomas and germ­cell tumors.

We will also present the limits and the absolute and relative contraindications of 18F­FDG PET­CT assessment of oncologic disease in children, including main causes of false­positive and false­negative results.

General considerations in patient preparation and ra­diation dosimetry will be discussed.

PET­CT Imaging in Oncopediatry ­ Advantages and Limits

www.revista-hipocrate.ro REZUMAT

l Dr. C. Mazilu, Dr. G. Ionescu, Dr. C. Stan, Fiz. C. Popescu

PET­CT Department Euromedic Fundeni

PurposeWe tried to analyze characteristics and amount of

18F­FDG uptake in soft tissue and bone tumors and in­vestigated the ability of 18F­FDG­PET/CT to differentia­te malignant from benign tumors; also we tried to in­vestigate the advantages and limits of FDG PET­CT in lo­cal and systemic assessment of musculoskeletal tumors.

Material and MethodWe included 39 patients, from June 10 to June 2012,

who performed PET­CT for assessment of local or syste­mic disease. The final diagnosis was obtained from sur­gical biopsy or clinical follow­up. We analyzed the cha­racteristics and amount of 18F­FDG uptake in soft tissue and bone tumors and ability of 18F­FDG­PET/CT to diffe­

rentiate malignant from benign tumors, using maximum standardized uptake value (SUVmax).

ResultsFinal diagnosis revealed 3 benign soft tissue tu­

mors (mean SUVmax 4.7), 2 benign bone tumors (5.1), 19 malignant soft tissue tumors (8.8), and 15 malignant bone tumors (10.8). There was a significant difference in SUVmax between benign and malignant musculoske­letal tumors in total, soft tissue tumors and bone tumors.

ConclusionsFDG­PET/CT allows delineation between malignant

and benign soft tissue and bone tumors, although the­re were many false­positive and false negative lesions. Further studies with all kinds of musculoskeletal tumors in large numbers are needed to improve the diagnostic accuracy of 18F­FDG­PET/CT.

Fusion Imaging Assessment of Musculo­Skeletal Tumoral Pathology

Detecting Mutations in the EGFR Gene in NSCLC in Order to Guide Personalized Therapy with Tyrosine­Kinase Inhibitors

l Georgeta Cardos1, Andi Palade1, Alina Geor-gescu1, Mihai Stoicea1, Diana Teletin1, Bogdanka Mi-litescu1, Gra]iela Tardei1,2

1„Personal Genetics” Medical Genetics Center, Bucha­rest, Romania

2„Dr. Victor Babe[” Hospital, Bucharest, Romania

The EGFR gene codifies the Epidermal Growth Fac­tor Receptor, which is a transmembrane protein with ti­rosine­kinase activity, involved in cell growth and diffe­rentiation. Somatic mutations in exons 18­21 of the EGFR gene, identified in 10­30% of non­Asian patients with non–small­cell lung carcinomas (NCSLC), trigger consti­

Supliment special Conferin]a Societ`]ii Na]ionale de Oncologie Medical` din România

Reclama

| Septembrie 20128

tutive activation of the EGFR receptor and play a cruci­al role in tumor progression. EGFR mutational status is a predictor of benefit for EGFR­TKI (tyrosine kinase inhibi­tors) therapy.

The aim of our study was to detect the EGFR mutati­onal status in exons 19 and 21 (cca 90% from all mutati­ons) in lung adenocarcinoma patients, in order to contri­bute to selection of patients for the new EGFR­TKI perso­nalized therapy.

DNA was extracted from fixed and paraffin embedded tumors from 87 lung adenocarcinoma patients and EGFR mutational status analyzed by ARMS­PCR and sequencing.

Activating mutations were detected in exons 19 and 21 of the EGFR gene in 19 tumors out of the 87 analyzed (21,84%), of which 15 tumors with deletions in exon 19 and 4 tumors with point mutations in exon 21; the amount of tumor cells was variable, between 90% and 5%. The 19

patients were aged between 47 and 85 year, and sex dis­tribution was 1,1:1 (F:M); 15 of t h e m were non­smokers.

Our results have confirmed the sen­sitivity and cost effectiveness of our molecular methods in tes­ting of the EGFR mutational sta­tus, contributing to an effective se­lection of patients with NSCLC for anti­EGFR personalized the­rapy.

www.revista-hipocrate.ro REZUMAT

An Observational Study to Assess the Safety and Efficacy of Eligard 7.5 mg and 22.5 mg for the

Treatment of Advanced Prostate Cancerl St`nculeanu D. L.1, Ullmann F.2. Sefchi C.3 1Prof. Dr. Alexandru Trestioreanu Oncology Clinical Institute, Bucharest, Romania 2Astellas Pharma International B. V., Medical Depart­ment, Leiderdorp, The Netherlands 3Astellas Pharma S.R.L., Medical Department, Bucha­rest, Romania

Introduction and ObjectivesDespite the effectiveness of orchiectomy to treat pros­

tate cancer, treatment with LHRH agonists is often prefer­red my physicians and patients. This observational study was conducted in 12 oncology centers in Romania, betwe­en February 2009 and Decenber 2010, assessing the safety, efficacy and handling of two formulations of Eligard (As­tellas Pharma).

Materials and MethodsIn this non­interventional survey with a duration of 12

months, Eligard 7.5 mg (1 month depot formulation) or 22.5 mg (3 months depot formulation) were administered to 120 patients with advanced hormone­dependent prosta­te cancer. The study was conducted in the setting of routi­ne outpatient medical care. Data were collected after 6 and 12 months of treatment and were analyzed descriptively.

ResultsEfficacy. Median PSA concentration at baseline was

9.1 (range 0.07­460) ng/mL, decreasing to 0.7 (0.01­74.8) at 6 months and 0.4 (0.001­397.5) at 12 months. Median tes­tosterone concentration decreased from 5.3 (0.1­862) ng/dL at baseline to 0.2 (0.1­28.3) at month 6 and 0.2 (0.1­58.6)

at month 12 (data available for 11 patients). Only a small number of patients discontinued the drug because of an inadequate response to treatment (4 of 120; 3.4%). Clinici­ans indicated that their primary reason for prescribing Eli­gard was its efficacy profile (89 of 165 reasons given).

Safety. Nine patients died from causes related to their primary diagnosis of cancer. Two patients experienced an adverse event which was not related to study drug. The number of tolerability issues and the non­serious adverse events were lower than the ones reported in the registrati­on studies and in the literature.

ConclusionsIn this Romanian observational study, Eligard 7.5 mg

and 22.5 mg were demonstrated as both efficacious and tolerable. Testosterone levels were reduced and main­tained during the 12 months study period and PSA con­centrations were brought be­ l o w normal levels at months 6 and 12. Healthcare professionals identi­fied the handling and administrati­on of the Eligard syringe as practi­cal. The data of this outpatient Romanian obser­vational study was consistent with that of the Eligard registrati­on studies.

Supliment special Conferin]a Societ`]ii Na]ionale de Oncologie Medical` din România

Reclama

| Septembrie 201210

Management of mCRPC Patients – A Closer Look at New Therapeutic Alternatives

l Anca Mihailov MDmCRPC patient population is highly heterogeneo­

us. Until recently, treatment of advanced prostate cancer was only palliative and once resistance to hormonal the­rapy had developed – so called ‘castration resistant pros­tate cancer’ (CRPC), median life expectancy did not exce­ed one year. The paradigm changed in 2004 when two lar­ge studies demonstrated, for the first time, a survival bene­fit with docetaxel. In June 2010 Jevtana was approved by the US Food and Drug Administration (FDA) and by Euro­pean Medicine Agency (EMA) in 2011 for the treatment of patients with hormone­refractory metastatic prostate can­cer who had been previously treated with a regimen con­

taining the taxane docetaxel.In TROPIC study, cabazitaxel treatment significantly

improved overall survival response in patients previously treated with docetaxel more than twofold compared with mitoxantrone, the probability of surviving at 2 years with cabazitaxel (28%) being much higher than with mitoxan­trone (17%). Also, cabazitaxel doubled median PFS com­pared with mitoxantrone (cabazitaxel 2.8 months vs mito­xantrone 1.4 months; p<0.0001), the PSA response rate was significantly higher in the cabazitaxel group and, also, the patients had a significantly longer time to PSA progression. The updated analysis data highlighted the benefit of cabazi­taxel over mitoxantrone across multiple patient subgroups.

www.revista-hipocrate.ro REZUMAT

l Dr. Dana St`nculeanu Institutul Oncologic „Prof. Dr. Al. Trestioreanu“ Bucure[ti

TAM therapy of ER+ breast cancer­ distant metas­tases compose the majority of early recurrences during TAM therapy (~75% of all early recurrences are distant metastases)(1, 2).

Adjuvant treatment strategies include:Upfront (early adjuvant at start);Sequencing;Switching;Extended adjuvant.Adjuvant regimens are presented: trial designs, pati­

ent characteristic, results(4, 5, 6).

BIG 1-98(3, 8, 9)Letrozole significantly reduced early distant me­

tastasis (initial 26 months follow­up data);The superiority of LET in the primary core analysis

led to the unblinding of the TAM monotherapy arm­> ITT analysis may have a potential bias against LET/ cen­sored analysis­ potential bias against TAM (for survival, recurrence events)­> a weighted analysis was necessary.

Inverse probability of censoring weighted­ IPCW analysis(8, 9):

Weights the follow­up for the women who stay on TAM to account for the censored follow­up of matched patients who crossover;

A validated methodology used in several clinical trials.

BIG 1­98 sequential and mono­therapy­ updates at 8.1 years: IPCW analyses on DFS, OS, DRFI, BCFI con­firms LET superiority over TAM(8, 9).

Other 8.1 years updates from BIG 1­98(9, 10) are:

Early LET treatment may be beneficial for patients with node­positive disease;

Patients at greatest risk for early recurrence had: tu­mors ≥ 5 cm, grade 3 tumors, ER+/PgR– tumors, ≥ 4 po­sitive nodes, vascular invasion.

Future directions include:Assess potential strategies to counter acquired en­

docrine resistance;Identification of most effective AI for adjuvant the­

rapy;Maximizing benefit from endocrine treatment.

Summary1. Adapted from Mansell J, et al. Breast Cancer Res Treat. 2009;117(1):91­98; 2. Baum M, et al. Lancet. 2002;359(9324):2131­2139; 3. Thürlimann B, et al. N Engl J Med. 2005;353(26):2747­2757. 4.Dowsett M, et al. J Clin Oncol. 2010;28(3):509­518; 5. Ingle JN, et al. Ann Oncol. 2008;19(5):877­882; 6. Jakesz R, et al. J Natl Cancer Inst. 2007;99(24):1845­1853. 7. Mauriac L, et al. Ann On­col. 2007;18(5):859­867. 8. Colleoni M, et al. JCO. 2011;29(9):1117­1124 . 9. Regan M et al: Lan­cet Oncol 2011; 12: 1101–08; 10. Viale G, et al. Ann Oncol. 2011; 22: 2201–2207

BIG 1­98 Trial ­ Clinical Impact and Recent Updates

Supliment special Conferin]a Societ`]ii Na]ionale de Oncologie Medical` din România

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| Septembrie 201212

Bevacizumab in Her2­Negative Metastatic Breast Cancer Patients, from Clinical Trials to Clinical

Practice ­ Results of Petra Non­Interventional Studyl Dr. Dana Lucia St`nculeanu Bucharest Oncology Institute, Medical Oncology De­partment

BackgroundAdvances in the treatment of early­stage breast cancer

have improved outcomes for patients. Despite these im­provements, however, many women ultimately develop metastatic breast cancer (MBC). MBC is essentially an in­curable disease, and the prognosis has changed little over the past decade. Avastin in combination with paclitaxel or capecitabine have proven to be effective in improving out­comes in HER2 negative metastatic breast cancer patients in E2100 and RIBBON 1 studies. This is a prospective, mul­ticenter, observational, non­interventional cohort study, in subjects with HER2 negative metastatic breast cancer re­ceiving therapy with Avastin. The study was sponsored by Roche Romania SRL

Study Rationale and ObjectivesThe rationale of the present non­interventional study

was to collect information from real world daily clinical prac­tice on efficacy and safety of Avastin treatment. The primary objectives were the incidence of serious adverse events re­lated to bevacizumab and the incidence of specific adverse events (serious and non­serious). The secondary objective was to assess the efficacy of bevacizumab, as measured by time to disease progression and duration of survival.

Patients and MethodBetween 2007 and 2010, 36 patients treated with Avas­

tin for their HER2 negative metastatic breast cancer, accor­ding to standard of care and in line with local labeling and local guidelines, were followed for safety and efficacy for the duration of their treatment with Avastin. The medi­

an age was 49 (range 26­69). 34 (94.45%) patients had an ECOG PS of 0 and 1 at baseline; 6 (17%) patients had hor­monal receptor status negative at baseline. 24 (67%) had one metastatic lesion, 10 (28%) had two metastatic lesions and 2 (5%) had 3 or more metastatic lesions at baseline.

ResultsAvastin was combined with taxane­based therapy

in 89% of patients. The median duration of therapy with Avastin was 45,5 weeks (range 3–124 weeks). The medi­an number of visits was 22 (range 2­63). 21 (58%) patients didn’t experience variation on blood pressure. 10 (28%) patients had an increase of blood pressure < 20 mmHg and one patient had an increase on blood pressure >20 mmHg. Only 2 (6%) patients had proteinuria 1+.

Other adverse events reported during Avastin therapy were: minor hemorrhage (2 patients), hand­foot syndrome (1 patient) and diarrhea (1 patient). There were no statisti­cally significant variations in treatment tolerability, ECOG PS and body weight, between first and last Avastin treatment vi­sits. The median time to disease progression was 79 weeks (95% CI: 37­109). The median overall survival couldn’t be evaluated by Kaplan­Meier method, because the patients were followed until disease progression. After 63 weeks, 80% of patients were alive (95% CI: 60%­90%) and after 122 weeks ,75% of patients were alive (95% CI: 55%­88%).

ConclusionsSpecifically, no new Avastin safety signals were obser­

ved. 88.89% of patients had very good and good tolerability at the end of the therapy. Safety and efficacy results were consistent with phase III data, further confirming the safety and efficacy of Avastin in combination with standard che­motherapy in a broad HER2 negative breast cancer popula­tion of patients, representative for routine oncology practice.

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Noi standarde în prevenirea evenimentelor scheletale asociate tumorilor solide: denosumab

(Xgeva®), la pacien]ii cu metastaze osoasel Dana St`nculeanu MD PhD

Metastazele osoase apar frecvent la pacien]ii cu cancer avansat. Aproape 100% dintre pacien]ii cu mie­lom multiplu, 65­75% dintre cei cu cancer de sân sau prostat` [i 30­40% dintre cei cu cancer pulmonar dez­volt` metastaze osoase. Jum`tate dintre ace[ti pacien]i dezvolt` una sau mai multe complica]ii, denumite ge­neric evenimente asociate scheletului ­ skeletal related

events (SRE). Acestea sunt: fractura patologic`, compre­sia medular`, chirurgia osoas` [i radioterapia paliativ` osoas`. Din anul 2002, inciden]a SRE a fost folosit` ca indice compozit, în studiile desf`[urate pentru a reduce complica]iile scheletice la pacien]ii cu metastaze osoa­se. SRE determin` morbidit`]i suplimentare, afecteaz` calitatea vie]ii [i reduc supravie]uirea.

