Oncology Tribune July 2012 HK

7/28/2019 Oncology Tribune July 2012 HK

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www.oncologytribune.com

Pan-ErbB blocker tops standard chemo

in lung cancer

CASE STUDY

Capecitabine

in advancedgastric cancer

NEWS

Asian study unveilsmechanism of HBV

integraon in HCC

CONFERENCE

Beer strategies neededfor ALL in adolescents

and young adults

INDUSTRY UPDATE

First-line temsirolimus

improves survival in

poor-prognosis

mRCC paents

June 2012July- August 2012


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Jul-Aug 20122

Pan-ErbB blocker tops standard chemo in

lung cancer

Christina Lau

Afatinib, an investigational drug that

irreversibly blocks EGFR (ErbB1),

HER2 (ErbB2), HER3 (ErbB3) and

HER4 (ErbB4), signicantly extended pro-

gression-free survival (PFS) vs pemetrexed

plus cisplatin in the largest phase III trial in

EGFR mutation-positive advanced lung ade-

nocarcinoma. [ASCO 2012; abstract LBA7500]

The oral pan-ErbB inhibitor was particu-

larly benecial for patients with deletion 19

or L858R common mutations that together

accounted for 89 percent of all EGFR muta-

tions in the trial.

Unlike reversible EGFR tyrosine kinase

inhibitors such as getinib and erlotinib,

afatanib blocks the entire ErbB family of

receptors permanently, said lead inves-

tigator Dr. James Yang of the National Tai-

wan University Hospital. While getinib

and erlotinib have demonstrated signicant

benets vs rst-line chemotherapy, LUX-

Lung3 is the rst trial in EGFR mutation-pos-

itive lung cancer to use pemetrexed/cisplatin

as a chemotherapy comparator.The global trial included 345 treatment-

nave patients from 25 countries who had

stage IIIB (wet) or IV disease (median age,

61 years; ECOG performance status, 0-1;

East Asians, 72 percent; never-smokers,

68 percent). Patients were randomized

2:1 to receive afatinib (40 mg) once daily

or pemetrexed (500 mg/m2) plus cisplatin

(75 mg/m2

) q21d until progression.The trial met its primary endpoint of PFS.

Aer a median follow-up of 8 months, patients

receiving afatinib had a signicant 4.2-month

improvement in PFS. Median PFS was 11.1

months with afatinib vs 6.9 months with

pemetrexed/cisplatin [hazard ratio (HR), 0.58;

p=0.0004], Yang reported. Twelve-month

PFS rate was 47 vs 22 percent.

Importantly, the PFS benet of afatanib

was consistent in all relevant subgroups, in-

cluding gender, age at baseline, race (Asian

or non-Asian), baseline ECOG performance

status, and smoking history (never smoked,

or smoked 1

year).

The benet of afatinib was even great-

er in patients with deletion 19 or L858RV

[n=308], he continued. In these patients,

afatinib doubled PFS to 13.6 months vs 6.9

months with pemetrexed/cisplatin [HR, 0.47;

p


3/53

Jul-Aug 20123

Cancer drug shortages a global problem

Naomi Rodrig

The European Hematology Association

(EHA), the American Society of Hema-

tology (ASH) and the European Can-

cer Patient Coalition (ECPC) issued a joint call

to action to address the looming crisis of can-

cer drug shortage. The announcement, issued

at the recent 2012 EHA Congress, comes onthe footsteps of the American Society of Clini-

cal Oncology (ASCO) 2012 Annual Meeting,

which also highlighted the problem.

According to ASCO ocials, disrupted

manufacturing and quality control are the

main culprits behind the shortages that have

le many cancer patients without necessary

treatments. Were never sure when a generic

drug is suddenly going to go out of supply,said Dr. Richard Schilsky, Chair of the ASCO

Government Relations Commiee.

Hundreds of drugs have been in short sup-

ply in the US over the past year, including

methotrexate, used frequently for leukemia;

liposomal doxorubicin, which treats ovarian

cancer; paclitaxel, used in a variety of cancers;

mustargen, used to treat lymphoma; and 5-u-orouracil (5-FU), a key component of adjuvant

therapy for colorectal and other cancers.

The situation in Europe seems to be

even more serious. In the US, legislation is

under way that may curb drug shortages,

but in Europe we do not even have a proper

understanding of the scope of the problem,

remarked EHA President, Dr. Ulrich Jager.

The US FDA is draing legislation requir-ing mandatory 6-month advance notication

cent], paronychia [11.4 vs 0 percent], and dry

skin [0.4 vs 0 percent], said Yang. These

adverse events were as expected with EG-

FR-targeting therapies, and were manage-

able and reversible. It is also important tonote that patients in the afatinib arm re-

ceived 16 cycles of therapy, vs 6 cycles in the

pemetrexed/cisplatin arm.

In LUX-Lung3, only 7.9 percent of

patients discontinued afatinib due to treat-

ment-related adverse events (vs 11.7 per-

cent with pemetrexed/cisplatin), and onlyabout 1 percent discontinued the drug due to

diarrhea.

PERSPECTIVESDr. Kwok-Chi LamDepartment of Clinical Oncology, Prince of Wales Hospital

The LUX-Lung3 trial has echoed what we have seen in other randomized phase III trials, with consistent HR or

progression-ree survival. It is dicult to compare the treatment ecacy o dierent EGFR TKIs across dierent trials.Aatinib can be one o the treatment options or patients with EGFR mutation-positive tumors. We might know which

EGFR TKI is better as results o the LUX-Lung7 trial (comparing aatinib with geftinib in EGFR mutation-positive che-

monave non-small cell lung cancer) become available in uture.


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Jul-Aug 20124

Increasing numbers of high-quality cancer genetics studies conducted in Asia are mak-

ing it into prestigious journals, arming the regions position as an upcoming hub of

advanced oncology research.

In the current issue, we report three stories of innovative research from Asia, as inves-

tigators from Hong Kong, China and Singapore are shedding new light on carcinogenesispathways. One of the studies focused on reversal of apoptosis, which may induce oncogenic

transformation in various cell types, while the others looked at specic cancers hepatocel-

lular carcinoma and an aggressive type of lymphoma that is common in China and Korea.

The expanding industry funding for basic research in Asia also reects increasing con-

dence in its quality as well as a fresh enthusiasm for long-term R&D investment in the region.

Although many of these studies are still at the preclinical stage, some may eventually lead to

new therapeutic or diagnostic products. The global pharma industry is now willing to stay

the course, which may give an even greater boost to Asian medical and life-science research.

The Editor

Big strides in cancer genetics researchin Asia

by drug companies for withdra-wals or man-

ufacturing interruption, with penalties for

non-reporting. Early alerts may enable gov-

ernment agencies to source the same or alter-native drugs from overseas manufacturers.

The situation in Europe is undoubt-

edly more complex. We are not one country;

we are 27 countries, each with its own rules

and regulations, noted Dr. Anton Hagen-

beek, The Netherlands, who emphasized that

drug supply and pricing are subject to gov-

ernment policies.

Asian countries have not been spared ei-ther. In my opinion, cancer drug shortage is

a global problem, and Hong Kong is aected

as well, commented Dr. Carol Kwok of the

Department of Oncology, Princess Margaret

Hospital. Just a few months ago, three com-

monly used cytotoxic drugs doxorubicin,

epirubicin and 5-FU were out of supply in

HA hospitals. The solution was substitution;

for example, epirubicin was used to substitute

doxorubicin and vice versa. For 5-FU, we usedother brands.

While the supply of these drugs has been

back to normal now, liposomal doxorubi-

cin, which is commonly used in second-line

treatment of recurrent ovarian cancer, has

been out of supply for almost a year. We

have to use topotecan, a more toxic drug,

for this indication, she said.

I guess the main reason for the shortagesis on the manufacturing side, such as lack of

raw materials. In other situations, the drug

company ceased to produce the drug because

it is not commonly used, such as mitotane for

adrenocortical carcinoma, a very rare can-

cer, Kwok suggested.


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NewsJul-Aug 20125

Asian study unveils mechanism of HBV

integration in HCC

Naomi Rodrig

The Asian Cancer Research Group

(ACRG) in collaboration with the

Shenzhen-based genomics company

BGI recently published the results of a ge-

nome-wide study unveiling the mechanism of

recurrent hepatitis B virus (HBV) integration

in hepatocellular carcinoma (HCC) genomes.[Nature Genetics 2012. DOI: 10.1038/ng.2295]

HBV integration is thought to be one of

the major causes underlying HCC develop-

ment, as previous studies have shown that

it may induce chromosomal instability, lead-

ing to carcinogenesis and tumor recurrence.