Tratamentul cu bisfosfona]i reprezint` o strategie important` în reducerea SRE la pacien]ii cu metastaze

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osoase. Cu toate acestea, bisfosfona]ii reduc inciden]a SRE cu numai 30­40% fa]` de placebo, determin` apari]ia reac]iilor adverse la infuzie, a osteonecrozei de maxi­lar (osteonecrosis of the jaw ­ ONJ) [i necesit` monitori­zarea frecvent` a func]iei renale(1).

Receptor activated nuclear factor kappa­B ligand (RANKL), unul dintre mediatorii diferen]ierii osteoclas­telor, atrage de asemenea [i celulele tumorale la ni­vel osos care, la rândul lor, activeaz` celulele stromale care produc [i mai mult RANKL, creând un cerc vicios al activ`rii osteoclastice [i distrugerii osoase 18­21. De­nosumab (Xgeva®) este un anticorp monoclonal com­plet uman împotriva RANKL, care a demonstrat efici­en]` în reducerea markerilor osteolitici [i a inciden]ei SRE. Acesta este administrat subcutanat [i nu este ex­cretat prin rinichi ­ un posibil avantaj pentru pacien]ii cu insuficien]` renal` cronic`(1).

Trei studii controlate au evaluat eficien]a tratamen­tului cu denosumab (Xgeva®) comparativ cu acidul zo­ledronic în reducerea inciden]ei SRE la pacien]i cu can­cer de sân, prostat`, respectiv alte tumori solide în afar`

de sân [i prostat`, inclusiv mielom. Rezultatele au ar`tat c` denosumab (Xgeva®) este superior acidului zole­dronic în prelungirea timpului pân` la apari]ia primului SRE, dar [i în reducerea inciden]ei SRE(2, 3, 4). Analiza combinat` (prespecificat`) a celor trei studii a ar`tat c` denosumab prelunge[te supravie]uirea f`r` eveniment cu 8,2 luni [i reduce riscul de apari]ie a unui SRE cu 17%(5). Nu s­au înregistrat diferen]e semnificative lega­te de inciden]a evenimentelor adverse, inclusiv a ONJ, între denosumab (Xgeva®) [i acidul zoledronic.

În concluzie, inhibarea RANKL cu denosumab (Xgeva®) reprezint` o op]iune nou`, superioar` de tra­tament pentru prevenirea SRE la pacien]ii cu cancer avansat [i metastaze osoase.

BIBLIOGRAFIEPeddi et al, 2012; Can Treat RevStopeck A et al, 2010; JCOFizazi K et al, 2011; Lancet Henry DH et al, 2010; JCOLipton A et al, 2012;Eur J Can

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New Approaches in Immunotherapy for Advanced Melanoma

l Dr. Kaan Harmankaya MD

Kaan Harmankaya obtained his MD and completed his doctoral thesis within the field of dermatology, at the Medical University of Vienna, Austria, in 2005. Since 2006, Dr Harmankaya has held an Assistant Medical Doctor po­sition within the Department of Dermatology, and during 2008–2009, he furthered his medical dermatologic trai­ning, holding an Internship position in internal medicine within the Department of Internal Medicine I, Division of Oncology, the Medical University of Vienna.

Dr. Harmankaya subsequently obtained his Austrian Board Certification for Dermatology and Venerology in 2011. He is a member of the Austrian Society for Derma­tology and Venereology, and the German Cancer Society. Dr. Harmankaya has co­authored several publications and abstracts. He has been both a sub­investigator and study coordinator for more than ten international multicenter clinical trials in stage III­IV melanoma, and his scientific re­search interests include dermato­oncology, the treatment of metastatic melanoma and the cutaneous side effects of therapies in oncology. Personally he has treated and ma­naged more than 60 patients with distant metastatic mela­noma in various clinical settings and protocols, including with anti­CTLA4 antibodies.

Ipilimumab is the first immunomodulating agent whi­ch significantly improves overall survival in two large ran­domized controlled phase III trials for patients suffering from distant metastatic melanoma. In studies MDX010­20,

which have led to the approval of the compound, patients in a second line treatment setting were randomized into a three arm design, comparing monotherapy with a gp100 vaccine vs. a gp100 vaccine plus Ipilimumab 3mg/kg ver­sus Ipilimumab 3mg/kg alone. A two­year survival rate of 24%, median overall survival of 10,1 months and a disease control rate of 28,5% for patients in the Ipilimumab alone arm could be achieved.

Ipilimumab monotherapy is a monoclonal antibody directly inhibiting the CTLA­4 receptor, expressed on T­cells. It is supposed to lead to increased T­cell activation and proliferation, through which antineoplastic activity against tumor cells is enabled. In the currently approved treatment regimen, Ipilimumab is administered i.v. at 3 mg/kg, in an interval of 21 days for four doses.

Radiologic assessments are to be performed after three months of therapy (at week 12) and, if necessary, at a later time point, to confirm a possible disease progression. Caused by the immunologic mode of action of the drug, anti­tumor response might be associated with an initial in­crease in size of tumor metastasis or even growth of new lesions, before leading to tumor shrinkage. These unique clinical characteristics of Ipilimumab therapy have led to the development of immune­related response criteria, whi­ch are a hallmark in the radiological assessment of those patients.

Blocking the CTLA­4 receptor and releasing activated T­cells does not only lead to anti­tumor activity, but also immunologically trigger side effects, called immune­re­

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l Dr. Adina Croitoru

În lume sunt diagnosticate anual aproximativ un mili­on de cazuri noi de cancer colorectal, cu circa 500.000 de decese din aceast` cauz`(1). De[i prognosticul bolii me­tastatice este rezervat, cu o supravie]uire la 5 ani de 5­8%, descoperirile succesive cu încorporarea agen]ilor terape­utici ]inti]i, în ultimii 20 de ani, au indus o cre[tere a supra­vie]uirii în cancerul colorectal metastatic de la aproxima­tiv 3­6 luni la 24­28 de luni(2).

Panitumumab (Vectibix®) este un anticorp mono­clonal complet umanizat care se leag` specific de recep­torul factorului de cre[tere al epidermei (EGFR ­epidermal growth factor receptor). Dezvoltat de Amgen, a fost apro­bat înc` din 2006 de c`tre FDA pentru tratamentul pacien]ilor cu cancer colorectal metastatic (mCRC) care exprim` EGFR [i care au progresat sub regimuri anterioare de chi­mioterapie, cu demonstrarea unei supravie]uiri f`r` pro­gresia bolii (PFS) de 8 s`pt`mâni(3). Panitumumab a fost primul anticorp monoclonal care a demonstrat utilizarea KRAS ca test predictiv. Ca urmare, FDA a modificat în anul 2009 indica]iile, astfel încât panitumumab se recomand` doar pacien]ilor care nu au muta]ie la nivelul genei KRAS (se folose[te [i termenul Wild­Type KRAS).

Ca [i la bevacizumab, anticorpii anti­EGFR par a fi mai eficien]i când sunt utiliza]i în combina]ie cu regimuri­le de chimioterapie. Dou` mari trialuri clinice randomiza­te au investigat panitumumab în combina]ie cu FOLFOX în linia I­a, respectiv cu FOLFIRI în linia a II­a de tratament pentru mCRC.

În aceste studii, combina]iile au ar`tat cre[terea su­pravie]urii f`r` progresia bolii (PFS) vs regimurile simple FOLFOX sau FOLFIRI. A mai fost observat` [i îmbun`t`]irea r`spunsului tumoral prin ad`ugarea de panitumu­mab (Vectibix®) la FOLFIRI. Ca [i în trialurile cu mono­terapie, beneficiile clinice asociate terapiei cu panitumu­mab (Vectibix®) au fost vizibile doar la pacien]ii cu tu­mori WT­KRAS. Toxicit`]ile observate în timpul tratamen­tului cu panitumumab (Vectibix®) combinat cu FOLFOX sau FOLFIRI include mai ales toxicitatea cutanat` [i gas­trointestinal`(4).

Beneficiile utiliz`rii panitumumab în cancerul colorectal metastatic

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lated adverse events (irAEs). They might occur in vario­us organ systems, often mimicking commonly known au­to­immune disease. Most frequently, they arise in the GI­tract (diarrhea, colitis), the liver (hepatitis with elevated LFTs), endocrine organs (hypophysitis or thyreoiditis) or

the nervous system (neuropathy, Guillain­Barré syndrome or myasthenia gravis­like symptoms). Treatment guidelines using systemic corticosteroid administration to counter va­rious irAEs exist and need to be followed meticulously, in order to avoid increased morbidity for the patient.

BIBLIOGRAFIEJemal A, et al. Cancer statistics, CA Cancer J Clin 2010; 60:277-300.Gallagher DJ Metastatic colorectal cancer: from improved survival to potential cure. Oncology 2010; 78:237-48.Van Cutsem E, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25:1658-64Peeters M et al. Panitumumab in Combination With Cytotoxic Chemotherapy for the Treatment of Metastatic Colorectal Carcinoma. Clinical Colorectal Cancer, 2012; 1 1(1): 14-23

Recent Recommendation for the Treatment of Neuroendocrine Tumorsl Dr. Doina Elena Motan Ganea Spitalul Jude]ean de Urgen]` “Sf. Ioan cel Nou”, Su­ceava

Neuroendrocrine tumors (NETs) are fairly rare neo­plasms. Although recognized for at least one century, they remain orphan tumors, about which little is known. Disa­ppointingly, survival of patients with NETs did not chan­ge appreciably over the past three decades, in either the USA or UK.

Many different types of physicians manage NETs, in­cluding endocrinologists, gastroenterologists, oncologists,

interventional radiologists and surgeons. Moreover, strate­gies vary depending on tumor type, spread, general health of the patient and predominant symptoms.

From the therapeutic point of view, surgery is nowa­days more extensive, aiming at reducing the tumor mass, in patients who could not be cured by surgery alone. Other means for tumor reduction are liver dearterializati­on by embolization with starch spheres.

The medical treatment of neuroendocrine tumors has made a real break through with the introduction of soma­tostatin analogues, particularly octreotide, and in present day, most of the hormonally related symptoms can be con­

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| Septembrie 201218

trolled by this kind of treatment. Octreotide has also shown to be an inhibitor of tumor growth, becoming the standard treatment for neuroendocrine tumors of gastrointestinal ori­gin. The use of long­acting formulation of somatostatin ana­logues significantly improved quality of life for patients with neuroendocrine tumors.

Chemotherapy, such as streptozotocin plus 5­fluorou­racil (5­FU) or doxorubicin, is used for grade3 Gl NET; is also used as first­line treatment in malignant endocrine pancrea­tic tumors, but it is combined with concomitant somatosta­tin analogue treatment. A comparison between treatments is difficult to make, because of heterogeneous patients and few randomised trials.

New targeted treatments as everolimus, an oral inhibi­

tor of the mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pan­creatic neuroendocrine tumors. In combination with oc­treotide, everolimus improved progression­free survival in patients with advanced neuroendocrine tumors, associ­ated with carcinoid syndrome. According with these re­cent findings from clinical trials, the international guideli­nes (NCCN, NANETS and ENETS) were changed.

The development of centers of excellence and NET clinical teams to coordinate multicentre studies, exten­ded clinical and tissue databases and, ultimately, deve­lopment of molecularly targeted therapeutics are needed to advance the treatment and improve survival for pati­ents with NETs

l Prof. Dr. Manuela Schmidinger,Medical University Vienna, Vienna, Austria

Last 6 years saw tremendous changes of treatment dogma in metastatic renal cell carcinoma. As a result of availability of many therapeutic options, the significan­ce of treatment management, a noteworthy part in itself in oncology, grew ever more important. Maximizing cli­nical benefit is of paramount importance. However, side

effects may lead to dose reduction and treatment in­terruption/discontinuation, if not prevented or managed properly.

This presentation describes the scientific rationale that demonstrates the importance of dosing and treatment duration. Treatment management algorithms of the most important adverse events are provided and all is exempli­fied with a wealth of data from clinical cases. ESMO 2012 latest information are also covered.

Therapy Management in mRCC: State of the Art in 2012

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l Prof. Dr. Tudor Ciuleanu, Institutul Oncologic “Prof. Dr. Ion Chiricu]̀ ”, Cluj, România,

Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor approved for the treatment of advanced and/or metastatic RCC. Sunitinib is recommended in in­ternational treatment guidelines as first line therapy for mRCC.

A randomized phase III trial of sunitinib compared

with interferon alfa as first line treatment for metasta­tic renal cell carcinoma showed superiority of suniti­nib over IFN in progression­free survival time (11 vs. 5 months), by independent, third­party radiologic assess­ment. Final overall survival analyses showed that suniti­nib treatment was associated with longer survival com­pared with IFN­alfa (26.4 vs. 21.8 months, respectively). Here we present the results of Cluj Oncology Institute ex­perience in the same setting as the pivotal study.

Sunitinib: proven efficacy in real life practice

l Conf. Dr. Dana St`nculeanu Institutul Oncologic „Prof. Dr. Al. Trestioreanu”, Bucure[ti, România

mTOR inhibitors addresses mRCC with a different mechanism of action than tyrosine kinase inhibitors. Through inhibition of mTOR complexes, they stop various intracellular processes that otherwise would lead to the activation of cell proliferation, angiogene­

sis and metastasis.Temsirolimus is the first mTOR inhibitor appro­

ved for the treatment of metastatic renal cell carci­noma in poor risk patients. Safety profile of mTOR inhibitors is a distinct one and needs to be approa­ched carefully, in order to maximize clinical bene­fit. The efficacy and safety results from a pivotal pha­se III study are presented, along with personal clini­cal experience.

Temsirolimus, Effective Therapy Management using a Powerful mTOR Inhibitor ­ Case Study

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l Michael Untch MD PhD

HannaH StudySubcutaneous versus intravenous administration of

(neo) adjuvant trastuzumab in patients with HER2­po­sitive, clinical stage I–III breast cancer (HannaH study) is a phase 3, open­label, multicenter, randomized trial. The IV formulation of Herceptin is the standard of care for HER2­positive BC. Herceptin IV is administered over 90 minutes (initial dose) or 30 minutes (maintenance dose). Dosage is based on body weight. The Herceptin SC formulation, which has been developed as an alter­native to the IV formulation, is administered in less than 5 minutes, thus offering the potential for improved con­venience, compliance and reduced medical resource utilisation.

The Herceptin SC formulation requires no loading dose and is administered as a fixed dose (600 mg). Her­ceptin SC formulation contains recombinant human hyaluronidase (rHuPH20), which facilitates the absor­ption of Herceptin into the circulation and allows the 5 mL injection volume to be administered comfortably via the SC route. The purpose of the study was to demons­trate the non­inferiority of Herceptin SC fixed­dose for­mulation, compared with the standard Herceptin IV for­mulation, based on the co­primary endpoints:

Serum Ctrough of Herceptin pre­dose at Cycle 8 (be­fore surgery;

pCR, defined as the absence of invasive neoplastic cells in the breast.

Secondary endpoints reported in this paper inclu­de total pCR (absence of invasive neoplastic cells in the breast and ipsilateral lymph nodes) and safety (inclu­ding immunogenicity).

Patients with HER2­positive, operable, locally advan­ced or inflammatory BC received 8 cycles of neoadju­vant chemotherapy, consisting of 4 cycles of docetaxel (75 mg/m2) followed by4 cycles of FEC (500/75/500 mg/m2).

Patients were randomized (1:1) to receive 8 cycles of Herceptin (q3w) administered as either:

Herceptin IV formulation (8 mg/kg initial dose, followed by 6 mg/kg maintenance dose);

Herceptin SC fixed­dose formulation (600 mg) ad­ministered into the patient’s thigh using a manual, hand­held syringe. Herceptin was administered concurrently with chemotherapy.

After surgery, patients continued to receive Hercep­tin, as per the initial randomization, to complete one year of treatment.

The primary analysis was conducted when all pati­ents had completed surgery and at least 100 patients in each arm had completed one year of treatment.

596 patients were enrolled at 81 centres in Europe (47), Asia (12) South and Central America (17), North

America (1) and Africa (4). Surgery data were available for 278 patients (93%) in the Herceptin IV arm and 275 patients in the Herceptin SC arm (93%). Baseline demo­graphics and tumor characteristics were similar betwe­en treatment arms. At the time of the analysis, 116 pa­tients from each arm had completed adjuvant Hercep­tin therapy.

Cleopatra StudyThis analysis of overall survival in the CLEOPATRA

study crossed the pre­specified boundary showing that the combination of Perjeta, Herceptin and docetaxel chemotherapy significantly improved overall survival in people with HER2­positive mBC, compared with Her­ceptin and chemotherapy. Overall survival is a secon­dary endpoint of the CLEOPATRA study.

The final progression free survival (PFS, the primary endpoint) and safety profile data from the CLEOPATRA study were published in December 2011 in the New En­gland Journal of Medicine and demonstrated that peo­ple who received Perjeta in combination with Hercep­tin and docetaxel chemotherapy had a statistically sig­nificant 38 percent reduction in the risk of their disea­se worsening or death (progression­free survival; PFS, HR=0.62, p­value<0.0001) compared to people who re­ceived Herceptin and chemotherapy plus placebo. The median PFS improved by 6.1 months, from 12.4 months for people who received Herceptin and chemotherapy plus placebo, to 18.5 months for those who received Per­jeta, Herceptin and chemotherapy.

In CLEOPATRA, the most common adverse reac­tions (rate greater than 30 percent) seen with Perjeta in combination with Herceptin and docetaxel chemothera­py were diarrhea, hair loss, low white blood cell count with or without fever, upset stomach, fatigue, rash and peripheral neuropathy (numbness, tingling or damage to the nerves). The most common Grade 3–4 adverse reac­tions (rate greater than 2 percent) were low white blood cell count with or without fever, decrease in a certain type of white blood cell, diarrhea, damage to the nerves, decrease in red blood cell count, weakness and fatigue.

CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) is an international, Phase III, ran­domized, double­blind, placebo­controlled study. The study evaluated the efficacy and safety profile of Perjeta combined with Herceptin and docetaxel chemotherapy compared to Herceptin and chemotherapy plus place­bo in 808 people with previously untreated HER2­positi­ve mBC or with HER2­positive mBC that had recurred af­ter prior therapy in the adjuvant or neo­adjuvant setting.

The primary endpoint of the study was PFS, as assessed by an independent review committee. Secondary endpoints were overall survival, PFS by investigator assess­ment, safety profile, overall response rate (ORR), duration of the response and time to symptom progression.

Temsirolimus, Effective Therapy Management using a Powerful mTOR Inhibitor - Case Study

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| Septembrie 201222

l Dr. Sophie Leymann, Senior Regional Medical Affairs Director, Oncology, EURIT region, Pfizer, Belgium

Personalized medicine is one of the greatest pro­mises of the future. Tailoring medical treatment to the individual characteristics of each patient will improve drastically clinical outcome. Lung cancer is one area in which many advances were taken in the last few years. Driver mutations associated with lung cancer

were discovered and targeted drugs directed to the re­sulting oncoprotein were developed. Improved outco­mes were, thus, achievable for the patients with those specific mutations. One can infer from this the impor­tance of identification of these mutations in lung can­cer patients.

Presentation outlines the definition of Personalized Medicine, the evolution towards biomarker driven the­rapy and what are the challenges and opportunities of personalized medicine in cancer.

The Emerging Role of Personalized Medicine in Cancer

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l Dr. Patrick Pauwels,Antwerp University Hospital, Antwerp, Belgium

Molecular testing in NSCLC is of paramount impor­tance if targeted agents are to be used. As only the group that has a specific oncogenic driver mutation will res­pond to the specifically designed therapeutic agent, cor­rect identification is mandatory. EGFR and ALK mutati­

ons are known to be key drivers of the lung oncogene­sis. Due to differences and difficulties in various types of molecular testing, extensive expertise is required from all involved counterparts.

This presentation sketches out technical aspects of molecular testing, recommendations for mutation tes­ting and a testing algorithm in non­small cell lung can­cer.

Molecular Testing in NSCLC

The Efficacy and Cost of Biological Targeted Agents in Oncology

l Doru Paul, MD Hematology­Oncology Attending NSLIJ Monter Can­cer Center

Significant advances in molecular biology over the past fifteen years led to the development of rationally de­signed new classes of drugs that target specific key factors involved in the malignant process. The term “biological targeted therapy” refers to this new generation of cancer drugs designed to interfere with a specific molecular target (typically a protein) that has been proved to have a critical role in tumor growth or progression(1).

The introduction of biological targeted agents has re­volutionized the management of certain cancer types and has contributed to recent improvements in survival rates of cancer patients, in certain subgroups of “novel nosological entities”(80). It is important to note that although the mo­lecular target of these agents is known and, in general, the­se agents act more selectively on the tumor cells than che­

motherapy, they may still have significant side­effects.In a recent long­term follow­up data on the imatinib

treatment of patients with chronic myelogenous leukemia (CML), the overall survival of patients was very impressi­ve, 80­90% of the patients taking this drug being alive at 10 years(11). The fact that the prognostic of patients with CML has improved significantly after the introduction of imati­nib on the market should not make us extrapolate positi­ve results of this level of magnitude to other tumor types. Imatinib success seems to be rather the exception than the rule(12). The reason for imatinib efficacy in CML is proba­bly related to the special pathophysiology of this disease; in CML, the tumors become “addicted” to a unique, consti­tutively active ABL kinase that has a direct, causal relation­ship with the development of CML(13) Mice made transge­nic with BCR/ABL DNA construct develop leukemia short­ly after birth(77). In contrast to this idiosyncratic patho­logic mechanism, solid tumors are much more complex than CML, each solid tumor is unique and bears a much hi­

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gher number of mutations than CML. For example, on ave­rage, breast tumors may have at least 105 mutated genes and colorectal cancer may have at least 81 mutated genes from which an average of 20 and 14, respectively, are can­cer genes directly involved in the malignant process(14). Individual pancreatic cancers may have at least 63 mutati­ons and glioblastoma multiforme tumors may bear at least 47 mutations(15). This complexity and heterogeneity ma­kes solid tumors much more difficult to treat than CML.

It became quickly clear that the benefit of these “smart agents” that target epidermal or vascular growth factors and tyrosine kinases is restricted to only a subgroup of pa­tients, and the quality of life of some patients may be even worsened by taking them. For example, it has been estima­ted that in US approximately 100,000 patients with metasta­tic colorectal cancer with tumors harboring mutant KRAS have received unhelpful and potentially detrimental the­rapy before clinical studies had shown that these patients do not benefit from cetuximab and, in fact, they may have been harmed by taking it(12).

Also, the added value of biological targets to the ar­mamentarium of contemporary cancer treatment comes with a monetary price which is not at all negligible. All the­se products are expensive and, unfortunately, their market cost does not match their clinical benefit, that in some ca­ses is modest, at best. Of course, as human beings we beli­eve that every life, is unquestionably, “of infinite value and we naturally avoid confronting the tension between not wanting to put a value on a life and having limited resour­ces”(81). It should be made clear that we do not advocate with holding potentially life prolonging medications from patients that may benefit from them. On the other hand, in order to better plan the best available care for the highest number of cancer patients and better allocate the resour­ces that may be scarce and much lower than the needs, we should also be knowledgeable of the financial aspects of these agents. More than 90% of the biological target agents approved by the FDA in the last decade cost more than $20,000 for a 4­month course of treatment(4). These appro­vals and the use of these drugs by oncologists in US im­plicitly signals to pharmaceutical companies our tolerance for high pricing, and “they set a higher threshold for what society considers acceptable”(81). According to the Uni­ted States Census Bureau, the median yearly household in­come in US is approximately 52,000(78) which disturbin­gly contrasts the cost of the majority of biological agents is significantly higher than this figure. For example, the cost of four months treatment of ipilimumab used in metasta­tic melanoma is ~$100,000 and three doses of sipoluecel T used in metastatic prostate cancer cost ~$93,000.

Given all these complex medical, social and econo­mical issues, we performed a systematic review of the FDA approved biological agents in US(3) and investigated both their potential benefits, measured by the most significant endpoints reported in the clinical trials i.e., overall survival (OS) and progression free survival (PFS) and their current market cost(4).

At present, in August 2012, in US there are twenty FDA approved biological agents for the treatment of solid tu­

mors. Here is a brief overview of the evidence of the bene­fit of these 20 drugs in different cancer types, as supported by the currently published Phase III studies. For compari­son, their US market price is included.

1. Trastuzumab (Herceptin)Trastuzumab is FDA approved for metastatic breast

cancer since September 1998 and since November 2006 for the adjuvant treatment of HER2­positive breast cancer. It is also approved since October 2010 to treat HER2­posi­tive gastroesophageal junction and gastric adenocarcino­ma.

In a pivotal phase III trial, trastuzumab administered in first­line in combination with chemotherapy to the patients with HER2­positive metastatic breast cancer significantly prolonged time to disease progression (TTP) (7.4 versus 4.6 months) and OS (25 versus 20 months), when compa­red to chemotherapy alone(19).

For the use of Herceptin in the adjuvant setting, the investigators from the National Surgical and Bowel Pro­ject (NSABP) and the North Central Cancer Treatment Group (NCCTG) reported a combined analysis of the con­trol arms for 2 trials (NSABP­B31, 1736 patients plus N 9831, 1615 women, respectively) versus the concurrent trastuzu­mab groups from each trial. The Pooled analysis showed that adjuvant trastuzumab combined with paclitaxel che­motherapy resulted in a greater than 50% reduction in re­currence risk: four­year PFS 86% versus 73%, hazard ratio (HR) of 0.51) and a 37% reduction in risk of death (four­year OS 93% versus 89%, HR 0.63)(20). A meta­analysis that included 8 adjuvant studies and approximately 12,000 pa­tients also significantly favored the trastuzumab­containing regimen both for OS and PFS(21).

Trastuzumab is also approved for the treatment of me­tastatic gastric cancer. In the TOGA trial, that randomized 594 patients, median OS was 13.8 months (95% CI 12­16) in the trastuzumab plus chemotherapy arm, compared with 11.1 months (10­13) in the chemotherapy alone arm (HR 0.74; 95% confidence interval (CI) of 0.60­0.91; p=0.0046)(22).

Cost. 440 mg of Herceptin solution costs $3675.85. The current adjuvant treatment recommendation is an initial loading dose of 4 mg/kg followed by 2mg/kg weekly for 12 weeks followed by 6mg/kg up to 52 weeks (one year). The total cost for the adjuvant treatment using the currently recommended adjuvant treatment protocol is $69,841.15.

2. Imatinib mesylate (Gleevec)Imatinib received FDA orphan drug approval for all

stages of CML since May 2001. It is also approved since Fe­bruary 2002 to treat gastrointestinal stromal tumor (GIST). Since October 2006, it is also approved to treat unresecta­ble dermatofibrosarcoma protuberans (DFSM).

For metastatic GIST, historical data shows a medi­an OS of 19 months for all patients with metastatic disea­se and 9 months for patients with metastatic disease and local recurrence(17). In a Phase 3 study that enrolled 746 patients with advanced unresected GIST, the median PFS was 18 months for patients on the standard­dose arm, and

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20 months for those receiving high­dose imatinib. Medi­an OS was 55 and 51 months, respectively(18). Thus, in the absence of controlled studies, historical comparison suggests that first­line treatment with imatinib may impro­ve survival by approximately threefold compared with standard of care in the pre­imatinib era. In the adjuvant setting, for resected GIST tumors, imatinib significantly pro­longed relapsed free survival (RFS) compared with place­bo (98% vs. 83% at 1 year; overall hazard ratio 0.35; one­sided p<0.0001). Overall survival (OS) was though similar (99.2% vs. 99.7% at 1 year; HR 0.66; p=0.47)(16). On the other hand, it has been shown that the 36 months of Glee­vec treatment significantly prolonged OS compared to 12 months of Gleevec treatment with a HR of 0.45 (95% CI: 0.22, 0.89), p=0.0187 (Package insert data). For DFSM there is data only in 18 patients. Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metas­tatic disease, five responded (62%), three of them comple­tely (37%) (Package insert data).

Cost. 30 tablets of 100 mg cost $1640.92; 30 tablets of 400 mg cost $5,963.04. The minimum cost of a month of treatment is $5,963.04. The recommended dose for treat­ment of GIST is 400 mg/day. This dose may be escalated to 800 mg/day.

3. Cetuximab (Erbitux)Cetuximab was FDA approved in colorectal cancer in

February 2004 in combination with irinotecan for patients with metastatic colorectal carcinoma who have been re­fractory to irinotecan based chemotherapy alone. In July 2009, there were some changes in the label as following: cetuximab, as a single agent, was indicated for the treat­ment of metastatic colorectal cancer after failure of both irinotecan­ and oxaliplatin­based regimens. Cetuximab, as a single agent, was also indicated in the treatment of me­tastatic colorectal cancer in patients who are intolerant to irinotecan­based regimens. Also a note was added to the label in July 2009 stating that retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for cetuximab or panitumumab in patients whose tumors had KRAS mutations in codon 12 or 13 and the use of cetuximab and panitumumab are not recommended for the treatment of colorectal cancer with these mutations.

In 2004, a Phase III randomized study established the role of cetuximab in combination with irinotecan in irino­tecan refractory patients with metastatic colorectal cancer. 329 patients whose disease had progressed during or wi­thin three months after treatment with an irinotecan­based regimen were randomized to receive either cetuximab and irinotecan or cetuximab monotherapy. The median time to progression was significantly greater in the combination­therapy group (4.1 vs. 1.5 months, P<0.001 by the log­rank test), but median OS was not statistically significant (8.6 months in the combination­therapy group and 6.9 months

in the monotherapy group (P=0.48). Despite of the lack of benefit in OS, cetuximab received FDA approval(76). More recently, the benefit of cetuximab in metastatic colorectal cancer has been addressed in two trials: the CRYSTAL(66, 67) and OPUS(68). In the CRYSTAL study for patients with wild­type KRAS, the benefit of cetuximab included a sig­nificantly better OS (median 23.5 versus 20 months), PFS (9.9 versus 8.4 months), and better response rate(66,67). In this study, 1198 patients were randomized and 676 pa­tients had wild type­KRAS (316 in the cetuximab + chemo arm and 350 in the chemo alone arm). On the other hand, in the OPUS study there was no significant difference in PFS between the two treatment arms. When retrospective efficacy analyses were carried out in the KRAS population of the OPUS study according to KRAS mutation status, an increase in the PFS was detected in the cetuximab + FOL­FOX arm (8.6 months vs 5.5 months. HR:1.83, p=0.02)(69). Two other large randomized studies failed to detect any improvement in the OS or PFS adding cetuximab to oxali­platin based chemotherapy in frontline metastatic colorec­tal cancer. The COIN study accrued 1,630 patients and 729 had wild type­KRAS tumors(70). The Nordic VII trial enrol­led 566 patients and 40% of them (303) had wild type­KRAS tumors(71). No benefit from adding cetuximab was found in any of these studies. Based on this data, it may be argued that cetuximab benefit is seen mostly when used in combi­nation with irinotecan based chemotherapy.