However, this is the rst whole-genome se-

quencing study to systematically investigate

the breakpoints of HBV DNA and the humangenes which are aected by such integration

in a large sample of 88 pairs of HCC tumor

and non-tumor liver tissue obtained from 88

patients operated at Queen Mary Hospital

[QMH], said Professor Ronnie Poon, Chief

of the Division of Hepatobiliary & Pancreatic

Surgery at the University of Hong Kong (HKU)

who was one of the study investigators. The

study was initiated by Dr. John Luk, a corre-sponding author of the paper, when he was

working at HKU. He subsequently moved to

the National University of Singapore where

he recruited talents in bioinformatics analysis

for the project.

In the study, which enrolled 81 HBV-pos-

itive and seven HBV-negative patients with

HCC, HBV integration was observed more

frequently in tumors than in normal tissues

(86.4 vs 30.7 percent).

The researchers also identied a specic

region of the viral genome that is most com-

monly cleaved during integration into the

host genome. Approximately 40 percent of

HBV breakpoints within the HBV genome

were located at a 1,800-bp region where the

viral enhancer, X gene and core gene are lo-cated, they wrote.

In addition to the previously reported

human genes TERT and MLL4, they discov-

ered three novel genes associated with recur-

rent HBV integration CCNE1, SENP5 and

ROCK1. All these genes are known to play

an important role in cancer development and

progression, and showed upregulated expres-

sion in tumor vs normal tissue.Another observation was that the number

of HBV integration events was positively cor-

related with tumor size, and serum levels of

hepatitis B surface antigen (HBsAg) and al-

pha-fetoprotein.

The number of HBV integrations was also

associated with patient survival. Patients with

3 integrations, suggest-

ing that the number of integrations may be a


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NewsJul-Aug 20126

prognostic indicator in HCC patients. This

is the rst study that correlated the HBV in-

tegration paerns with clinical outcome in

patients with HBV-related HCC, Poon toldOncology Tribune.

Notably, a higher frequency of HBV inte-

gration was observed in HCC patients who

were in their twenties or thirties, which may

explain the development of the tumors in

younger individuals without chronic hepati-

tis or cirrhosis.

According to Poon, over 6 percent of the 3,500

primary HCC cases who presented to QMH be-tween 2001 and 2010 were


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NewsJul-Aug 20127

Reversal of apoptosis may drive carcinogenesis

Christina Lau

Arecent study from the Chinese Uni-

versity of Hong Kong (CUHK) dem-

onstrated that the process of apop-

tosis can be reversed even aer passing the

critical checkpoints of no return, which may

lead to genetic changes that contribute to car-

cinogenesis or resistance to cancer treatments.

[Mol Biol Cell 2012;23:2240-2252]

Accor ding to the researchers, this unan-ticipated rescue mechanism observed in both

normal and malignant cells may have impor-

tant applications in cancer treatment.

It is generally believed that apoptosis which

is a protective mechanism that eliminates dam-

aged cells through programmed cell death is

irreversible once cells pass certain checkpoints,

including cell shrinkage, mitochondrial frag-

mentation, nucleus condensation, DNA break-down and caspase-3 activation, said Professor

Ming-Chiu Fung of the Department of Biol-

ogy. Our previous work showed that human

cancer cells could evade the apoptotic process

even aer passing the presumed point of no re-

turn, and this may be one of the causes of can-

cer recurrence. [Br J Cancer 2009;100:118-122]

In their current study, Fung and colleagues

treated primary liver and heart cells, macro-phages, embryonic NIH 3T3 broblasts, cer-

vical cancer HeLa cells and brain cells with

apoptosis inducers.

Surprisingly, the vast majority of dying cells

arrested the apoptotic process and recovered

when the inducer was washed away.

More importantly, some cells acquired per-

manent genetic changes and underwent oncogen-

ic transformation aer the reversal of apoptosis,

Fung pointed out. In normal cells, these genetic

changes may cause new tumors to form aer can-

cer therapy. In cancer cells that undergo reversalof apoptosis aer treatment, new mutations may

develop, causing the cancer to become more

aggressive or metastatic.

The researchers proposed naming the rever-

sal of apoptosis as anastasis, a Greek term for

rising to life. While recent research indicates

that cancer stem cells [CSCs] are resistant to che-

motherapy and implicated in metastasis, our

observation is that anastasis occurs not only inCSCs, but also in most cancer cells, Fung told

Oncology Tribune. Further study is needed on

the relationship between CSCs and anastasis.

Although carcinogenesis represents a harm-

ful side eect of anastasis, anastasis may be con-

ducive to tissue repair and formation of new ge-

netic combinations. Our ndings suggest that

inhibiting anastasis may enhance the eect of

chemotherapy, while promoting anastasis mayfacilitate tissue recovery, said principal inves-

tigator Dr. Ho-Lam Tang of CUHKs School

of Life Sciences and John Hopkins University

School of Medicine.

For example, ongoing studies demonstrated

that genistein a predominant isoavone in soy-

bean with well-documented anticancer eects

could inhibit anastasis in cancer cells. This ef-

fect was observed at non-toxic concentrations of2.5-25 g/mL in our work with CUHKs Center

for Soybean Research, said Fung. Genistein

had a synergistic anti-cancer eect in combina-

tion with chemotherapy. Further investigation

will be carried out on the mechanism.

However, Fung warned against improper

use of herbal medicine with potential anti-

cancer properties, as they may drive cancer

progression or oncogenic transformation in

normal cells.


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Conference CoverageJul-Aug 20128

Better strategies needed for ALL in

adolescents and young adults

American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, 1-5 June 2012, Chicago, USA

Christina Lau

A

dolescents and young adults with

high-risk acute lymphoblastic leu-

kemia (ALL) have poorer survival

and higher toxicity from treatment than theiryounger counterparts, according to new data

from a major phase III study which highlights

the need for beer treatment strategies for

this group of patients. [Abstract CRA9508]

Historically, ALL patients older than 16

years have an inferior outcome compared

with patients aged 1 to 15 years because older

patients have higher rates of relapse and tox-

icity, said lead author Dr. Eric Larsen of theMaine Childrens Cancer Program in Scarbor-

ough, Maine, USA. In the Childrens Oncol-

ogy Group [COG] study ALL0232, we tested

dexamethasone vs prednisone during induc-

tion and high-dose methotrexate vs escalating

Capizzi methotrexate plus PEG asparaginase

during interim maintenance 1 in a 2 x 2 fac-

torial design. For the st time, patients aged

21-30 years were eligible for enrollment in anALL study.

ALL0232 enrolled patients with newly-di-

agnosed B-precursor high-risk ALL. Of 2,571

eligible patients, 501 (20 percent) were aged

16-30 years. This represents the largest co-

hort of adolescent and young adult ALL pa-

tients to date in a single clinical trial, he said.

At 5 years, patients aged 16-30 years had

signicantly poorer event-free survival (EFS)

and overall survival (OS) than those


9/53


trial was to try to improve disease control in

the CNS.

Remission, dened as


10/53


11/53



Continuous androgen deprivation still

standard of care for prostate cancer

Yen Yen Yip

C

ontinuous androgen deprivation

remains standard of care in hor-

mone-sensitive metastatic prostate

cancer, according to a large multinationalphase III study. [Abstract 4]

Some doctors recommend intermient

hormonal therapy to men with metastatic pros-

tate cancer, believing it will reduce their risk of

side eects without compromising outcome,

but our ndings demonstrate a clear downside

to this approach for certain men, said lead in-

vestigator Dr. Maha Hussain from the Univer-

sity of Michigan, Ann Arbor, USA.The primary objective of the SWOG (South-

west Oncology Group) 9346 study, which

spanned 17 years, was to determine if inter-

mient androgen deprivation was non-inferi-

or to continuous therapy.

The study included more than 1,500 pa-

tients newly diagnosed with hormone-sen-

sitive prostate cancer, with prostate-specic

antigen (PSA) levels 5 ng/mL prior to initia-tion of androgen deprivation therapy, and a

SWOG performance status of 0 to 2. The sub-

jects were treated with goserelin and bicalu-

tamide for 7 months, and those who achieved

PSA 4 ng/mL at the 6th or 7th month were

then randomized to receive continuous or in-

termient therapy.