In squamous cell cancer of the head and neck (SCCHN), cetuximab is approved since March 2006, in combination with radiotherapy, for the treatment of locally or regionally advanced disease. It is also approved since November 2011 in recurrent locoregional disease or me­tastatic disease, in combination with platinum­based thera­py with 5­FU and also as single agent in recurrent or metas­tatic squamous cell carcinoma of the head and neck pro­gressing after platinum­based therapy.

Cetuximab was evaluated in a multinational trial, in combination with radiotherapy, in locoregionally advan­ced cancers of the oropharynx, hypopharynx, or larynx. With a median follow­up of 54 months, the median durati­on of OS was 49 months among patients treated with com­bined therapy and 29.3 months among those treated with radiotherapy alone (HR for death, 0.74; P=0.03). Locoregio­nal control rates were also significantly better. The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (HR for lo­coregional progression or death, 0.68; P=0.005)(74). An underpowered subset analysis showed that patients with oropharyngeal tumours, early AJCC T, stage (T1–3), treat­ment in the USA, concomitant boost, advanced AJCC N stage (N1–N3), high KPS (90–100), male sex, and age less than 65 years were factors associated with a potential in­creased benefit from cetuximab combined with radiothe­rapy versus radiotherapy alone. However, the trial was not powered for this unplanned subgroup analysis and, there­fore, these observations should be interpreted with cauti­on(75).

In a phase III trial, 442 patients with recurrent or me­

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tastatic head and neck cancer were assigned to a first­li­ne regimen of platinum (cisplatin or carboplatin plus flu­orouracil every three weeks) with or without cetuximab. Adding cetuximab to platinum­based chemotherapy with fluorouracil significantly prolonged the median OS from 7.4 months in the chemotherapy­alone group to 10.1 months in the group that received chemotherapy plus ce­tuximab (HR for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median PFS time from 3.3 to 5.6 months (HR for progres­sion, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001)(72).

Cetuximab administered as a single agent was studied in a multicenter Phase II clinical trial in 103 patients with recurrent or metastatic SCCHN. All patients had documen­ted disease progression within 30 days of a platinum­ba­sed chemotherapy regimen. Patients received a 20­mg test dose of cetuximab on Day 1, followed by a 400 mg/m2 ini­tial dose, and 250 mg/m2 weekly until disease progressi­on or unacceptable toxicity. The median age was 57 years, 82% were male, 100% caucasian, and 62% had a Karnofsky performance status of more than 80. The objective respon­se rate was 13% (95% confidence interval 7%–21%). Me­dian duration of response was 5.8 months (range 1.2–5.8 months). In the single­agent phase, response rate was 13%, disease control rate (complete response/partial response/stable disease) was 46%, and median time to progression (TTP) was 70 days. Median OS was 178 days(73).

Cost. 100 mg/50 ml cost $575.99; 200 mg/100 ml cost $1061.94. The average cost for a month treatment is appro­ximately $10,000. The initial loading dose is 400 mg/m2 followed by a weekly 250 mg/m2.

4. Panitumumab (Vectibix) Panitumumab is FDA approved since September 2006

in US as a single drug, as a last option to treat some pa­tients with KRAS non­mutated metastatic colon cancer with disease progression on or following fluoropyrimidi­ne­, oxaliplatin­, and irinotecan­containing chemotherapy regimens. The effectiveness of panitumumab for the treat­ment metastatic colorectal carcinoma is based on PFS data only. Currently no data is available that demonstrate an im­provement in disease­related symptoms or increased survi­val with panitumumab. The benefit of panitumumab mo­notherapy was initially shown in a multicenter trial in whi­ch 463 patients refractory to 5­FU, irinotecan, and oxalipla­tin were randomly assigned to best supportive care (BSC) with or without panitumumab (6 mg/kg every two weeks). The objective response rate with panitumumab was 10%, and 27% had stable disease; the corresponding rates with BSC alone were 0 and, respectively, 10%. Patients receiving panitumumab were significantly more likely to be alive and progression­free at eight weeks (49 versus 30 %). Medi­an PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumu­mab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (stan­dard error) PFS time was 13.8 (0.8) weeks for panitumu­mab and 8.5 (0.5) weeks for BSC. No difference was obser­ved in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which may have been confounded by 76% patients from the BSC group crossing over to the panitumumab arm(45).

Cost. 100 mg/5ml cost $951.99, 400 mg/20 ml cost $4349.40. The average cost for a month treatment is appro­ximately $10,600. The recommended dose of panitumu­mab is 6 mg/kg every 2 weeks.

5. Temsirolimus (Torisel)Temsirolimus was FDA approved in May 2007 to

treat patients with advanced renal cell carcinoma (RCC). Temsirolimus was evaluated in a phase III trial in previous­ly untreated poor­prognosis patients with metastatic or re­current RCC were randomly assigned to temsirolimus (25 mg IV/week), temsirolimus (15 mg IV/week) plus IFNa (es­calated up to 6 million units three times per week as tole­rated), or IFNa monotherapy (escalated up to 18 million units three times per week as tolerated). Temsirolimus as a single agent significantly prolonged the median OS com­pared to IFNa as a single agent (10.9 versus 7.3 months; HR for mortality 0.73, 95% CI 0.58­0.92). Also the median PFS of the patients receiving single agent temsirolimus was impro­ved compared to the patients receiving single agent IFNa, according to both investigator and independent radiolo­gic assessment (3.8 versus 1.9 months and 5.5 versus 3.1 months, respectively)(37).

Cost. 1 dose of 25 mg costs $1343.96. The average cost for a month treatment is approximately $5,376. The recom­mended dose of Torisel is 25 mg once a week.

6. Everolimus (Afinitor)Everolimus was FDA approved in March 2009, to treat

patients with advanced RCC whose disease has progressed after treatment with other therapies and patients with pan­creatic neuroendocrine tumors that cannot be removed by surgery, are locally advanced, or have metastasized. In No­vember 2010, it has been approved for patients with sube­pendymal giant cell astrocytoma who also have tuberous sclerosis and are unable to have surgery. It has been also approved in July 2012, for the treatment of postmenopa­usal women with advanced hormone receptor­positive, HER2­negative breast cancer (advanced HR+ BC) in com­bination with exemestane, after failure of treatment with le­trozole or anastrozole.

A randomized Phase III trial compared everolimus with placebo in patients with metastatic renal cell cancer that progressed on vascular endothelial growth factor ty­rosine kinase inhibitors (VEGF TKI), (sorafenib, sunitinib) or within 6 months after completing such a therapy. The­re was no statistically significant difference in OS (medi­an 14.8 versus 14.4 months, HR 0.87), but patients who had been assigned to placebo were eligible for crossover to everolimus when progressive disease developed and 80% of placebo patients received everolimus. The median PFS was 4.9 months (everolimus) versus 1.9 months (pla­cebo) (HR, 0.33; P<0.001) by independent central revi­ew and 5.5 months (everolimus) versus 1.9 months (Pla­cebo) (HR, 0.32; P<0.001) by investigators. Also stable di­sease was more common in the patients receiving everoli­mus vs the patients receiving placebo (63 and 32%, respec­tively) (9, 38).

The Radiant­3 Study Group evaluated patients with low­grade or intermediate­grade pancreatic neuroendo­

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crine tumors with radiologic progression within the previ­ous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The median PFS was 11.0 months with everolimus as compared with 4.6 months with placebo (HR for disease progression or death from any cause with everolimus, 0.35; 95% CI, 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death(39).

Everolimus is also approved in patients with subepen­dymal giant cell astrocytoma (SEGA) who also have tu­berous sclerosis (TS) and are unable to have surgery ba­sed on the results of a Phase II study. Twenty­eight pati­ents were enrolled in the study and ranged in age from 3 to 34 years old. All had a diagnosis of TS and documen­tation of serial growth (on two successive MRI scans) of a SEGA. The primary end point was the change in volu­me of the SEGA during 6 months’ treatment, while seizure frequency, neuro­cognition and quality of life were secon­dary end points. At 6 months into the study, nine patients (32%) had a greater than 50% reduction in tumor volume of their largest SEGA tumor lesion. Seven of these patients retained the >50% reduction in tumor volume at time of last follow­up. Patients participating in the study did not de­velop any new tumors. However, no tumor resolved com­pletely. Based on the encouraging results observed on this study, FDA granted accelerated approval of everolimus for patients with SEGAs that are not candidates for surgical re­section(40).

Everolimus has been also approved in July 2012 for the treatment of postmenopausal women with advan­ced hormone receptor­positive, HER2­negative breast cancer (advanced HR+ BC) in combination with exe­mestane, after failure of treatment with letrozole or ana­strozole. In an updated report of the Bolero­2 study, PFS by investigator assessment showed a hazard ra­tio (HR) of 0.44 (95% CI: 0.36–0.53) and a median dura­tion of 7.4 (everolimus+exemestane) vs 3.2 months (exe­mestane alone) (P<1 x 10–16) and 12­month estimate of 31% vs 10%. PFS by central assessment showed an HR of 0.36 (95% CI: 0.28–0.45) and a median duration of 11.0 (everolimus+exemestane) vs 4.1 months (exemestane alo­ne) (P<1 x 10–16)(36).

Cost. 2.5 mg tabs/28 cost $7054.34. 5 mg tabs/28 cost $7187.62, 10 mg tabs/28 cost 7580.37. The average cost for a month treatment is approximately $8,000. The recommen­ded dose is 10 mg once a day.

7. Vandetanib (Caprelsa)Vandetanib was FDA approved in April 2011 to treat

patients with metastatic medullary thyroid cancer who are ineligible for surgery. Vandetanib’s safety and effectiveness were established in a single, Phase III, randomized interna­tional study of 331 patients with late­stage medullary thy­roid cancer. Patients in the study were selected to recei­ve vandetanib or placebo. In this study, there was a signifi­cant prolongation of PFS in patients who received vandeta­nib compared with placebo, with an HR of 0.46 and an esti­mated 11­month prolongation of median PFS. The median PFS was 19.3 months in the placebo group and, although

the median had not yet been reached for the vandetanib group, fitting a statistical Weibull model indicated a predic­ted median of 30.5 months. OS data were immature at data cutoff and the authors stated that a final survival analysis will take place when 50% of the patients have died(41).

Cost. The price per tablet is $195.00, equating to a cost of $5850 per month. The recommended dose of Caprelsa® is 300mg taken once daily.

8. Vemurafenib (Zelboraf)Vemurafenib was FDA approved in August 2011 to

treat certain patients with inoperable or metastatic melano­ma. This small­molecule drug blocks the activity of a per­manently activated mutant form of the serine/threonine ki­nase BRAF (known as BRAF V600E). A landmark phase III trial compared vemurafenib with dacarbazine in previous­ly untreated patients whose tumors contained the V600E mutation in BRAF. In the BRIM­3 trial, 675 patients were randomly assigned to either vemurafenib (960 mg twice a day) or dacarbazine (1000 mg/m2 intravenously every three weeks). Treatment was to be continued until disea­se progression. All patients had either metastatic disease or unresectable stage IIIC disease (95 and 5 percent, respecti­vely). OS was significantly increased in patients assigned to vemurafenib compared with dacarbazine. The estimated survival rates at 6 months were 84% for patients receiving vemurafenib versus 64% of the patients receiving dacarba­zine (HR for death 0.37, 95% CI 0.26­0.55). PFS was also sig­nificantly longer in those initially treated with vemurafenib (median 5.3 versus 1.6 months, HR 0.26, 95% CI 0.20­0.33). Finally, the objective response rate was significantly higher with vemurafenib (48 versus 4% with a P<0.001)(42).

Cost per month of 480 tabs (120 mg tabs) is $10,748.44. The recommended dose is 960 mg twice a day.

9. Crizotinib (Xalkori)Crizotinib was FDA approved in August 2011 to treat

certain patients with locally advanced or metastatic non­small cell lung cancer (NSCLC). This approval is indepen­dent on whether or not the patients have received previo­us treatment for NSCLC. There is no data available demon­strating improvement in patient reported outcomes or sur­vival with criozotinib. The FDA approval is based on res­ponse rate rather than survival data(43). This small­mole­cule drug inhibits the tyrosine kinase activity of a fusion protein called echinoderm microtubule­associated prote­in­like 4­anaplastic lymphoma kinase (EML4­ALK), resul­ting in decreased tumor cell growth, migration, and invasi­veness. Crizotinib is recommended for patients with EML4­ALK gene rearrangements that are present in approxima­tely 1% of patients with adenocarcinoma of the lung. Cri­zotinib is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic NSCLC that is ALK­positive, as detected by an FDA­approved test. The ef­ficacy of crizotinib was established in two multicenter, sin­gle arm studies. In total, these studies included 255 pati­ents, all of whose tumors contained an ALK gene rearran­gement, as shown by FISH. Overall, 95% of patients had metastatic disease and 5% had locally advanced NSCLC. The combined objective (complete plus partial) response

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rate was 55 percent, the majority of which was achieved during the first eight weeks of treatment. The median dura­tions of response at the time of analysis on the two studies were 42 and 48 weeks, respectively. The majority of the­se patients were heavily pretreated: 76% had received two or more treatment regimens(43). Retrospective analysis of the results from a non­randomized, Phase I study sugges­ts improvement in the survival of patients receiving crizo­tinib. The one and two­year survival rates for patients trea­ted with crizotinib were 74 and 54%, respectively, with a median follow up of 18 months. For comparison, in a co­hort of 36 patients with the ALK fusion oncogene who were not treated with crizotinib, the survival rates at one and two year were 44 and 12%, respectively(44).

Cost of 30 200 mg capsules is $5151.25. The cost of a treatment/month is $10,302.5. The recommended dose is 200 mg po bid.

10. Pertuzumab (Perjeta)Pertuzumab is FDA approved since June 2012, in com­

bination with trastuzumab and docetaxel to treat metasta­tic breast cancer that expresses HER­2 and has not been treated with chemotherapy or a HER­2­directed therapy. Pertuzumab is a monoclonal antibody that binds to HER­2 at a region distinct from trastuzumab. This region allows HER­2 to interact with other receptors, such as the epider­mal growth factor receptor (EGFR), to send growth­pro­moting signals. In a pivotal Phase III trial, 808 patients with HER2­positive metastatic breast cancer were randomized to receive as first­line treatment placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus tras­tuzumab plus docetaxel (pertuzumab group). The treat­ment was given until the time of disease progression or the development of unmanageable toxic effects. The median PFS was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (HR for progres­sion or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The inte­rim analysis of OS showed a strong trend in favor of per­tuzumab plus trastuzumab plus docetaxel(50).