Aer a median follow-up of 9.2 years, the

primary endpoint of overall survival (OS) was

inferior in the intermient therapy group (5.1

years vs 5.8 years with continuous therapy; HR,

1.09). Among patients with minimal disease, OS

was signicantly beer for those who received

continuous therapy (7.1 vs 5.2 years; p=0.034).

However, in patients with extensive disease

spread, intermient and continuous therapieswere comparable.

Androgen deprivation therapy leads to sig-

nicant setbacks in quality of life, and is also

associated with increased fractures, decreased

cognitive function, increased risk of diabetes

and altered lipid proles. In addition, many

patients eventually progress to castration-re-

sistant disease, commented Dr. William Oh

from the Mount Sinai School of Medicine,New York, USA.

Previous preclinical data have suggested

that intermient therapy can re-induce apop-

tosis and prolong time to castration resistance.

[Cancer 1993;71:2782-2790]

The advantages of the intermient ap-

proach and its comparable ecacy were con-

rmed by at least 23 phase II trials, Oh noted.

However, these studies were essentially un-derpowered to evaluate survival.

The SWOG 9346 ndings will be practice

changing for many doctors who routinely use

intermient therapy, said Hussain.

Neither SWOG 9346 nor any randomized

trial has ever shown a superior cancer out-

come with intermient androgen deprivation

therapy, said Oh. This preclinical concept

[supporting intermient therapy] must no

longer be propagated.


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Regorafenib offers hope for GIST patients

failing TKIs

Christina Lau

T

he multi-kinase inhibitor regorafenib

may represent the rst targeted treat-

ment option for patients with metastatic

and/or unresectable gastrointestinal stromaltumor (GIST) who progressed despite prior use

of both imatinib and sunitinib.

The phase III GRID (Regorafenib in Pro-

gressive Disease) trial included 199 patients

from 17 countries who failed at least imatinib

and sunitinib the only two drugs approved

for GIST worldwide. Patients were random-

ized to receive regorafenib 160 mg once daily

plus best supportive care (BSC) (n=133), orplacebo plus BSC (n=66), on a 3-weeks-on

1-week-o schedule. The trial was unblinded

on disease progression, when placebo-treated

patients were eligible for crossover to open-

label regorafenib and regorafenib-treated

patients continued on their treatment. On

the next progression, patients were taken o

treatment. [Abstract LBA10008]

The trial met its primary endpoint, withprogression-free survival [PFS] being four

times longer in the regorafenib arm. Median

PFS was 4.8 months for regorafenib vs 0.9

months for placebo [HR, 0.27; p


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Antidepressant relieves chemo-induced

neuropathic pain


Yen Yen Yip

F

or the rst time, a randomized con-

trolled trial has found the serotonin-

norepinephrine reuptake inhibitor

(SNRI) duloxetine to be eective againstchronic neuropathic pain associated with tax-

ane- or platinum-based chemotherapy. [Ab-

stract CRA 9013]

In the study, duloxetine conferred a 30 per-

cent reduction in pain score for 33 percent of

patients. In the placebo group, only 17 percent

achieved a similar reduction in pain. A 30 per-

cent decrease in pain is clinically signicant

and important to patients, commented leadinvestigator Dr. Ellen Lavoie Smith, University

of Michigan School of Nursing, Ann Arbor,

USA.

A total of 220 patients with peripheral neu-

ropathic pain associated with paclitaxel or ox-

aliplatin were randomized to receive dulox-

etine (30 mg daily in the rst week, then 60 mg

daily for 4 weeks) or placebo.

Although mean pain scores fell in the pla-cebo group as well, patients who received du-

loxetine achieved a signicantly greater degree

of pain relief (p=0.003).

Overall, 59 percent of patients taking du-

loxetine achieved some degree of pain re-

lief vs 38 percent of placebo recipients. Pain

scores fell by half in 21 percent of patients onduloxetine vs 9 percent on placebo. However,

a small proportion of patients felt more pain

aer receiving treatment; fewer patients on

duloxetine experienced this eect compared

with the placebo group.

Not everyone responded to duloxetine,

Lavoie Smith said. Duloxetine... works by

increasing amounts of pain-inhibiting neu-

rotransmiers; we think patients who respondmay have some abnormalities in the way their

brain processes pain and we have to iden-

tify who might respond so we can target the

use of this drug.

The drug was generally well tolerated. Fa-

tigue, insomnia, nausea, somnolence and diz-

ziness were the most common adverse events.

Seven percent of recipients experienced se-

vere adverse events and 11 percent droppedout of the study as a result of side eects.


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ASCO 2012 Sa te l l i te Sympos iumJul-Aug 201214

Everolimus plus exemestane improves

PFS in advanced breast cancerUpdated data rom the BOLERO-2 trial

demonstrate that everolimus (Anitor, Novartis)

in combination with exemestane more than

doubled progression-ree survival (PFS) in women

with estrogen receptor positive (ER+), human

epidermal growth actor receptor 2-negative

(HER2-) advanced breast cancer who are resistant

to hormonal therapy. The data, presented at a Novartis-sponsored symposium held in

conjunction with the American Society o Clinical Oncology (ASCO) 2012 Annual Meeting,

conrm evidence rom previous analyses on the survival benets o adding everolimus to

exemestane.

Overcoming endocrine resistanceOver two-thirds o breast cancers

express the ER which contributes to tumor

growth and progression. Patients who are

ER+ benet rom endocrine therapeutic

agents, such as anti-estrogens that target

ERs. In postmenopausal patients, aroma-

tase inhibitors (AIs) are the rst-line treat-

ment choice. However, up to 25 percent o

all breast cancer patients do not respond

to endocrine therapy (de novo resistance),

whereas others will eventually relapse de-

spite an initial response due to either in-

trinsic or acquired resistance. [Clin Cancer

Res 2010;16:1979-1987] Molecular mech-

anisms o resistance are emerging. This

has led to the development o targeted

therapies. However, the challenge is to de-

ne which patients will most likely benet

rom these therapies, and which do not

need them, said Proessor Ian Smith o the

Royal Marsden Hospital and Institute o

Cancer Research in London, UK.

Everolimus: Targeting the PI3K/AKT/mTOR Pathway

Abnormalities in the phosphatidylinosi-

tol 3-kinase (PI3K)/AKT/mammalian target

o rapamycin (mTOR) pathway have been

implicated in several orms o human can-

cer. Activation o the AKT/mTOR pathway

leads to resistance to endocrine therapy

and their inhibition reverses the resis-

tance, explained Dr. Fabrice Andr o the

Institute Gustave Roussy Villejui, France.

Research on endocrine-resistant cells

showed that selective inhibitors o the PI3K/

AKT/mTOR pathway provide signicant

growth inhibition in long-term estrogen-

deprived breast cancer cells. [Nat Rev Drug

Discov2005;4:988-1004] Kinase activation

induced by long-term estrogen deprivation

and genomic alteration acquired during

the natural course o the disease may lead to

acquired resistance, said Andr.

We still have no idea how to identiy

patients who are resistant to endocrine

Pro. RugoDr. AndrPro. Smith


15/53


therapy beore they relapse, or patients

who are more likely to respond to treat-

ments that may reverse resistance, said

Proessor Hope Rugo o the University o

Caliornia, San Francisco, USA.

Everolimus, an oral mTOR inhibitor, has

promising clinical activity in women with

HER2+, HER2-, and ER+ breast cancer when

combined with HER2-targeted therapy,

chemotherapy, and hormonal ther-

apy, respectively. [Pharmacotherapy

2012;32:383-396] The phase II TAM-

RAD trial, conducted by the Groupe

dInvestigateurs Nationaux pour lEtudedes Cancers Ovariens et du sein (GINECO

Group, France), was designed to evaluate

the ecacy and saety o everolimus in

combination with tamoxien vs tamoxien

alone in patients with hormone receptor-

positive (HR+), HER2- metastatic breast

cancer with prior exposure to AIs. Results

showed that addition o everolimus to

tamoxien delayed disease progressioncompared to tamoxien alone, with me-

dian time to disease progression o 8.6 vs

4.5 months. [Ann Oncol2012; 23(suppl 2):

ii17ii24; abstract 13O_PR]

BOLERO-2 studyBOLERO-2 (Breast cancer trials o OraL

EveROlimus-2) is an international, random-

ized phase III trial designed to evaluateeverolimus in combination with exemes-

tane vs exemestane alone in postmeno-

pausal women with ER+ HER2- advanced

breast cancer reractory to treatment with

nonsteroidal AIs (NSAIs) such as letrozole

or anastrozole. The study included 724 ad-

vanced breast cancer patients rom 189

sites worldwide. Eligible patients were ran-

domized (2:1) to exemestane (25 mg/day)with everolimus (10 mg/day) or placebo.