Cost. 30 mg/ml X 14 mls costs $4279.44. The average cost of a treatment/month is $5,700. Initial loading dose is 840 mg followed by 420 mg Q 3 weeks.

11. Lapatinib (Tykerb)Lapatinib is FDA approved since March 2007 for the

treatment of certain types of advanced or metastatic breast cancer. In a randomized Phase III study Tykerb + capecita­bine vs capecitabine alone improved time to progression in the combination arm to 8.4 months vs 4.4 months in the capacitabine alone arm. HR 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001). The median OS was 75.0 weeks for the combination arm and 64.7 weeks for the monothera­py arm (HR, 0.87; 95% confidence interval [CI], 0.71­1.08; p =0.210) (not statistically significant). However, if the 36 patients who crossed over to combination therapy are ex­cluded from the analysis, the combination of lapatinib and capecitabine resulted in a statistically significant improve­ment in median OS. (75.0 versus 56.4 weeks)(29,30).

Cost of 150 tabs of 250 mg is $3300. The average cost of a treatment/month is $3300­4000 depending on the combi­

nation used. The daily approved dose of lapatinib is 1250 mg (in combination with capecitabine) and 1500 mg (in combination with letrozole).

12. Gefitinib (Iressa)Gefitinib is FDA approved since May 2003 (in areas of

the world where gefitinib is available, it may be used in pla­ce of erlotinib) to treat patients with advanced non­small cell lung cancer. Gefitinib was originally approved in 2003, but in June 2005, the FDA approved new labeling that limi­ted the approval, i.e., only for patients who are currently benefiting (or have previously benefited) from this agent. The reason for this change is that the post approval pha­se III placebo­controlled study of gefitinib, the Iressa Sur­vival Evaluation in Lung Cancer (ISEL) trial, was negative showing only a small difference in OS between the experi­mental arm and placebo (5.6 vs 5.1 months, P = .087)(2). In a pivotal phase III trial study, IPASS, 1217 patients light smokers or no smokers with adenocarcinoma randomized to receive gefitinib or carbo­taxol. The study was initially published in New England Journal of Medicine (NEJM) in September 2009, then a follow­up was published in the Journal of Clinical Oncology in July 2011. Results for PFS: in the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, PFS was significantly longer among those who received ge­fitinib than among those who received carboplatin­pacli­taxel. In the subgroup of patients with Epidermal Growth Factor Receptor (EGFR) mutation–positive tumors, (HR, 0.48; 95% CI, 0.36 to 0.64; P<0.001; median PFS, 9.5 v 6.3 months) whereas in the subgroup of 176 patients who were negative for the mutation, PFS survival was significantly longer among those who received carboplatin­paclitaxel chemotherapy (HR, 2.85; 95% CI, 2.05 to 3.98; P<0.001; me­dian PFS, 5.5 v 1.5 months). There was no significant di­fference in OS for gefitinib versus carboplatin/paclitaxel in any subgroup(24). Please note that gefitinib is endorsed by NCCN for use in NSCLC patients with EGFR mutations, but it is not approved by FDA for this indication.

Cost/month of 250 mg (30 tabs) is $1805.91. The appro­ved daily dose of gefitinib is 250 mg po.

13. Erlotinib (Tarceva)Erlotinib is FDA approved since November 2005 to

treat pancreatic cancer that cannot be removed by sur­gery or has metastasized. A phase III trial from the National Cancer Institute of Canada (NCIC) compared gemcitabine with and without erlotinib and found a benefit in OS in the combination arm of 2 weeks (HR 0.81, p = 0.038, median 6.2 versus 5.9 months, one­year survival 23 versus 17 per­cent, respectively). The PFS was also better by 2 weeks in the combination arm(28). Please note that, in lung cancer, erlotinib has three current National Comprehensive Can­cer Network (NCCN) indications but only the first two are FDA approved:

1. Erlotinib is approved since April 2010 for maintenan­ce treatment in locally advanced or metastatic non­small cell lung cancer. In the SATURN study, 884 patients were analyzable for PFS at ~11.5 months of follow­up. PFS was significantly longer in patients with EGFR­positive immu­

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nohistochemistry irrespective of mutational status (me­dian PFS 12.3 vs 11.1 weeks; HR 0·71, 95% CI 0·62–0·82; p<0·0001). OS was also significantly prolonged with erloti­nib versus placebo in the intention­to­treat population (me­dian 12 vs 11 months; HR 0.81, 95% CI 0.70–0.75; p=0.0088)(25).

2. Erlotinib is also approved for second and third line treatment in all types of NSCLC, since November 2004. In a study published in the NEJM, PFS for erlotinib versus pla­cebo used in second or third line was 2.2 months and 1.8 months, respectively (hazard ratio, 0.61, adjusted for stra­tification categories; P<0.001). OS was 6.7 months and 4.7 months, respectively (HR, 0.70; P<0.001), in favor of Tarce­va(26).

3. Erlotinib is recommended by NCCN (but it is not FDA approved so the package insert does not include this indication) for NSCLC patients with EGFR mutations. In a pivotal phase III trial study (EURTAC) 1227 patients were screened for mutations and 174 were found to have mutati­ons and were randomized to receive erlotinib vs platinum­based CT. PFS in the erlotinib arm was 9.4 months (HR, 0.42; P<0.0001), compared to 5.2 months (95%CI, 4.4­5.8 m) in the CT arm. Median OS, not statistically significant, was 22.9 months in the erlotinib arm and 18.8 months in the CT arm (HR, 0.80; P=0.42)(27).

Cost per month ranges from $4688.87(30 tabs of 100 mg) to $6535.04 (30 tabs of 150 mg). The dose used in pan­creatic cancer is 100 mg once a day and in NSCLC is 150 mg once a day.

14. Axitinib (Inlyta)Axitinib has been FDA approved in January 2012 for

the treatment of advanced renal cell carcinoma, in pati­ents in which other agents have not been effective. This approval was based on the AXIS phase III trial that inclu­ded 723 patients with metastatic clear cell RCC who were randomly assigned to treatment with either axitinib (5 mg twice a day) or sorafenib (400 mg twice a day)(10). This study found a significant improvement in PFS (7 versus 5 months, HR for PFS, 0.67, 95% CI 0.54­0.81). The benefit in PFS was higher in patients previously treated with cytoki­nes (median 12 versus 7 months, HR 0.46, 95% CI 0.32­0.68) than in patients previously treated with sunitinib (median 5 versus 3 months, HR 0.74, 95% CI 0.57­0.96)(10).

The recommended dose is 5mg po bid. One1mg tablet cost is $22. One 5 mg tablet cost is $165. The cost per month using 1 mg tabs is $6600 and using 5 mg tabs is $9900.

15. Bevacizumab (Avastin)Bevacizumab is an anti­vascular endothelial growth

factor (VEGF) monoclonal antibody that is FDA approved since February 2004 for front line and since June 2006 for second line in the treatment of metastatic colorectal can­cer in combination with chemotherapy. It is also approved since October 2006 as front line treatment of non­squamo­us lung cancer, in combination with chemotherapy. In May 2009, bevacizumab is also approved for the second line treatment of grade 3 and grade 4 malignant gliomas. Also, since August 2009 bevacizumab was approved for metastatic renal cell cancer.

In patients with metastatic colorectal cancer, in a pi­votal early trial, the addition of bevacizumab to the bolus irinotecan/5 FU/leucovorin (IFL) regimen significantly im­proved response rates (45 versus 35 percent, P=0.004)), PFS (10.6 versus 6.2 months, HR for disease progression, 0.54; P<0.001), and OS (20.3 versus 15.6 months, HR for death of 0.66 (P<0.001)(53). In 2004, the Intergroup N9741 trial(54) showed a significant improvement in OS in pati­ents treated with FOLFOX versus bolus IFL and since then FOLFOX became the standard of care frontline treatment of patients with metastatic colorectal cancer. To date, the­re are still only limited data on the benefit of adding be­vacizumab to an oxaliplatin­based regimen in frontli­ne treatment of metastatic colorectal cancer but, despite the lack of data, the majority of oncologists in US use the FOLFOX+bevacizumab combination in this setting. In fact, a large randomized Phase III study, that used a 2 x 2 facto­rial design and investigated the benefit of adding bevacizu­mab versus placebo to XELOX or FOLFOX­4 did not show any improvement in survival using bevacizumab. A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median PFS was 9.4 months in the bevacizumab arm and 8 months in the placebo arm (HR, 0.83; 97.5% CI, 0.72 to 0.95; P = 0.0023). Median OS was 21.3 months in the bevacizu­mab arm and 19.9 months in the placebo arm, but these re­sults were not statistically significant. (HR, 0.89; 97.5% CI, 0.76 to 1.03; P =0 .077)(55). Interestingly, in the second line setting, adding bevacizumab to an oxaliplatin based regi­men showed an improvement of both the OS (12.9 months compared with 10.8 months for the group treated with FOL­FOX4 alone; HR for death = 0.75; P =0.0011) and in PFS (7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone HR for progression = 0.61; P <0.0001)(56).

Bevacizumab demonstrated significant clinical acti­vity in second line treatement of grade 3 and grade 4 ma­lignant gliomas both alone and in combination with irino­tecan. The prognosis for recurrent malignant glioblastomas is gruesome, with median survivals of 3 to 9 months(57). Most of the data come from a noncomparative phase II tri­al, in which 167 patients with recurrent glioblastoma multi­forme (GBM) were randomly assigned to bevacizumab (10 mg/kg), either as a single agent or at the same dose in con­junction with irinotecan (125 mg/m2 for those not taking enzyme­inducing antiepileptic agents and 340 mg/m2 for those taking these agents). Treatment cycles were repea­ted every two weeks. The median OS time from the time of random assignment were 9.2 months (95.0% CI, 8.2 to 10.7 months) for the bevacizumab group and 8.7 months (95.0% CI, 7.8 to 10.9 months) for the bevacizumab+ CPT­11 group. The estimated 6­month PFS rates were 42.6% (97.5% CI, 29.6% to 55.5%) in the BV group and 50.3% (97.5% CI, 36.8% to 63.9%) in the bevacizumab + CPT­11 group(58).

There are two randomized Phase III studies that esta­blished the benefit of Bevacizumab in the treatment of me­tastatic renal cell cancer. In the AVOREN study, 649 previ­ously untreated patients were randomized to receive inter­feron alpha (IFNa, 9 million units three times per week for one year) plus either bevacizumab (10 mg/kg every two weeks) or placebo. PFS was significantly prolonged in the

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bevacizumab arm (10.2 versus 5.5 months, HR 0.63, 95% CI 0.45­0.72)(59), but the improvement in the OS was not statistically significant (median survival 23.3 versus 21.3 months, HR 0.86, 95% CI 0.72­1.04)(60). In a second Pha­se III study, 732 previously untreated patients with metasta­tic renal cell carcinoma were randomly assigned to either IFN­alpha plus bevacizumab or IFN­alpha plus placebo, on schedules similar to that used in the AVOREN trial. An in­terim analysis found that the PFS was significantly better in the patients receiving bevacizumab+IFN­alpha: 8.5 months for patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 months (95% CI, 3.1 to 5.6 months) for patients receiving IFN monotherapy (log­rank P<.0001)(61). The median OS time was 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN­alpha and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN­alpha mo­notherapy (unstratified log­rank P = .097) which was not statistically significant. Adjusting on stratification factors, the hazard ratio was 0.86 (95% CI, 0.73 to 1.01; stratified log­rank P = .069) favoring bevacizumab plus IFN­alpha(62).

Initially, it has been shown that, for patients with NSCLC and good performance status, the addition of be­vacizumab to the paclitaxel and carboplatin doublet im­proved the PFS and the OS, compared with chemothera­py alone. The median OS was 12.3 months in the group as­signed to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy­alone group (HR for death, 0.79; P=0.003). The median PFS in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for di­sease progression, 0.66; P<0.001), with corresponding res­ponse rates of 35% and 15% (P<0.001)(63). Subsequently, in a second randomized phase III trial of 1043 patients, the addition of bevacizumab to the cisplatin and gemcitabine doublet did not confirm a statistically significant effect on OS(64, 65).

Bevacizumab was also initially approved for metas­tatic breast cancer in February 2008, under the FDA’s ac­celerated approval program, which allows a drug to be approved based on data that are not sufficiently comple­te to permit full approval. On November 18, 2011, FDA re­voked the agency’s accelerated approval of the breast can­cer indication for Avastin manufactured by Genentech. Be­vacizumab used for metastatic breast cancer has not been shown to provide a benefit, in terms of delay in the growth of tumors that would justify its serious and potentially life­threatening risks. Nor was there enough evidence that use of bevacizumab will either help women with breast can­cer live longer or improve their quality of life. In a pooled analysis of data for bevacizumab and first­line chemothe­rapy from E2100, AVADO, and RIBBON­1, the addition of bevacizumab significantly improved median PFS (9.2 ver­sus 6.7 months), but not OS (26.7 versus 26.4 months). Wi­thout an OS advantage, it is unclear whether the magnitu­de of improvement in PFS (2.5 months) is clinically mea­ningful, given the excess toxicity and expense of adding bevacizumab(23).

Cost. 100 mg/4ml cost $645.96, 400 mg/16 ml cost $2,525.85. Bevacizumab is approved at a dose of 5mg/kg or 10 mg/kg every 2 weeks for the treatment of metastatic colorectal cancer. The dose used in NSCLC, GBM and re­

nal cell cancer is 10 mg/kg every 2 weeks.

16. Sorafenib (Nexavar)Sorafenib is a small­molecule inhibitor of tyrosine ki­

nases that is approved for the treatment of advanced renal cell carcinoma since December 2005 and since November 2007 for some cases of hepatocellular carcinoma. The ac­tivity of sorafenib in advanced RCC was demonstrated in the phase III TARGET trial, in which patients with advan­ced RCC who had failed prior standard therapy were ran­domly assigned to sorafenib (400 mg orally twice daily) or placebo. The median PFS was significantly longer in those receiving sorafenib compared with placebo (5.5 versus 2.8 months, HR 0.44, 95% CI 0.35­0.55). OS was not significantly prolonged compared to placebo (median 17.8 versus 15.2 months, HR 0.88, 95% CI 0.74­1.04). However, when post­cross­over placebo survival data were censored, the diffe­rence became significant (17.8 v 14.3 months, respectively; HR = 0.78; P = .029)(34).

For liver cancer, the multicenter European SHARP trial randomly assigned patients with inoperable hepatocellu­lar carcinoma and Child­Pugh A cirrhosis to sorafenib or placebo. OS was significantly longer in the sorafenib­trea­ted patients (10.7 versus 7.9 months), as was time to radio­logic progression (5.5 versus 2.8 months)(35).

The monthly cost of treatment is $8377.13 (120 tabs of 200 mg). The approved daily dose of Nexavar is 400 mg twice a day.

17. Sunitinib (Sutent) Sunitinib is another small­molecule tyrosine kinase in­

hibitor that is approved since January 2006 for the treat­ment of patients with metastatic renal cell carcinoma. It is also approved since May 2007 for the treatment of gastro­intestinal stromal tumors (GIST) that are not responding to imatinib, and since May 2011 for the treatment of pancrea­tic neuroendocrine tumors that cannot be removed by sur­gery, are locally advanced, or have metastasized.