[Cancer Res 2011;71(24 suppl):abstract S3-

7; N Engl J Med2012;366:520-529]Updated results o an 18-month ollow-

up showed a median PFS o 7.8 months

or patients receiving exemestane plus

everolimus (n=485) (7.4 in the 12-month

ollow-up) vs 3.2 months or patients re-

ceiving exemestane alone (n=239). (Fig-

ure 1) An independent review showed a

PFS o 11 months in the combination arm

vs 4.1 months in the exemestane-onlyarm. Compared to 32.2 percent o patients

who died in the exemestane-only arm,

25.4 percent in the combination arm died.

[J Clin Oncol2012;30(suppl): abstract 559]

New subgroup analyses

The clinical benet o everolimus

was observed in all subgroups in the BO-

LERO-2 study. It is very encouraging thatthere are numerically ewer deaths in the

everolimus arm vs the placebo arm, and

this dierence has continued with the lat-

est analysis o data, said Rugo.

Delaying bone progression

Subgroup analysis showed that evero-

limus delayed bone progression in pa-

tients with or without bone metastasis atbaseline, said Rugo. The delay was more

Median PFS:

EVE + EXE: 7.8 months

PBO + EXE: 3.2 months

HR=0.45Log-rank p value


16/53


signicant in patients with bone metastases

at baseline. [Eur J Cancer2012;48(suppl 1): ab-

stract LBA3]

NSAIs are associated with decrease inbone mineral density and increased risk o

ractures. Thereore, it is important to evalu-

ate whether new therapies in combination

with exemestane aect bone turnover. A

BOLERO-2 subanalysis evaluated the eect

o everolimus in combination with exemes-

tane vs exemestane alone on markers asso-

ciated with bone ormation and resorption.

Results showed that bone turnover markerswere reduced in the combination arm vs the

exemestane-alone arm during the rst 12

weeks o therapy, suggesting clinical benets

on bone health.

Maintaining quality o lie (QoL)

A subgroup o patients was assessed to de-

termine whether any disruption in health-re-

lated quality o lie (HRQoL) occurred with theeverolimus-exemestane combination. Re-

sults demonstrate that median time to deni-

tive deterioration in HRQoL was 8.3 months

or everolimus plus exemestane vs 5.8 or

exemestane alone, suggesting that adding

everolimus to exemestane maintained QoL

in the patients. (Figure 2) [Beck JT, et al. ASCO

2012; abstract 539]

In Asian patients

O 143 Asian patients in the BOLERO-2

study, 98 received everolimus plus exemes-

tane and 45 received exemestane alone. At

the time o database lock, 56 percent o Asian

patients in the combination arm had expe-

rienced disease progression vs 76 percent

in the exemestane-alone arm. Combination

therapy reduced the risk o disease progres-

sion by 44 percent vs exemestane alone

among Asian patients (HR=0.56; p


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ASCO 2012 Meet ing H igh l ightsJul-Aug 201217

PISCES study: mRCC patients favor

pazopanib for better QoL

Pro.

Escudier

Pazopanib and sunitinib: Compa-rable ecacy, dierent saety

Pazopanib and sunitinib are both ap-

proved treatments or mRCC, with compara-

ble ecacy but dierences in terms o saety

prole, noted Escudier. An indirect compari-

son suggested that PFS rates associated

with pazopanib in treatment-nave subjects

were not signicantly dierent rom suni-

tinib (hazard ratio [HR], 0.93). However, pa-

zopanib was less toxic, with lower rates o

grade 3 or 4 adverse events (44 percent) as

compared with sunitinib (67 percent). [Mc-

Cann L. ASCO GU 2010; abstract 413]

Saety and tolerability takes on a

special signicance in mRCC, where pa-tients may have to be treated or many

months, or even years. While the evalua-

tion o drug tolerability is not easy, a strong

association between adverse events and

HRQoL suggests that patient preerence

is a legitimate and useul endpoint, said

Escudier. The PISCES (Patient Preerence

Study o Pazopanib vs Sunitinib in Ad-

vanced or Metastatic Kidney Cancer) wasthus designed to assess the impact o tol-

Pazopanib is an oral multi-kinase angiogenesis inhibitor which signicantly

improves progression-ree survival (PFS) in patients with metastatic renal cell

carcinoma (mRCC). It has also demonstrated a unique saety prole compared

with other approved agents or mRCC. As Proessor Bernard Escudier o the

Institut Gustave Roussy, France, elaborated at the American Society o Clinical

Oncology (ASCO) 2012 Annual Meeting, drug tolerability is a major determinant

o health-related quality o lie (HRQoL), which in turn determines patient

preerence or one therapy over another.

erability and HRQoL on a patients choice

o treatment.

PISCES: Are dierences in drugtolerability clinically meaningul orpatients?

PISCES was a double-blind, cross-

over study, in which 169 patients were

randomized 1:1 to receive pazopanib

800 mg or 10 weeks, ollowed by a 2-week

washout period, and then sunitinib 50 mg

or 10 weeks, or vice versa (sunitinib then pa-

zopanib). Patients were eligible i they had

previously untreated mRCC, any renal can-

cer histology, measurable or non-measur-

able disease, Eastern Cooperative Oncol-ogy Group (ECOG) perormance status 0 or

1, good or intermediate prognosis, no brain

metastases, and adequate cardiac and renal

unction. [Abstract CRA4502]

The subjects were stratied based on

their ECOG perormance status and the

number o metastatic sites (1 vs 2). CT

scans were perormed beore the start o

the trial, during the 2-week washout pe-riod, and again at the end o the second


18/53


treatment period.

Patients who had received 1 dose in

both treatment periods completed a ques-

tionnaire at the end o the study, whilethey were still blinded and beore end-

o-study imaging results were disclosed,

said Escudier. The primary endpoint o the

study was patient preerence, where the

subjects indicated which drug they pre-

erred to continue treatment with. Two ad-

ditional questions were asked to determine

the reasons that infuenced their choice,

and the single most important reason or

their preerence.

Other endpoints included physician pre-

erence, saety and quality o lie.

Patients preer pazopanib

Results showed that patients had a strong

preerence in avor o pazopanib, said Es-

cudier. In the primary endpoint analysis, 70

percent o patients said they preerred to

continue treatment with pazopanib vs 22

percent or sunitinib. Only 8 percent o pa-

tients did not have any preerence. These

dierences were statistically signicant

(p1 reason

0 10 20 30 40 50 60 70

Less hair colour change

Other

Less diarrhea

Less stomach pain

Less loss of appetite

Less soreness in hands/feet

Less nausea/vomiting

Less soreness in mouth/throat

Less changes in food tastes

Less fatigue

Better quality of life

Number of patients

Pazopanib preferred (n=80)

Sunitinib preferred (n=25)

i

i i i

Figure 2. Reasons infuencing patients choice o therapy

Adapted rom Escudier BJ, et al. ASCO 2012; abstract CRA4502.

70%(n=80)

22%

(n=25) 8%

Difference (pazopanib vssunitinib)

49.3%

p value < 0.001

Primary analysis population90

80

70

60

50

40

30

20

10

0Pazopanib preferred Sunitinib preferred No preference

Percentofpatients

(n=9)

Figure 1. PISCES primary endpoint: Patient preerence


Primary analysis population

61%

22%

17%

Pazopanib preferred

Sunitinib preferred

No Preference

90

80

70

60

50

40

30

20

100

Percentofphysicians

Pazopanib preferred Sunitinib preferred No preference

Figure 3. Physician preerence in PISCES



19/53


physicians preerred pazopanib, compared

with 22 percent who preerred sunitinib.

Seventeen percent o the physicians had no

preerence at all. (Figure 3)

Improved quality o lie and drug saety

Using the Functional Assessment o

Chronic Illness Therapy-Fatigue (FACIT-

F) tool to evaluate atigue, the PISCES in-

vestigators conrmed that patients were

signicantly less likely to experience

atigue when they received pazopanib

(p=0.002), said Escudier. A supplemen-

tary questionnaire that evaluated sore-

ness in the mouth/throat, hands and eet

also established pazopanibs superiority

over sunitinib (p


20/53


Trastuzumab emtansine: A new

weapon against HER2-positive mBCApproximately 15 to 20 percent o all breast cancers involve human epidermal

growth actor receptor 2-positive (HER2+) disease. Targeted therapy options

or patients with HER2+ metastatic breast cancer (mBC) have been limited,

with a median time to progression o


21/53


Superior PFS

EMILIA met its primary endpoint oimproving PFS with T-DM1 treatment, de-

livering an absolute improvement o 3.2months in median PFS as compared withcapecitabine/lapatinib, reported Black-well. The median PFS or the two treat-ment arms was 9.6 months vs 6.4 months(p


22/53


23/53


Bevacizumab shows benefit in

platinum-resistant ovarian cancerPlatinum-resistant ovarian cancer is notoriously dicult to treat as therapeutic

options are limited in number and ecacy. This may change, as the phase

III AURELIA trial demonstrated that bevacizumab (Avastin Roche, Roche),

when added to standard chemotherapy, signicantly improves progression-

ree survival (PFS) in patients with platinum-resistant recurrent disease.

Results were presented recently at the American Society o Clinical Oncology

(ASCO) 2012 Annual Meeting by Proessor Eric Pujade-Lauraine o the Group

dInvestigateurs Nationaux pour lEtude des Cancers Ovariens (GINECO) and

Universit Paris Descartes in France.

Unmet need in dicult-to-treatdisease

Most patients with advanced ovariancancer will relapse. At rst relapse, 25 per-cent o patients have platinum-resistantdisease, and almost all patients with re-

current ovarian cancer will ultimately de-velop platinum resistance, said Pujade-Lauraine.

However, treatment options or plati-num-resistant ovarian cancer are limited.While single-agent weekly paclitaxel, pe-gylated liposomal doxorubicin (PLD) ortopotecan is the current standard o care,combination regimens have ailed to im-

prove ecacy vs monotherapy. Medianoverall survival [OS] is typically less than12 months, he pointed out.

Ovarian cancer is a highly VEGF-drivendisease. As bevacizumab has demonstrat-ed single-agent activity in platinum-resis-tant ovarian cancer, our objective was toevaluate the ecacy and saety o addingbevacizumab to chemotherapy in this set-ting, he said. [J Clin Oncol 2007;25:5180-

5186;J Clin Oncol2008;26:1773]

AURELIA: Bevacizumab in platinum-resistant recurrent disease

AURELIA is a multicenter, internation-al trial in 361 patients with epithelialovarian, primary peritoneal or allopiantube cancer whose disease progressed

within 6 months ater 4 cycles o plati-num-based therapy. Study patients hadreceived 2 prior anticancer regimens,and had no history o bowel obstruc-tion or abdominal istula, or clinical orradiological evidence o recto-sigmoidinvolvement. [Abstract LBA5002]

The patients were randomized 1:1 toreceive chemotherapy based on inves-

tigator choice (n=182), or bevacizumab(15 mg/kg q3w) in combination withchemotherapy (n=179). Chemotherapyoptions in the trial were paclitaxel (80mg/m2 days 1, 8, 15 and 22 q4w), topo-tecan (4 mg/m2 days 1, 8 and 15 q4w or1.25 mg/m2 days 1-5 q3w), and PLD (40mg/m2 day 1 q4w).

Treatment in both arms was contin-ued until progression or unacceptable

toxicity. At disease progression, patients

Pro.

Pujade-

Lauraine


24/53


in the chemotherapy-alone arm were al-lowed to cross over to bevacizumab mono-therapy, while those in the bevacizumab/

chemotherapy arm continued with theirchemotherapy without bevacizumab.The chemotherapy drugs used in the

trial are equally eective or resistantovarian cancer, diering only in their tox-icities. Investigators selected the chemo-therapy based on each patients previousexperience with the drugs, said Pujade-Lauraine. Baseline characteristics werewell balanced between the two treat-

ment arms.Signicant improvements in PFS and

response

The trial met its primary endpoint o PFS.PFS nearly doubled, with bevacizumab/che-motherapy reducing the risk o progressionby 52 percent vs chemotherapy alone. Thedierence was highly signicant, Pujade-Lauraine reported. The PFS benet was con-

sistent in all patient subgroups regardless oage, platinum-ree interval, tumor size, pres-ence o ascites, or assigned chemotherapy.(Figures 1 and 2)

Overall response rates (ORR) were alsosignicantly higher with bevacizumab/che-motherapy vs chemotherapy alone. (Figure3) The responses in the chemotherapy armare in line with whats expected in platinum-resistant patients, he noted.

OS data were not yet mature and will bereleased in 2013.

Saety and tolerabilityThe saety prole o bevacizumab was

consistent with ndings o pivotal trials obevacizumab across various tumor types.Grade 3 adverse events that were higherin the bevacizumab/chemotherapy arm in-cluded hypertension (7.3 vs 1.1 percent withchemotherapy alone), proteinuria (20.1 vs 6.6percent), gastrointestinal peroration (1.7 vs 0percent), and stula or abscess (1.1 vs 0 per-

cent). Other grade 3 adverse events, includ-ing bleeding, thromboembolic event, hema-tologic toxicity, wound-healing complication,reversible posterior leukoencephalopathysyndrome and cardiac disorders, were notsignicantly dierent between the two arms.

The rates o gastrointestinal peroration,stula or abscess were very low with bevaci-zumab/chemotherapy in the AURELIA trial,

noted Pujade-Lauraine. Excluding patientsat high risk o gastrointestinal perorationhelped limit the incidence o these adverseevents.

In the trial, atigue, abdominal pain,vomiting and dyspnea were less com-mon with bevacizumab/chemotherapy vschemotherapy alone.

Although peripheral sensory neuropathyand hand-oot syndrome were increased

CT BEV + CT

(n=182) (n=179)

Events, n (%) 166 (91%) 135 (75%)

Median PFS, months 3.4 6.7

HR (unadjusted) 0.48

Log-rank p-value


25/53


with bevacizumab/chemotherapy, Pujade-Lauraine pointed out that patients treatedwith bevacizumab/chemotherapy hadhigher exposure to chemotherapy than

those treated with chemotherapy alone.Bevacizumab delayed disease progression,allowing patients to be treated or a lon-ger period o time, which led to increasedcumulative toxicities o chemotherapy, heexplained. The other hypothesis that beva-cizumab could potentiate the toxicity o che-motherapy was unproven, because the timecourses o cumulative hand-oot syndrome

and cumulative neuropathy were similar

between bevacizumab/chemotherapy andchemotherapy alone.

Conclusions

AURELIA is the rst randomized phase IIItrial in platinum-resistant ovarian cancer todemonstrate a signicant benet with bio-logic therapy, and a signicant benet witha combination regimen vs mono-th-erapy,commented Pujade-Lauraine. In view othese signicant benets, bevacizumab incombination with chemotherapy shouldbe considered a new standard option in

platinum-resistant ovarian cancer.

Phase III trials on bevacizumabin ovarian cancer

Bevacizumab-based therapy has dem-onstrated signicant improvements inPFS in our phase III trials totaling nearly4,000 patients with newly-diagnosedor recurrent ovarian cancer. Adverseevents related to bevacizumab were as

expected, with no new saety signalsidentied.

First-line therapy in advanced disease

In the GOG-0218 (Gynecologic Oncol-ogy Group-0218) trial o patients withnewly-diagnosed stage III (incompletelyresectable) or IV disease who had un-dergone debulking surgery, median PFS

was 14.1 months with carboplatin/pacli-taxel plus concurrent and maintenancebevacizumab, vs 11.2 months with car-boplatin/paclitaxel plus concurrent bev-acizumab and 10.3 months with carbo-platin/paclitaxel plus placebo. [N Engl JMed 2011;365:2473-2483]

In the ICON-7 (International Collabo-ration on Ovarian Neoplasms-7) trial(stage IIIC or IV disease, 70 percent), me-

dian PFS was 19.8 months with carbopl-

atin/pacltaxel plus concurrent and main-tenance bevacizumab, vs 17.4 monthswith carboplatin/paclitaxel alone. [NEngl J Med 2011;365:2484-2496]

These results ormed the basis o theapproval o bevacizumab or treatmento ovarian cancer in Europe in December2011.