Sunitinib was evaluated in a phase III trial with largely good­ or intermediate­prognosis metastatic clear cell RCC who had not received prior systemic therapy. Median PFS was significantly prolonged (11 versus 5 months, HR 0.54). OS was also prolonged with sunitinib (median 26.4 versus 21.8 months, HR0.82, 95% CI 0.67­1.00, p=0.051)(6, 7, 31).

An international phase III trial of sunitinib versus pla­cebo in 312 patients with refractory GIST established the role of sunitinib in this setting. 312 patients were randomi­zed in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned in­terim analysis showed significantly longer time to tumor progression with sunitinib. The duration of PFS was cle­arly in favor of sunitinib: median PFS was 24.1 weeks (95% CI 11.1–28.3) for sunitinib, 6.0 weeks (4.4–9.9) for place­bo, respectively (HR 0.33; 95% CI, 0.24–0.47; p<0.0001). OS obtained with initial sunitinib treatment was better than the one obtained with placebo, despite the option to cross over (HR 0.49, 95% CI 0.29–0.83; p=0.007). The authors sta­ted that, since more than half the patients in the sunitinib group were still alive at the time of the interim analysis, a median OS value could not be calculated(52).

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Sunitinib was also studied in patients with advanced, well­differentiated pancreatic neuroendocrine tumors in a phase III multinational randomized, double­blind, place­bo­controlled study. 171 patients were randomly assigned to receive either sunitinib at a dose of 37.5 mg per day or placebo. Median PFS was 11.4 months in the sunitinib arm as compared with 5.5 months in the placebo arm (HR for progression or death, 0.42; 95% CI, 0.26 to 0.66; P<0.001). Nine deaths were reported in the sunitinib arm (10%) and 21 deaths were reported in the placebo group (25%) and most patients were still in follow­up at the data cut off point. The hazard ratio for death was 0.41 (95% CI, 0.19 to 0.89; P = 0.02) in favor of sunitinib. The authors stated that, due to the relatively high number of censored events, median OS could not be estimated for either study group(51).

The approved daily dose for renal cell carcinoma and GIST is 50 mg/day and the dose for pancreatic neuroen­docrine tumors (PNET) is 37.5 mg/day. Costs are: 12.5 mg (28 tabs) $2596.10; 25 mg (28) $5508.22; 50 mg (28 tabs) $10465.92. The monthy cost of treatment ranges from 8100 (PNET) to 10,465.92 (renal cell cancer and GIST).

18. Pazopanib (Votrient)Pazopanib is FDA approved since January 2012 to

treat patients with advanced renal cell carcinoma and sin­ce March 2012 to treat advanced soft tissue sarcoma. In a phase III trial, patients, patients who were previously un­treated or had received only cytokine therapy, were ran­domly assigned to Votrient or placebo. There was a signifi­cant increase in PFS with Votrient compared with placebo (median 9.2 versus 4.2 months, HR 0.46, 95% CI 0.34­0.62), with significant increases both in previously untreated pati­ents and in those who had received cytokine therapy(32). Almost all patients had good or intermediate risk. In the fi­nal analysis of the study presented in 2010 at ESMO, H.R. 0.91, CI 0.71­1.16) the increase in OS was non­significant. (median OS of 22.9 versus 20.5 months). The authors’ im­pression was that the final analysis of OS was confounded by the early, frequent, and prolonged crossover to Votrient from patients originally randomized to placebo(33).

Pazopanib has also activity in advanced non­adipo­cytic soft­tissue sarcoma. An international Phase III study was conducted in 13 countries and 369 patients were ran­domly assigned in a 2:1 ration to receive pazopanib or pla­cebo. Median PFS was 4.6 months (95% CI 3.7—4.8) for pazopanib compared with 1.6 months (0.9—1.8) for pla­cebo (HR 0.31, 95% CI 0.24—0·40; p<0.0001). OS was 12.5 months (10.6—14.8) with pazopanib versus 10.7 months (8.7—12.8) with placebo, but this was not statistically signi­ficant (HR 0.86, 0.67—1.11; p=0.25)(87).

The recommend daily dose is 800 mg once a day. The cost per month using 120 tabs of 200 mg tabs is $6250.64.

19. Ipilimumab (Yervoy)Ipilimumab is FDA approved since March 2011 to

treat patients with unresectable or metastatic melano­ma. This monoclonal antibody is directed against cyto­toxic T­lymphocyte­associated antigen­4 (CTLA­4), whi­ch is expressed on the surface of activated T cells as part of a “checkpoint” to prevent a runaway immune respon­

se. By inhibiting CTLA­4, ipilimumab stimulates the immu­ne system to attack melanoma cells. There were two Pha­se III studies that established the benefit of ipilimumab in the treatment of metastatic melanoma. In a placebo con­trolled, Phase III trial, 676 patients were randomly assig­ned in a 3:1:1 ratio to ipilimumab plus a glycoprotein 100 (GP100) vaccine, ipilimumab alone, or GP100 alone. All patients were HLA­A0201 positive and had unresectable metastatic melanoma. All patients had received prior syste­mic treatment for advanced disease with either cytotoxic chemotherapy or interleukin­2. OS was significantly incre­ased in the two groups that received ipilimumab (medi­an 10.0 and 10.1 versus 6.4 months, in the ipilimumab plus gp100, ipilimumab alone, and gp100 groups, hazard ratio (HR) for death 0.68 and 0.66 versus gp100 alone, respecti­vely). OS rates for the three groups were 44, 46, and 25% at 12 months and 22, 24, and 14% at 24 months, respectively. The PFS in the three groups was the same. The median PFS was 2.76 months (95% CI, 2.73 to 2.79) in the ipilimumab­plus gp100group, 2.86 months (95% CI, 2.76 to 3.02) in the ipilimumab­alone group, and 2.76 months (95% CI, 2.73 to 2.83) in the gp100­alone group.(48) In the second study, 502 patients with previously untreated metastatic mela­noma, were randomized in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body­surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. The median OS in the ipilimumab–dacarbazine group was 11.2 months (95% CI, 9.4 to 13.6), as compared with 9.1 months (95% CI, 7.8 to 10.5) in the dacarbazine group, with estimated survival rates in the two groups, re­spectively, of 47.3% and 36.3% at 1 year, 28.5% and17.9% at 2 years, and 20.8% and 12.2% at 3 years (HR for death with ipilimumab­dacarbazine, 0.72; P<0.001). There was a 24% reduction in the risk of progression in the ipilimumab­da­carbazine group as compared with the dacarbazine group (HR for progression, 0.76; P =0.006). The median values for PFS were similar. The authors interpreted this lack of diffe­rence in PFS as a result of a too early first assessment done at 12 weeks; after the first assessment the Kaplan Meier cur­ves separated(49).

The approved dose is 3 mg/kg every 3 weeks for 4 do­ses. The cost of 50 mg is $6000. The total cost of an ipilimu­mab treatment is approximately $100,000.20. Sipoleucel T (Provenge)

Sipoleucel T is FDA approved since April 2010 for the treatment of asymptomatic or minimally symptomatic pa­tients with metastatic hormone­refractory prostate cancer patients. Two Phase II trials failed to demonstrate an im­provement in PFS but showed a non­statistically significant improvement in the OS (23.2 versus 18.9 months, HR 1.50, 95% CI 1.10­2.05)(46). OS was the primary endpoint in the phase III IMPACT trial that enrolled 512 men. At a medi­an follow­up of 34 months, patients assigned to the sipu­leucel­T therapeutic vaccine had a statistically significant 4.1 month improvement in median OS (25.8 versus 21.7 months). Differences in OS could not be accounted for by variations in subsequent treatments. As in the phase II tri­

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als, PFS was not significantly prolonged (14.6 versus 14.4 weeks)(47). Per one dose that contains more than 50 milli­on autologous CD54 cell activated with PAP­GM­CSF the cost is $31.000. Doses are administered at ~ 2 weeks inter­val for a total of 3 doses.

The total cost of a sipoleucel T treatment is $93.000.It is clear that, for certain cancer types, the treatment

with biological targeted agents represents a progress. For example, since its approval in US in 1998, trastuzumab has revolutionized the management of Her 2­positive breast cancer, specifically in the subset of patients whose tu­mors express the human epidermal growth factor receptor

(HER)­2 protein. According to observational data, the use of trastuzumab has reversed the worse prognosis associa­ted with HER2­positive status in women with breast cancer. In a multivariate analysis published in 2010, trastuzumab recipients with Her2­positive disease had a 44% reduction in the risk of death, versus women with Her2­negative di­sease (HR 0.56; 95% CI, 0.45 to 0.69; P < 0.0001)(82).

Currently, there are several biological targeted agents available for the treatment of metastatic renal cell cancer (mRCC). Despite the recent advances of the treatment for this disease, very recently, two world experts in mRCC made a sobering statement about the therapeutic progress

Commercial nameType of cancer in which the agent is FDA approved

Improvement of OS Improvement of PFSAverage cost for 4 months of treatment in US

HerceptinAdjuvant Breast Yes YesMetastatic Breast Yes (5 mt) Yes Gastric Yes (3 mt) Yes $23,400

GleevecAdjuvant GIST No Yes Metastatic GIST Yes(~30mt) Yes $24,000

Erbitux

CR + Irinotecan refractory No Yes (2.6 mt)CR + FOLFIRI frontline Yes (3.5 mt) Yes (1.5 mt)Adjuvant H&N+RT Yes (20 mt) Yes (10 mt)Metastatic H&N +chemo Yes (3 mt) Yes (2.3 mt)Metastatic H&N alone N/A N/A $40,000

Vectibix Colorectal No Yes (1 mt) $42,400 Torisel Renal Yes (3.6 mt) Yes (2.3 mt) $21,500

Afinitor

Renal No Yes (3 mt)PNET No Yes (6.4 mt)SEGA N/A N/ABreast No Yes (4.2 mt) $32,000

Caprelsa Thyroid No Yes (11 mt) $23,400 Zelboraf Melanoma Yes Yes (4mt) $43,000 Xalkori Lung+ALK rearrangement N/A N/A $41,200 Perjeta Breast No Yes (7mt) $22,800 Tykerb Breast No Yes (4 mt) $13,200 Iressa Lung (EGFR mut) NCCN end No Yes (3 mt) $7,200

Tarceva

Pancreatic Yes (2 wk) Yes (2 wk)Lung (maintenance) Yes (1 mt) Yes (1 wk)Lung (2d and 3d line) Yes (2 wk) Yes (2 mt)Lung (EGFR mut) NCCN end No Yes (4.2 mt) $18,700-26,100

Inlyta Renal No Yes ( 2mt) $26,400

Avastin

CR met front+non-oxali chem. Yes (4.7mt) Yes (4.4mt)CR met front +oxali chem. No Yes (1.4 mt)CR met sec +oxali chem. Yes (2.1 mt) Yes (2.6 mt)Lung/nonsquamous +CarTax Yes (2 mt) Yes (1.7 mt)Lung/nonsquamous +CisGem No Yes (2wk)Brain N/A N/ARenal No Yes (4.7 mt) $20,200-40,400

NexavarLiver Yes (3 mt) Yes (2.7 mt)Renal No Yes (2.7 mt) $33,500

SutentPNET Yes Yes (6 mt)GIST Yes Yes (4.5mt)Renal Yes (4.6 mt) Yes (6 mt) $32,400-41,800

VotrientSoft Tissue Sarcoma No Yes (3 mt)Renal No Yes (5 mt) $25,000

Yervoy Melanoma Yes (3.5 mt) No $100,000 Provenge Prostate Yes (4.1 mt) No $93,000 GIST=gastrointestinal stromal tumor; DFSP=dermatofibrosarcoma protuberans; PNET= pancreatic neuroendocrine tumors; SEGA=subepenymal giant cell astrocytoma; N/A=data not available, no Phase III studies reported; PFS=progression free survival; OS=overall survival; mt=months, wk=weeks; CR=colorectal cancer; met=metastatic; oxali=oxaliplatin; mut=mutated; CarTax=Carboplatin/Taxol; CisGm=Cisplatin/Gemcitabine NCCN end=NCCN endorsed (not FDA approved).

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in this disease: “despite advances in treatment, most pati­ents with advanced disease still face a dramatically shorted life expectancy. An objective look at the therapeutic lan­dscape shows development of only two classes of agents, after an expenditure of billions of dollars and involvement of thousands of patients in clinical trials, with little or no effort to understand the determinants of response and re­sistance”(8).

For many cancer types, the benefit of biological tar­geted agents appears to be borderline and the treatment is prohibitively expensive. As shown above, there is no OS proven benefit of cetuximab in second or third line in re­fractory metastatic colorectal cancer and the price of ad­ministering cetuximab weekly for one at 250 mg/m2 is $120,000. In a clinical setting like this, when the proven be­nefit is so small and the treatment is so expensive, should we mention this therapeutic option to patients that can not afford paying for the drug? Similar questions pose serious ethical dilemmas.

What can be done? The regulating agencies play a key role in establishing the standards of care for can­cer patients. The medical community should also sha­re some responsibility and be proactive in discussing the clinical aspects of these issues. The withdrawal by the FDA of the indication of bevacizumab in metastatic breast cancer, for example, raises fundamental clinical questions about the validity of the PFS as an endpoint, especially when the OS is not affected and the impro­vement in PFS is doubled by questionable ameliorati­on of quality of life and potentially life­threatening side effects. Some authors advocate the use of OS as the gold standard marker for efficacy and consider PFS a measu­re of a drug effect while administered and not a surro­gate for overall survival(84,85). Other authors argue that the measurement of OS typically requires a long follow­up period, a large population to ensure significant diffe­rences between the study groups and is vulnerable to the confounding effects of subsequent therapy and crosso­ver(86). It is possible that both positions may be right in different clinical settings. For certain tumors (e.g. metas­tatic ovarian cancer or metastatic renal cell carcinoma), PFS may represent a valid surrogate point for OS while, in other (e.g. metastatic melanoma or metastatic prosta­te cancer), OS should be used. It is also important to re­cognize that, due to their specific mechanisms of acti­ons, some of the new agents (Ipilimumab or Sipoleucel T, for example) may improve the OS without affecting the PFS(47, 49).

Few months ago, the American Society of Clinical Onco­logy has published its top five “DO NOT” list for oncology(5):

1. Don’t use cancer­directed therapy for solid tumor patients with the following characteristics: low performan­ce status (3 or 4), no benefit from prior evidence­based in­terventions, not eligible for a clinical trial, and no strong evidence supporting the clinical value of further anti­can­cer treatment.

2. Don’t perform PET, CT and radionuclide bone scans in the staging of early prostate cancer at low risk for me­tastasis.

3. Don’t perform PET, CT and radionuclide bone scans in the staging of early breast cancer at low risk for metastasis.

4. Don’t perform surveillance testing (biomarkers) or imaging (PET, CT and radionuclide bone scans) for asymp­tomatic individuals who have been treated for breast can­cer with curative intent.

5. Don’t use white cell stimulating factors for primary prevention of febrile neutropenia for patients with less than 20% risk for this complication.

Specific guidelines to reduce unnecessary costs of using biological target agents have also been suggested. Here are some of them:

FDA­approved should be strictly adhered to and extra­polations should be avoided. For example, a drug appro­ved for first line treatment should not be used in second or third line treatment if it is not approved for that indication. There are, of course, exceptions to this rules, but this are very few. For example, although not FDA approved for this indication, erlotinib and gefitinib are endorsed by NCCN for use in patients with lung cancer that bear EGFR muta­tions. In US, the endorsement of a drug by a nationally re­cognized group like NCCN is considered by the insuran­ce companies and the practitioners a surrogate for FDA approval.