Previously-treated, recurrent disease

The OCEANS and AURELIA trials dem-onstrated signicant PFS improvementswith bevacizumab-based therapies inpatients with previously-treated, recur-rent ovarian cancer.

In the OCEANS trial o patients withplatinum-sensitive disease, bevaci-

zumab plus carboplatin/gemcitabineollowed by single-agent bevacizumabsignicantly increased PFS by 21 percentvs carboplatin/gemcitabine alone. [J ClinOncol 2011;29(June 20 suppl): abstractLBA5007]

Results o AURELIA oer hope orpatients with platinum-resistant dis-ease, with bevacizumab/chemotherapysignicantly extending PFS vs chemother-

apy alone.


26/53


Bevacizumab beyond progression

extends survival in mCRCResults rom a large phase III study conrm that continuing bevacizumab (BEV)

(Avastin Roche, Roche) beyond rst progression signicantly extends survival

in patients with metastatic colorectal cancer (mCRC) previously treated with

BEV plus chemotherapy. The ndings were presented recently at the American

Society o Clinical Oncology (ASCO) 2012 Annual Meeting by Proessor Dirk

Arnold o the University Cancer Center Hamburg, Germany.

ML18147 study

BEV in combination with fuoropyrimi-

dine-based chemotherapy is a standard o

care or mCRC in rst-line and, in BEV-nave

patients, second-line settings. In nonran-

domized observational studies o mCRC

patients, continuing BEV plus chemothera-

py beyond rst progression was associated

with prolonged survival vs stopping BEV,

said Arnold. [J Clin Oncol 2008;26:5326-

5334; J Clin Oncol 2010;28(15 suppl): ab-

stract 3596] However, the ecacy and

saety o continuing BEV ater rst pro-

gression had not been investigated in a

randomized clinical trial.

Design

The ML18147 study is the rst randomized

phase III trial that prospectively investigated

the impact o continued VEGF inhibition with

BEV in mCRC patients who progressed ater

rst-line BEV plus standard chemotherapy

(oxaliplatin- or irinotecan-based at physi-

cians discretion). The study included 820 pa-

tients who were randomized 1:1 to receive

oxaliplatin- or irinotecan-based chemother-

apy with or without BEV (2.5 mg/kg/week)

until urther disease progression. Patients

who received oxaliplatin-based chemother-

apy in the rst-line setting were switched to

irinotecan-based chemotherapy, and vice

versa. [Abstract CRA3503]

The study started as a national academic

trial rom the AIO Group [Working Group or

Medical Oncology o the German Cancer

Society] in Germany with progression-ree

survival [PFS] as primary endpoint. Subse-

quently, with growing interest throughout

Europe, more patients were enrolled, and

the primary endpoint was changed to over-

all survival [OS], said Arnold.

To be eligible or participation, patients

had to be 18 years old with histologically

conrmed mCRC, with disease progression

4 weeks prior to starting the study treat-

ment. Those with progressive disease diag-

nosed >3 months ater the last BEV adminis-

tration, rst-line PFS


27/53


line BEV were excluded.

Patients were stratied by rst-line che-

motherapy, PFS in rst-line setting [9 or

>9 months], time rom last BEV dose [42

or >42 days], and ECOG [Eastern Coopera-

tive Oncology Group] perormance status at

baseline [0/1 or 2], added Arnold.

Baseline characteristics

Baseline characteristics were well bal-

anced between the BEV/chemotherapy

(n=409) and chemotherapy-alone (n=411)

arms. In the rst-line setting, more than hal

o the patients in each arm had a PFS o

9 months (54 vs 56 percent) and received

irinotecan-based chemotherapy (59 vs 58

percent). The duration between the last BEV

dose and randomization was 42 days or

77 percent o patients in each arm.

Use o second-line chemotherapy was

well balanced during the study. The propor-

tions o patients receiving irinotecan- and

oxaliplatin-based chemotherapy were 42

and 58 percent, respectively, in the BEV/che-

motherapy arm, vs 43 and 57 percent in the

chemotherapy-alone arm.

Continuing BEV into second-line increases OS

The trial met its primary endpoint, with

OS signicantly increased in patients who

continued BEV beyond progression ater

rst-line BEV/chemotherapy. Ater a me-

dian ollow-up o 11.1 months or the BEV/

chemotherapy arm and 9.6 months or the

chemotherapy-alone arm, median OS was

11.2 vs 9.8 months. (Figure 1)

The OS benet was consistent in all pre-

specied subgroups, said Arnold. While

there appeared to be a dierence in treat-

ment eect according to gender, we ound

no real interaction between BEV benet and

gender as the treatment-gender interaction

test was not statistically signicant. (Figure 2)

In the study, 68.6 percent o patients in the

BEV/chemotherapy arm and 67.7 percent in

the chemotherapy-alone arm received 1

line o subsequent therapy, which included

BEV [11.5 vs 12.2 percent], anti-EGFR therapy

[39.2 vs 41.3 percent], and other therapies

[54.9 vs 50.4 percent]. The balance in urther

lines o treatment indicates the robustness o

the OS eect seen with continuing BEV into

the second-line setting ater rst progression,

suggested Arnold.

OSe

stimate

Time (months)

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42 48

No. at risk

CT 410 293 162 51 24 7 3 2 0

BEV + CT 409 328 188 64 29 13 4 1 0

9.8 mo 11.2 mo

CT (n=410)

BEV + CT (n=409)

.

I .

.

.

.

.

.

.

.

.

.

.

I .

.

.

.

.

. .

.

.

.

.

.

.

Unstratifieda HR: 0.81p=0.0062

Stratifiedb HR: 0.83p=0.0211

: ..

: ..

Figure 1. OS: ITT population

a Primary analysis method; b stratied by rst-line CT, rst-line PFS, time rom last dose o BEV, ECOG perormance status at baseline;BEV = bevacizumab; CT = chemotherapy; ITT = intention-to-treat; OS = overall survival

Adapted rom Arnold D, et al. ASCO 2012; abstract CRA3503.

.

.

.

.

.

. .

Category Subgroup n HR

All All 819 0.81

Patient populationa AIO 260 0.86

ML18147 559 0.78

Gender Female 294 0.99

Male 525 0.73

Age 9 months 369 0.73

First-line CT Oxaliplatin-based 343 0.79

Irinotecan-based 476 0.82

Time from last BEV 42 days 630 0.82

>42 days 189 0.76

Liver metastasis only No 592 0.81

Yes 226 0.79

No. of organswith metastasis

1 307 0.83

>1 511 0.77

HR 0 1 2

.

.

.

.

.

: ..

: .

.

: .

.

: ..

Figure 2. Subgroup analysis o OS: IT T population

a Patient population reers to sequential enrolment o patients in ori ginal AIO and subsequent enrolment in ML18147 when study wastranserred to Roche, all patients listed under AIO were included in primary analysis; AIO = Working Group or Medical Oncology o theGerman Cancer Society; BEV = bevacizumab; CT = chemotherapy; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; ITT= intention-to-treat; OS = overall survival; PFS = progression-ree survival

Adapted rom Arnold D, et al. ASCO 2012; abstract CRA3503.


28/53


Secondary endpoints

PFS was signicantly prolonged with BEV/

chemotherapy vs chemotherapy alone (5.7 vs

4.1 months). (Figure 3)

Overall response rates were similar in both

arms (5.4 percent or BEV/chemotherapy vs

3.9 percent or chemotherapy alone). How-

ever, disease control rate was signicantly

higher with BEV/chemotherapy (68 vs 54 per-

cent; p


29/53

Case StudyJul-Aug 201229

Use of capecitabine in advanced metastatic

breast cancer

Dr. Foon-Yiu CheungClinical Oncologist

Presentation and treatmentA 47-year-old Chinese woman presented

in 2002 with a mass in her right breast. She

underwent modied radical mastectomy in

August 2002. Pathology revealed a 1.7-cm

invasive ductal carcinoma with grade 3 dis-ease. Nine out of 23 resected axillary lymph

nodes were involved by tumor. Resected mar-

gin was clear (5 mm). Estrogen receptor (ER)

and progesterone receptor (PR) were positive

while human epidermal growth factor recep-

tor 2 (HER2) was negative. Metastatic work-

up was negative.