Drugs shown to be active in one subset of patients sho­uld be prescribed for that subset only.

Cheaper alternate chemotherapy regimens should be offered, if available.

Side effects and quality of life should be taken into consideration, especially when the biological targeted treatment offers only marginal benefit(81).

Ideally, in order to optimize cost­effectiveness, biologi­cal targeted agents should rise to the promise of their name and be used only in patients with tumors expressing the re­levant molecular target. Standardized and reliable means of measuring the target should be made available before blindly using new drugs. A retrospective analysis published in June 2011 in the Journal of Clinical Oncology supported the idea that molecular targeted agents produced the hi­ghest relative benefit when the target population was selec­ted by a biomarker(83). However, in practice, the priorities and rationales of drug marketing are different from those of scientific research. The development of biomarkers is a la­borious and costly process. “Marketing departments in the pharmaceutical industry tend to favor ‘organ’­based drug registrations, while scientific data increasingly suggest that only those that express the relevant biomarker target will benefit from the treatment”(80).

The treatment of cancer evolves very fast and almost every month new drugs or new indications are appro­ved. This overview of twenty currently approved biolo­gical targeted agents in solid tumors is just a snapshot of the situation in August 2012 and most likely it will beco­me quickly outdated. Recently, Hem­Onc today published a list of more than 430 oncology drugs currently in the pipe­line(79). How many of these agents are going to be proven to be beneficial and at what price?

Doru Paul, MD has no conflicts of interest.

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BIBLIOGRAFIESawyers C. Targeted cancer therapy. Nature, 2004, 432: 294-298.Thatcher N. Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 2005; 366:1527-1537.http://www.accessdata.fda.gov/scripts/cder/drugsatfda/http://www.drugstore.comLowell E. Schnipper, Thomas J. Smith, Derek Raghavan, Douglas W. Blayney, Patricia A. Ganz, Therese Marie Mulvey, and Dana S. Wollins. American Society of Clinical Oncology Identifies Five Key Opportunities to Improve Care and Reduce Costs: The Top Five List for Oncology. JCO May 10, 2012:1715-1724.Figlin RA, Hutson TE, Tomvzak P, et al. Overall survival with Sunitinib versus interferon (IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC). JCO August 18, 2008; 26 (Suppl); Abstract 5024.Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus Interferon alfa in metastatic renal cell carcinoma. NEJM 2007; 356: 115-124.Jonasch E and Motzer RJ. Ten years of progress in Renal Cell Carcinoma. JNCCN, June 2012 Vol. 10, Number 6: 690-693.Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma; a double blind, randomised, placebo controlled phase III trial. Lancet 2008; 372; 449-456.Rini BI, Esxcudier B, Tomczak P, et al. Comparative effectiveness of Axitinib versus Sorafenib in advanced renal cell carcinoma (AXIS); a randomized phase 3 trial. Lancet 2012; 378: 1931-1939.Kantarjian H, et al. Very long-term follow-up results of imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy. Cancer 15 June 2012, Vol. 118; Issue 12: 3116–3122.Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: Are we making too much of too little or are we achieving too little by giving too much? Clin Cancer Res, 2010 16:5972-5980.Weisenberg E, et al. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nature Reviews Cancer 7, 345-356 (May 2007).Sjoblom T, et al. The Consensus Coding Sequences of Human Breast and Colorectal Cancers Science, Vol. 314 no. 5797 pp. 268-274, September 7, 2006.The Cancer Genome Atlas Research Network Nature Vol 455, September 4 (2008).DeMatteo RP et al. Placebo-Controlled Randomized Trial of Adjuvant Imatinib Mesylate Following the Resection of Localized, Primary Gastrointestinal Stromal Tumor (GIST). Lancet. 2009 March 28; 373(9669): 1097–1104.Demetri GD, et al. Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors. NEJM, August 15, 2002, Vol. 347, No. 7.472-480.Blanke CD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32.Slamon DJ, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. NEJM. 2001; 344(11):783-792.Edward HR, et al. Trastuzumab plus adjuvant Chemotherapy for Operable Her 2-Positive Breast Cancer. NEJM. 2005; 353(16):1673-1684.Moja L, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4: CD006243.Bang YJ, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376(9742):687-697.O’Shaughnessy J, et al. A meta-analysis of overall survival data from three randomized trials of bevacizumab (BV) and first-line chemotherapy as treatment for patients with metastatic breast cancer (MBC). J Clin Oncol. 2010; 28:7s (abstract# 1005).Fukukoa M, et al. Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS). Journal of Clin Oncol. Jul 20, 2011:2866-2874.

Cappuzzo F, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicenter, randomised, placebo-controlled phase 3 study. Lancet Oncology June 2010, Vol. 11, 521-529.Shepherd LA, et al. Erlotinib in previously treated non-small-cell lung cancer. NEJM. 2005; 353(2):123-132.Rosell R, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. J Clin Oncol 29: 2011 (suppl; abstr 7503).Moore MJ, et al. Erlotinib plus Gemcitabine compared with Gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966.Geyer CE, et al. Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. NEJM. 2006; 355(26):2733-2743.Cameron D et al. Lapatinib plus Capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010; 15(9):924-34.Motzer RJ et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584-3590.Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010; 28(6):1061.Sternberg CN, Hawkins RE, Szczylik C, et al. Randomized, double-blind phase III study of Pazopanib in patients with advanced/metastatic renal cell carcinoma: Final overall survival results (abstract # LBA22). Ann Oncol 2010; 21: (Supplement 8): viii1–viii12.Escudier B, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009; 27(20):3312-3318.Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. NEJM. 2008;359 (4):378-390.Hortobagyi GN, Piccart M, Rugo H, et al. S3-7: Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial. Cancer Research: December 15, 2011; Vol. 71, Issue 24, Supplement 3.Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. NEJM. 2007; 356(22):2271-2281.Motzer RJ, Escudier B, Oudard S et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010; 116(18):4256-4265.Yao JC et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. NEJM 2011; 364:514-523.Krueger DA, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. NEJM. 2010 Nov 4; 363(19):1801-11.Wells SA, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012 Jan 10; 30 (2):134-41.Chapman PB, et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. NEJM 2011; 364:2507-2516. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s003lbl.pdf.Shaw AT et al, Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011; 12(11):1004-1012.Van Cutsem E, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007; 25(13):1658-1664.Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009; 115(16):3670-3679.Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. NEJM. 2010; 363(5):411-422.Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. NEJM. 2010; 363(8):711-723.Robert C, et al. Ipilimumab plus dacarbazine for previously

untreated metastatic melanoma. NEJM. 2011; 364(26):2517-2526.Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM. CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. NEJM. 2012 Jan; 366(2):109-119.Raymond E, et al. Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. NEJM. 2011; 364:501-513.Demetri GD, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338.Hurwitz H, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. NEJM. 2004; 350(23):2335-2342.Goldberg RM, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004; 22(1):23-30.Saltz LB, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008; 26(12):2013-2019.Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd. Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007; 25(12):1539-1544.Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17: 2572–2578.Friedman HS, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009; 27(28):4733-4740.Escudier B, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007; 370(9605):2103-2111.Escudier B, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010; 28(13):2144-2150.Rini BI, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008; 26(33):5422-5428.Rini BI, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010; 28(13):2137-2143.Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355(24):2542-2550.Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009; 27(8):1227-1234.Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C, BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010; 21(9):1804-1809.Van Cutsem E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. NEJM 2009; 360(14):1408-1417.Van Cutsem E, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011; 29(15):1-10.Bokemeyer C, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009; 27(5):663-671.Bokemeyer C, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4000).

Septembrie 2012 | 41

Supliment special Conferin]a Societ`]ii Na]ionale de Oncologie Medical` din România

| Septembrie 201242

l Dr. Louise S. Wilkinson Director of South West London Breast Screening Ser­vice and Consultant Breast Radiologist, St. George’s Healthcare NHS Trust, London

Most women with breast cancer are diagnosed be­cause of symptoms or following routine mammographic screening. The National Health Service Breast Screening Programme was set up in the early 1990s with a remit to screen women between the ages of 50 and 65 on a 3 yearly cycle. Emphasis was placed on careful monitoring of the service and rigorous data collection. The availability of data allows ongoing service improvement and open dis­cussion about the benefit and harm of screening. Over 2.75 million women between the ages of 45 and 74 were invited for screening in 2009/10, 2.1 million women were screened and 16476 cancers were detected. Around one

third of all breast cancers in the UK are detected through screening(1).

Symptomatic breast services in the UK have also chan­ged over the same time, in response to changing national strategies with a greater reliance on imaging and by mirro­ring improvements in the screening services. Data collecti­on is now seen as the key to providing uniformly high qua­lity services. In 2009, 48417 women and 371 men in the UK were diagnosed with breast cancer(2).

This lecture will discuss the organisation of both scre­ening and symptomatic services in a large London hospi­tal, addressing the challenges of service improvement in a time of financial constraint, and dealing with the need for earlier diagnosis while avoiding overtreatment.

l R. Pietrosanu, R. Mehta, H. Gay, L. WilkinsonSt. George’s Healthcare NHS Trust

DCIS being an essential screening diagnostic, as a re­sult of the implementation of different National Health Breast Screening Programmes, the apparent incidence has significantly increased, in the last decade.

The purpose of this presentation is to show what and how common DCIS is, but also how to maximize its detec­tion, make an accurate local staging, establish its relation­ship with invasive cancer and to point out the most impor­tant radiological features, as well as pathological­radiolo­gical correlation of the different grades of DCIS.

Last, but not least, communication of the diagnos­tic to patients and the possibilities of treatment should be considered as a very important aspect.

The future of DCIS would probably consist in better prediction of risk, more widespread screening, increasing the diagnosis of high nuclear grade DCIS and starting tri­als with minimal treatment for low nuclear grade DCIS, as well as improving the technology

Breast Diagnostic Services in the UK ­ the Challenges of Maintaining Quality, Improving Efficiency, Promoting

Early Diagnosis and Avoiding Overtreatment

DCIS: which path to follow?

REFERENCES:1. http://www.cancerscreening.nhs.uk/breastscreen/publications/2011review.html2. http://info.cancerresearchuk.org/cancerstats/types/breast/incidence/

REFERENCES:Radiologic-Pathologic Correlation of DCIS- Yamada et al, Radiographics 2010Surgical management of breast cancerPerceptions of DCIS among UK health professionals-Kennedy et al, The breast 2010www.cancerscreening.nhs.uk/beastscreen/publications/2011review.htmlDCIS Radiology and communicating the diagnosis- R. Given-Wilson 2012

www.revista-hipocrate.ro REZUMAT

Maughan T, et al. Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): Mature results of the MRC COIN trial. J Clin Oncol 28:15s, 2010 (suppl; abstr 3502).Tveit K, et al. Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: The NORDIC VII study (NCT00145314), by the Nordic Colorectal Cancer Biomodulation Group. J Clin Oncol 29: 2011 (suppl 4; abstr 365).Vermorken JB, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. NEJM. 2008; 359(11):1116.Vermorken JB, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007; 25(16):2171-2177.Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. NEJM. 2006; 354 (6):567-578.

Bonner JA, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010; 11(1):21-28.Cunningham D et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. NEJM 2004:351:337-345.Voncken JW, Morris C, Pattengale P, Gunther D, Kikly C, Groffen J, and Nora Heisterkamp N. Clonal Development and Karyotype Evolution During Leukemogenesis of BCR/ABL Transgenic Mice. Blood, 1992, Vol. 79, No4:1029-1036.http://quickfacts.census.gov/qfd/states/00000.html.HemOnc Today Volume 13, Number 10, May 25 2012, Page 67-79.Soria JC., J. Y. Blay JY, Spano JP, Pivot X, Coscas Y and Khayat D. Added value of molecular targeted agents in oncology. Annals of Oncology Vol. 22, Issue 8:1703-1716.Fojo T and Grady C. How much is life worth: Cetuximab, Non-Small Cell Lung cancer and the $440 billion question. 2009, Vol. 101, Issue 15, 1044-1048.

Dawood S, et al. Prognosis of women with metastatic breast Cancer by HER2 status and Trastuzumab treatment: An institutional-based review. J Clin Oncol 2010, Vol.28, Number 1, 92-98.Amir E, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol 2011, Vol. 29, Number 18:2543-2549.Driscoll JJ and Rixe O. Overall Survival: Still the Gold Standard Why Overall Survival Remains the Definitive End Point in Cancer Clinical Trials. The Cancer Journal, 2009, Vol .15, Number 5: 401-406. Wilkerson J and Fojo T. Progression-Free Survival is simply a measure of a drug’s effect while administered and is not a surrogate for overall survival. The Cancer Journal, 2009, Vol. 15, Number 5:379-385.Lebwohl D, Kay A, Berg W, Baladi JF, and Zheng J. Progression-Free Survival gaining on overall survival as a gold standard and accelerating drug development. The Cancer Journal, 2009, Vol.15, Number 5:386-394.van der Graaf, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet, 2012, Vol. 379, Issue 9829; 1879 – 1886.

l Dan Jinga MD PhD, Adina Croitoru MD PhD The Oncotype DX® Assay in the Contemporary Ma­nagement of Invasive Early­stage Breast Cancer

The Recurrence Score® Result uses key genes linked to critical molecular pathways. The final gene set used for the Oncotype DX® assay includes the 16 cancer genes identified in the clinical trials: 5 genes are in the proliferation group, 2 in the HER2 group, 4 in the estrogen­receptor group, 2 in the invasion group, and 3 are unaligned. Some of the genes are well known in the breast cancer literature; others are relatively new. The 5 reference genes are used for normalizing the expressi­on of the cancer­related genes.

The Recurrence Score® Result assesses individu­al tumor biology for ER+ breast cancer. The Oncotype DX® Recurrence Score® is correlated with distant re­currence rate at 10 years, hormone therapy benefit, and chemotherapy benefit. There is a continuous biology of breast cancer that is revealed by the Recurrence Sco­re. There are clear underlying phenotypes that corres­pond to low recurrence score disease and high recur­rence score disease:

Distant recurrence rate at 10 years with 5 years of tamoxifen treatment: the higher the score, the higher the risk of distant recurrence;

Hormone therapy benefit: the lower the score, the greater the impact of tamoxifen given for 5 years on proportion of patients recurrence­free at 10 years;

Chemotherapy benefit: the higher the score, the greater the proportion of patients distant recurrence­free at 10 years.

The Oncotype DX® Assay identifies patients for whom tamoxifen alone may be appropriate therapy and, also can predict benefit from chemotherapy ad­ded to tamoxifen. The Kaplan­Meier estimates of the risk of death from breast cancer at 10 years indicate that systemic treatment with tamoxifen is more benefi­cial in low­ and intermediate­risk patients and the addi­tion of chemotherapy to tamoxifen is more beneficial in high­risk patients.

Oncotype DX® Colon Cancer AssayThe Recurrence Score contains gene groups con­

sistently identified in the 1851 patients from the deve­lopment studies, and the validation of the Recurrence Score in QUASAR provides strong support for their bio­logical relevance. The 12­gene Recurrence Score inclu­des 7 cancer genes and 5 reference genes. The 7 cancer

genes include the 2 key biologic pathways (cell cycle genes and stromal genes) identified as being associa­ted with recurrence in the development studies, as well as an individual gene GADD45B (associated with cellu­lar response to stress).