The patient received adjuvant chemo-

therapy with the Milan scheme (four cyclesof 3-weekly adriamycin and eight cycles of

cyclophosphamide, methotrexate and 5-uo-

rouracil [5-FU]), followed by locoregional ra-

diotherapy (RT). She received tamoxifen from

June 2003 until June 2008.

In June 2009, she presented with an inci-

dental nding of lung masses on chest X-ray

(CXR). Transbronchial biopsy conrmed met-

astatic carcinoma. ER and PR were stronglypositive, while HER2 and thyroid transcrip-

tion factor-1 (TTF-1) were negative.

Paclitaxel and carboplatin were given for

six cycles, completed in October 2009. CXR

showed partial response. She underwent

ovarian ablation with irradiation in October

2009 and was started on letrozole in March

2010.

A few months later, the patient was found

to have a secondary brain tumor at the le

parieto-occipital region by CT scan while on

investigation for dizziness.

Palliative whole-brain irradiation was

given in June 2010 with 30 Gy in 10 fractions.

Follow-up CXR in November 2011 revealedinterval increase in size of the secondary lung

tumor.

A PET-CT in March 2012 revealed bilobar

liver metastases, multiple hypermetabolic

mediastinal lymph nodes and bilateral lung

metastases. The le parieto-occipital brain

metastasis remained hypermetabolic.

Palliative capecitabine (2500 mg/m2 daily

for 2 weeks in each 3-weekly cycle) was start-ed in March 2012. Treatment was well toler-

ated.

Repeat PET-CT in May 2012 aer the third

cycle revealed:

Metabolic remission of bilobar liver metas-

tases

Signicant metabolic improvement of

hypermetabolic media-stinal lymph nodes

Signicant metabolic improvement of

hypermetabolic intrapulmonary and le

Figure. PET-CT scans beore (top) and ater (bottom)

capecitabine treatment

(A) Brain metastasis (B) Liver metastasis (C) Right hilar metastasis


30/53


parieto-occipital brain metastases

No new hypermetabolic meta-static lesions

These ndings suggest a partial treatment

response.The patient plans to continue the present

treatment.

DiscussionBreast cancer is the most common cancer

among females in Hong Kong; in 2009, it was

the third cause of cancer mortality.1 This pa-

tient rst presented at a time when third-gen-

eration adjuvant chemotherapy with taxaneswas either unavailable or very expensive. Ad-

juvant chemotherapy using the Milan scheme

was the most potent option we could oer at

that time.

Aer relapse, she received subsequent

systemic therapy in line with the consensus,

using a taxane rst. The choice of paclitaxel

rather than docetaxel was solely a nancial

consideration, as paclitaxel is free. The subse-quent use of capecitabine aer progression is

also in line with international recommenda-

tions, such as the NICE guideline.2

Single-agent capecitabine has a response

rate of 14-28 percent in pretreated metastatic

breast cancer, and the median duration of

response is about 4.5-9 months. The most com-

monly reported side eects are hand-foot syn-

drome (2-21 percent); diarrhea (3-10 percent)and nausea (3-8 percent).3 Whether it should

be used in combination with other agents or

as monotherapy aer anthracyclin and tax-

ane failure remains inconclusive. Combina-

tion with IV or oral vinorelbine is common.

Although there is no phase III randomized tri-

al for this scheme, the response rate reported

in a phase II trial was 33-70 percent.4

This case illustrates that capcitabine is aneective agent for advanced breast cancer

patients aer anthracycline and taxane fail-

ure, which concurs with current published

evidence. The treatment is well tolerated and,

in this case, demonstrated activity against

brain metastasis as well.

References:1. Top 10 cancers in 2009. hp://www.ha.org.hk/cancereg. 2. NICEpathways: Advanced breast cancer, chemotherapy and biolog-ical therapy. hp://pathways.nice.org.uk/pathways/advanced-breast-cancer#path=view%3A/pathways/advanced-breast-cancer/advanced-breast-cancer-chemotherapy-and-biological-therapy.xml&content=close. 3. National Collaborating Center for Cancer.Advanced Breast Cancer: Diagnosis and treatment. EvidenceReview. NICE 2009. 4.Clinical Breast Cancer 2012;12:30-39.


31/53


Capecitabine in advanced gastric cancerFigure. PET scan

Dr. Wai-Tong Ng

Department of Clinical OncologyPamela Youde Nethersole EasternHospital Hong Kong

PresentationA 58-year-old Chinese man presented to

Pamela Youde Nethersole Eastern hospital,

Hong Kong, in February 2011 with a 2-month

history of dysphagia. Upon admission, he

could only tolerate uid diet.

Investigations and diagnosisEsophago-gastroduodenoscopy showed

a circumferential tumor growth at the lower

esophagus with extension to the gastric car-

dia. Biopsy revealed adenocarcinoma, HER2

immunohistochemistry (IHC) 3+. Computed

tomography (CT) showed an irregular growth

at the cardia extending to the gastroesopha-geal junction, and multiple slightly enlarged

lymph nodes over the gastroesophageal,

gastro-hepatic and upper para-aortic regions.

Positron emission tomography (PET) scan re-

vealed a primary tumor involving the distal

esophagus, gastric cardia and proximal lesser

curvature, and a hypermetabolic focus in the

liver, which was compatible with a liver me-

tastasis. (Figure A)

TreatmentThe patient was given palliative chemo-

therapy using cisplatin, 5-uorouracil (5-FU)

and trastuzumab. Aer 2 cycles of treatment,

there was a signicant improvement in symp-

toms and the patient could resume normal

solid diet. However, impaired renal function

was noted due to the use of cisplatin. He was

thus switched to oxaliplatin, capecitabine

The arrow indicates the site of liver metastasis.

(A) Beore chemotherapy

(B) Beore chemotherapy


32/53


and transtuzumab; 8 cycles of treatment were

given in total. A follow-up PET scan showed

good response and the liver metastasis be-

came hypometabolic. (Figure B)Total radical gastrectomy and distal esoph-

agectomy were performed in November 2011

with clear margins. The liver lesion was not

identiable during the operation. Repeat PET

scan aer the operation showed no gross

FDG-avid lesion.

In early February 2012, he was given

stereotactic body irradiation (55 Gy over

10 fractions) to the liver lesion (tumor lo-cation based on the pre-treatment PET

scan). Trastuzumab was continued for up

to 1 year and treatment was completed

in April 2012. He was stable and doing

well at the time of last follow-up, with no

deterioration in cardiac function.

Discussion

The combination of 5-FU and cisplatin is awidely accepted standard regimen for meta-

static gastric cancer (mGC). However, the

need for several days of hospital stay with

5-FU infusion and the potential renal toxicity

associated with cisplatin have prompted the

evaluation of alternative treatment regimens.

Two important studies ML17032 and

REAL-2 have evaluated the replacement of

these agents by capecitabine (an oral uoro-pyrimidine) and oxaliplatin (a platinum ana-

logue with less renal toxicity).1,2 Similar an-

titumor activity has been conrmed in these

studies.

In addition, a more interesting observa-

tion was noted in a recent combined analysis

of these two studies.3 In this meta-analysis,

a total of 1,318 patients who were random-

ized within REAL-2 (n=1,002) and ML17032

(n=316) were included. Overall survival (OS)

was compared for the 664 patients treated

with 5-FU combinations vs the 654 patients

treated with capecitabine combinations. The

median OS was 285 days for patients treatedwith 5-FU and 322 days for patients who re-

ceived capecitabine, with an unadjusted haz-

ard ratio (HR) of 0.87 in favor of capecitabine

(p=0.027). This meta-analysis is practice

changing as capecitabine is not only beer

than 5-FU in terms of survival, but also far

more convenient as patients can avoid unnec-

essary hospitalization or central line insertion

for the 5-FU infusion.Another important advance in the man-

agement of mGC is the integration of target-

ed agents into the chemotherapy backbone.

Trastuzumab is currently the most widely

used targeted therapy for patients with

HER2-positive tumors. In the ToGA trial,

median OS was 14 months among patients

assigned to trastuzumab plus chemotherapy

vs 11 months for those assigned to chemo-therapy alone (p=0.0046).4 A subgroup anal-

ysis indicated that trastuzumab was most

eective in prolonging survival in patients

with HER2 IHC 3+ or IHC 2+ and FISH

(uorescence in situ hybridization)-positive

tumors (HR=0.65). In these HER2-positive

patients, the median OS was 16.0 months in

the trastuzumab arm, compared with 11.8

months in the chemotherapy-alone arm.Currently, approximately 20 percent

of mGC patients are HER2-positive, and

trastuzumab plus chemotherapy repre-

sent the standard of care for this group of

patients.