QUASAR Results:The validation study protocol specified secondary

analyses to characterize risk resolution across the ran­ge of Recurrence Score.

Protocol­specified cutpoints at 30 and 41 were used to separate the population into 3 groups of pati­ents of sufficient size to enable statistical analyses.

Kaplan­Meier analysis of the 3 groups defined by the pre­specified cutpoints demonstrates a separation of 3 year recurrence risk between the groups, with ave­rage risk in the low risk group of 12% and average risk in the high risk group of 22%.

Protocol­specified comparison of the high vs low recurrence risk groups in a Cox model shows signifi­cant HR 1.47 (with p<0.05)

It is important to note that the clinical utility of the assay resides in the continuous Recurrence Score, whi­ch provides individualized recurrence risk information over a range from 9­11% at the low end to 25­27% at the high end. Our discussions with oncologists would suggest that thresholds for clinical actionability (i.e. the decision to recommend treatment or not) will depend on the individual patient’s clinical situation.

Protocol specified secondary analyses included univariate and multiva­riate analyses of cli­nical and patho­logic covaria­tes with RFI in Cox pro­por t ional h a z a r d s models. In univariate analyses, the clini­cal and pathologi ­cal covariates found to have the most signifi­cant relationship to recurrence­free interval

Septembrie 2012 | 43

Importance of OncotypeDX in breast and colorectal cancer

treatment planning

Supliment special Conferin]a Societ`]ii Na]ionale de Oncologie Medical` din România

| Septembrie 201244

l Winald Gerritsen, MD, PHD

Prof dr. Winald Gerritsen is medical oncologist with a background in translational research with a special inte­rest in tumor immunology and prostate cancer. Currently, he is leading the tumor immunology program for melano­ma and prostate cancer at the Radboud University medical center in Nijmegen. He was director of Vumc Cancer Cen­ter Amsterdam.

Prof. Gerritsen has chaired the Dutch Society of Gene Therapy and became honorary member of the society. He has served as a chairman of the commission of clinical re­

search of the Dutch Cancer Society (KWF). He chaired the commission of biotherapy of the National Translatio­nal Cancer Research Network, UK and is a member of the Cancer Research UK Immunotherapy Quinquennial Revi­ew Committee. He is also member of the Royal Holland So­ciety of Sciences and Humanities and has a Adjunct pro­fessorship at John Hopkins University. Recently, he was vi­siting professor at Oxford University Cancer Center.

Following his medical training at the University of Nijmegen, Prof. Gerritsen achieved his PhD in 1989 on bone marrow transplantation at the Medical School of the Erasmus University of Rotterdam. From 1989 till 1991

Current Focus of Cancer Immunotherapy ­ Improving Clinical Benefit and Prolonging Survival

www.revista-hipocrate.ro REZUMAT

Current Treatment of Bone Sarcomal Juergen Bruns Unit for orthopaedic surgery, AGAPLESION­Diakonieklinikum Hamburg

Bone sarcomas are rare primary malignant tumors and account for nearly 1% of all malignant tumors. While osteo­ and Ewing’s sarcomas are the most frequent sarcomas of all, with a peak incidence in the first two decades, the most often bone sarcomas in adults are the different types of chondrosarcomas.

Osteosarcomas occur most frequently in the knee region and in the hip region, less frequently in the pelvis and other long bone of the skeleton. Ewing’s sarcoma are located more often in the proximal femur, the pelvis and the ribs. Chondrosarcoma have a predominance in the proximal and distal femur, the pelvis and the long bone of the upper extremities. So­called secondary sarcoma of bone occur after radiation for others reasons, following long­lasting Paget’s disease, chondromas or giant­cell tumors of the bone.

In most of these sarcomas, the treatment protocol includes pre­ and postoperative chemotherapy

(osteosarcoma and Ewing’s sarcoma and some rare entities) and/or additional radiotherapy (Ewing’s sarcoma). In order to ensure the optimal conditions for a recurrence­free survival in all patients, a wide resection is the treatment of choice.

In most of the cases, a wide resection is possible without amputation. There are several reconstructional procedures, such as megaprostheses or biological reconstructions using non­ or vascularized autologous bone such as fibulae. In rare cases, such as in the scapula, clavicle or fibula, simple resection of bone without reconstruction is possible. In recent years, the rate of rotational plasties is decreasing.

In order to achieve the main goal “wide resection”, sometimes additional reconstructional techniques, in cooperation with a plastic surgeon are necessary.

(RFI) were mismatch repair status (MMR) and T­stage (data not shown in this presentation). In a protocol­spe­cified multivariate analysis, Recurrence Score remained significantly associated with RFI after simultaneously controlling for the prognostic effects of MMR, T stage, tumor grade, number of nodes examined, and LVI, with Recurrence Score retaining the HR and significance le­vel observed in univariate analyses. In these multivaria­te analyses, three factors ­ Recurrence Score, MMR status and T stage ­ were found to be the most significant inde­pendent predictors of recurrence risk following surgery.

ConclusionAlthough the Recurrence Score will likely yield its hi­

ghest value when used as a continuous measure, to obtain individualized estimates of recurrence risk, an analysis of the QUASAR data permits the identification of “guideposts” whi­ch may be useful for clinical decision­making. These guide­posts have been identified on the basis of internal consisten­cy within the data, and are not, in any manner, meant to be prescriptive – ultimately, decision making with an individual patient should be based on clinical judgment after review of the relevant clinical data, including Recurrence Score.

Septembrie 2012 | 45

l Delia Mateescu

Anul acesta, în ianuarie, s­au împlinit 10 ani de când a fost aprobat de c`tre FDA pegfilgrastim (Neulasta® Amgen), pentru reducerea riscului neutropeniei febrile (FN) la pacien]i oncologici trata]i cu regimuri de chimio­terapie agresive.

Introducerea acestui inovator factor de cre[tere a coloniilor de granulocite, dup` ce ini]ial compania Amgen lansase Filgrastim (Neupogen®), primul com­pus în clasa cu administrare zilnic`, a marcat un eveni­ment istoric de mare anvergur`, oferind oportunitatea de îmbun`t`]ire a complian]ei pacientului la tratament. De­riv` din filgrastim, îns` are ata[at` o grupare de polieti­lenglicol [PEG] care îi confer` o greutate molecular` mai mare, permi]ând moleculei s` persiste mai mult timp în organism. Cu alte cuvinte, este un compus cu ac]iune lung`, care î[i autoregleaz` metabolismul [i care se ad­ministreaz` o singur` dat` pe cura de chimioterapie. Se administreaz` la cel pu]in 24 de ore dup` chimioterapie,

dar nu mai devreme de 14 zile înaintea urm`torului ciclu de chimioterapie.

În trialurile clinice, pegfilgrastim a dovedit aceea[i efi­cacitate crescut` ca [i predecesorul lui [i aceea[i tolerabi­litate excelent`. Într­o metanaliz` recent` (Cooper KL et al. BMC Oncol 2011), reunind 25 de studii clinice mari adre­sate factorilor de cre[tere a coloniilor de granulocite, la pacien]i cu tumori solide sau limfoame, s­a ar`tat c` peg­filgrastim (Neulasta®) reduce inciden]a FN într­o m`sur` mai mare decât filgrastim (Neupogen®), [i anume riscul relativ este mai mic cu 33% (p =0,04). Rezultate similare au fost publicate [i anterior (2007), în dou` recenzii sistema­tice: Kuderer NM, J Clin Oncology si Pinto L, Current Med Research & Opinion.

În ciuda pa[ilor îndr`zne]i care s­au f`cut în privin]a abord`rilor terapeutice, mii de pacien]i afla]i sub chimio­terapie sunt înc` spitaliza]i anual din cauza episoadelor de neutropenie febril`. De aici deriv` prioritatea companiei Amgen de a trata pacien]ii eligibili, servind interesele pro­fesionale ale corpului medical.

Pegfilgrastim (Neulasta®): 10 ani aniversari de existen]` în arsenalul terapeutic

Supliment special Conferin]a Societ`]ii Na]ionale de Oncologie Medical` din România

he worked as a special fellow at Memorial Sloan Kettering Cancer Center in New York, after which he held several po­sitions at respectively the University Hospital Utrecht, The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital and the VU Medical Center.

Although the concept of immune surveillance in can­cer was first proposed more than 40 years ago, the recent discovery that agents that modulate immune regulatory checkpoints or target driver oncogenes can significantly improve the survival of patients with cancer, especially those with advanced malignancies, has led to a new era of innovation in oncology.

The challenge of immunotherapy is to boost the patient’s antitumor immune response by overcoming tu­mor­induced ‘immune editing’ and shifting the balance from protumor to antitumor immunity. The ultimate goal of immunotherapy in oncology is to utilize the immune system to eradicate and, ideally, to cure cancer.

In terms of types of cancer, the focus is on solid tu­mors and specifically melanoma. This reflects the pivotal role melanoma has played in the emergence and develop­ment of immunotherapies for cancer. This is a consequen­ce, in part, of the observed spontaneous immune respon­ses to melanoma in some patients and the ease with whi­ch melanoma cells can be cultured in vitro. It is also a func­tion of clinical necessity, because of the recalcitrant natu­re of this cancer to nonimmunological therapies and older immunotherapies.

Advances in basic molecular immunology have ena­bled identification of new immune system targets for trea­ting cancer, some of which have resulted in novel agents

that are in late­stage clinical development. These agents, either alone or in combination, have the potential to offer real, long­term benefit to patients with advanced disease. Advances in targeted therapies (inhibitors of BRAF, MEK, c­KIT, PI3K) and immunotherapy (anti­PD1) are expected and will influence treatment landscape. As is mentioned in the recently issued ESMO guidelines, the role of life expec­tancy for patient selection at different points can be a dri­ver of treatment decisions.

At this symposium, we will discuss new treatment approaches, review ongoing research into immunologi­cal markers for novel immunotherapies and discuss the practicalities and challen­ges associated with integrating novel treatments into clinical prac­tice.

| Septembrie 201246

l Prof. Dr. Doris Henne-Bruns Head of the Department of Surgery, University of Ulm, Germany

Primary hepatocellular carcinoma (HCC) is one of the most frequently encountered solid organ tumors worldwide. The tumor is mainly observed in patients with chronic liver disease or cirrhosis, but can also develop in normal parenchyma.

For the treatment of HCC, several therapeutic options exist:

primary resection;liver transplantation;local destruction (e.g. radiofrequency ablation, etha­

nol injection);transarterial chemo­embolisation.The individual treatment will depend on the following

parameters:benign, malignant (safety margin);size of the tumor;number of tumors;localization within the liver;preexisting liver disease (steatosis, fibrosis, cirrhosis);estimated function of the remaining liver parenchyma

(volume of the remaining liver, length of operation, blood loss, transfusion, postoperative infections, impaired coa­gulation).

Colorectal liver metastases are the most common in­

dication for liver resections in Europe and North America. Colorectal liver metastases occur synchronously or meta­chronously with the primary tumor and are resectable in about 20% of the cases. For the resection of liver metasta­ses, the same parameters as described above have to be taken into account, prior to an operation.

The actual discussion on the treatment of colorectal li­ver metastases tries to answer several ques­tions like:

which pati­ents benefit from neo­adjuvant che­motherapy, prior to liver resection?

which pati­ents benefit from adjuvant chemothe­rapy after liver resec­tion?

Surgical Strategies in Primary and Secondary Liver Tumors

REFERENCES:HCC Leitlinie Am. Ass. Study of Liver Disease , Hepatology, 42, 2005, Barcelona Clinic Liver Cancer Staging ClassificationR. Cabrera, D.R. Nelson: The Management of Hepatocellular Carcinoma. Review, Aliment Pharmakol Ther 31, 461-476, 2010N. C. Tsim et al: Surgical treatment for liver cancer. World J Gastroenterol. 16(8), 927-933, 2010,

www.revista-hipocrate.ro REZUMAT

l Doru Ghizdavescu MD

Anemia reprezint` o complica]ie frecvent` a tumori­lor maligne sau a chimioterapiei [i contribuie la cre[terea mortalit`]ii [i reducerea calit`]ii vie]ii. Eritropoietina uman` recombinant` (rHuEPO) reprezint` un tratament eficace pentru anemie, la pacien]ii care primesc chimiote­rapie, determinând cre[terea nivelului de hemoglobin` [i reducând sau eliminând necesarul de transfuzii de mas` eritrocitar`(1, 2).

Darbepoetin alfa (Aranesp®) este singurul agent de stimulare a eritropoiezei de genera]ia a 2­a înregistrat pen­tru tratamentul anemiei induse de chimioterapie. Arane­sp® are o structur` unic` de aminoacizi, un con]inut mai mare de acid sialic în molecul`, timp de înjum`t`]ire cres­cut (74 de ore la pacien]ii cu cancer) [i o valoare biologic` superioar` celei a rHuEPO. Datorit` propriet`]ilor farmaco­cinetice diferite fa]` de rHuEPO, darbepoetina alfa se poa­te administra mai rar, la 3 s`pt`mâni, fa]` de administra­rea s`pt`mânal` pentru epoetinele de prima genera]ie(1).

Eficacitatea administr`rii a 500 µg Aranesp® la 3

s`pt`mâni (Q3W), fa]` de administrarea s`pt`mânal` (QW) a 2,25 µg/kg corp, a fost evaluat` într­un studiu con­trolat randomizat(2). Administrarea Q3W a fost cel pu]in la fel de eficient` cu administrarea QW atât prin reduce­rea necesarului de transfuzii de mas` eritrocitar`, cât [i prin corectarea nivelului de Hb(2).

O metaanaliz` a tuturor studiilor controlate (n =6) care au evaluat eficacitatea [i siguran]a DA versus place­bo a ar`tat c` Aranesp® reduce necesarul de transfuzii cu 57% versus placebo. Tratamentul cu Aranesp® nu a afectat supravie]uirea f`r` progresie (HR =0.93 (95% CI, 0,84­1,04)) sau supravie]uirea general` (HR =0,97 (95% CI, 0,85­1,10)), dar inciden]a evenimentelor tromboembolice a fost mai mare la pacien]ii trata]i cu Aranesp®(3).

Darbepoetin alfa reprezint` un tratament modern [i eficace al anemiei simptomatice indus` de chimioterapie care se poate administra la 3 s`pt`mâni.

Excelen]a în tratamentul anemiei indus` de chimioterapie

BIBLIOGRAFIEKiss Z et al. 2009; Eur J Clin PharmacolCanon JL et al. 2006; JNCILudwig H et al. 2009; JCO

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Revista 4P

Învingem cancerul!

O dată-n viaţă

Sănătatea copilului:Sănătatea copilului:

Cum luptăm cu efectele adverse

ale chimioterapiei?

O lecție de autoapărare: vaccinarea

Tulburările de creștere și dezvoltare

Sănătatea adultului:Sănătatea adultului:

Jurnalul unui supraviețuitor de infarct

Să rupem tăcerea din jurul prostatei

Osteoporoza: boala care te fură pe neștiute

Legături periculoase între inimă și creier:

fibrilația atrială și accidentul vascular cerebral

Util: Cele mai active asociaţii ale pacienţilor din România

Povesteamea

Sănătatea vârstei a treia:

Sănătatea vârstei a treia:Iuliana Tudor

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