References1.Ann Oncol 2009;20:666-673. 2.N Engl J Med 2008;358:36-46. 3.Ann

Oncol 2009;20:1529-1534. 4.Lancet 2010;376:687-697.


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NewsJul-Aug 201234

New evidence linking H. pylori with colon

cancer

Naomi Rodrig

While the association between Helico-bacter pylori (H. pylori) infection andan increased risk of gastric adenocar-

cinoma has been well established, evidence re-garding its role in the development of colorectalcancer (CRC) remains controversial.

Recently, a large epidemiological study re-ported at the 2012 Digestive Disease Week inSan Diego, USA has shown an increased risk ofcolon neoplasms in patients with H. pylori infec-tion.

The investigators reviewed the records ofnearly 157,000 patients who had undergone

both colonoscopy and esophago-gastroduoden-oscopy between 2008 and 2011.

Overall, 16,759 patients, or 11 percent, hadH. pylori infection conrmed by immunohisto-chemistry, reported lead author, Dr. AmnonSonnenberg of Oregon Health and Science Uni-versity and the Portland VA Medical Center,US. The prevalence of H. pylori gastritis was 9percent among patients without colonic polyps,11 percent in patients with hyperplastic polyps,12 percent in those with adenoma, 14 percent inpatients with advanced adenoma and 18 percent

in those with adenocarcinoma. The prevalencewas similar regardless of the site of the coloniclesion.

Furthermore, there was a trend of increasedprevalence of H. pylori infection with increasingnumber and size of adenomatous polyps.

The data suggest a link between the preva-lence of infection and lesion severity. H. pyloriconfers an increased risk for all types of colonic

neoplasms, and the risk appears to increase withadvancing stage of the neoplasm, from hyper-plastic and adenomatous polyps to tubulovil-

lous adenoma, adenoma with high-grade dys-plasia and adenocarcinoma, he concluded.

Another report published earlier this yearsuggested that H. pylori infection may be as-sociated with an increased risk of CRC in spe-cic colorectal sites. [Am J Epidemiol 2012. DOI:10.1093/aje/kwr331]

The authors assessed the association of H. py-

lori seroprevalence with risk of CRC in a largepopulation-based case-control study conductedin Germany between 2003 and 2007. Serum an-tibodies to H. pylori in general and the cytotox-in-associated gene A protein (CagA) were mea-sured in 1,712 incident CRC patients and 1,669controls. CagA-positive strains of H. pylori areconsidered more toxic or carcinogenic.

The association between H. pylori prevalenceand CRC risk was adjusted for potential con-founders and stratied by age group, gender,anatomic subsites, and cancer stage.

Overall, H. pylori seroprevalence was high-er in CRC patients than in controls (46.1 vs40.1 percent, respectively). Age- and gender-adjusted odds ratios (OR) were 1.3 and 1.14,respectively.

Stratied analyses showed that the risk eleva-tion was essentially conned to le-sided CRC,

with an OR of 1.22. H. pylori infection may beassociated with a small yet relevant risk increasein the le colorectum, the authors concluded.

The results of both recent studies are incontrast with previously published data. Forexample, a nested case-control study of menin the ATBC (Alpha-Tocopherol, Beta-Caro-tene) cancer prevention clinical trial in Finland,which analyzed data from nearly 30,000 sub-

jects, found no evidence of H. pylori being a riskfactor for CRC development. [Ann Epidemiol1994;4:1-10]


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Minimum Product InformationHerceptin (trastuzumab) Powder for Concentrate for infusion 150 mg single dose vial & 440 mg multidose vial (with solvent)Indications:HER2 positive patients with: (i) metastatic breast cancer (MBC), either as monotherapy following at least 2 chemotherapy (CT) regimens; or in combination with paclitaxel forpatients who have not received CT; or in combination with docetaxel for patients who have not received CT; or in combination with an aromatase inhibitor for the treatment ofpostmenopausal patients with hormone-receptor positive MBC, or (ii) early breast cancer (EBC) following surgery, CT (neo/adjuvant) and radiotherapy (if applicable); or followingadjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel; or in combination with adjuvant chemotherapy consisting of docetaxeland carboplatin, or (iii) metastatic gastric cancer (MGC) in combination with capecitabine or 5-FU and cisplatin. Dosage & administration:Please refer to Herceptin PI for full guidance.HER2 testing is mandatory prior ini tiation of therapy. EBC/MBC/MGC 3-weekly: loading dose - 8mg/kg; subsequent doses 6mg/kg repeated at 3-weekly intervals. BC weekly: loadingdose - 4mg/kg; subsequent doses: 2mg/kg weekly. Administer as IV infusions over approx. 90 min. Infusion time reduced to 30 min for subsequent doses if initial loading dose was welltolerated. Do not administer as an IV push or bolus. Observe for infusion-related symptoms. In MBC or MGC, treat until disease progression. Patients with EBC should be treated for 1 yearor until disease recurrence. Contraindications:Known hypersensitivity to trastuzumab or any product excipients. Warnings & Precautions:Discontinue Herceptin infusion in case of seriousadverse reactions. Patients experiencing dyspnoea at rest may be at risk of fatal infusion reactions or severe pulmonary reactions. Interstitial lung disease may occur as part of aninfusion-related reaction or with a delayed onset especially in patients with prior or concomitant therapy with other anti-neoplastic therapies, these patient should not be treated withHerceptin. Heart failure has been observed. Caution in patients with symptomatic heart failure, history of hypertension or documented coronary artery disease and in EBC, in thosepatients with an LVEF 10%): nasopharyngitis, anaemia, thrombocytopenia, weight changes, decreased appetite, insomnia, Nervous system disorders (including dizziness,headache, paraesthesia, hypoaesthesia), lacrimation increased, conjunctivitis, lymphoedema, Respiratory, thoracic and mediastinal disorders (including dyspnoea, epistaxis,oropharyngeal pain, cough, rhinorrhoea), Gastrointestinal disorders (including diarrhoea, vomiting nausea, abdominal pain, dyspepsia, constipation, stomatitis), erythema, rash,alopesia, arthralgia, myalgia, General disorders and administration site conditions (including asthenia, chest pain, chills, fatigue, influenza-like symptoms, infusion related reaction, pain,pyrexia, peripheral oedema, mucosal inflammation) & nail toxicity. Post Marketing refer to package insert.Date of preparation: December 2011Full prescribing information should be viewed prior to prescribing.


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NewsJul-Aug 201236

Overcoming treatment resistance in

pancreatic cancer

Christina Lau

Researchers in the US have discovered

how pancreatic cancer becomes resis-

tant to chemotherapy and identied

ways to improve treatment based on their nd-

ings.

The studies, presented recently at the Amer-

ican Association for Cancer Researchs (AACR)

rst-ever conference on pancreatic cancer, rep-

resent progress in a disease that is notoriously

dicult to treat, with 90 percent of patients

likely to die within 1 year from diagnosis.

Pancreatic cancer cells are largely resis-

tant to cell death induced by chemotherapy

and radiation. Fortunately, our data show that

this seemingly unconquerable disease has an

Achilles heel its toxin exhaust system, said

Professor Sanjay Awasthi of the City of Hope

Comprehensive Cancer Center in Duarte, USA.

The weak point Awasthi and colleagues

identied is the RLIP76 protein, which pumps

out toxic chemicals accumulating in pancreatic

cancer cells as a result of chemotherapy or ra-

diotherapy before they can cause cell death.

We found a higher level of RLIP76 inhuman pancreatic cancer cells than in normal

human pancreatic cells. Depletion of RLIP76

levels killed human pancreatic cancer cells

in culture and shrank established human

pancreatic tumors in mice, he reported.

Moreover, blocking or depleting levels of this

protein dramatically enhanced the ability of

radiation and doxorubicin to destroy human

pancreatic cancer cells in culture.An added benet to depleting RLIP76 levels

in mice with established tumors was a decrease

in blood glucose, cholesterol and triglycerides,

added Awasthi, who is founder of a company

that makes recombinant RLIP76 protein for

treatment of radiation poisoning.

Another approach already being tested in

the clinic is inhibition of the Hedgehog signal-

ing pathway, said Dr. Edward Kim of the Uni-

versity of Michigan Comprehensive Cancer

Center in Ann Arbor, USA. Early results look

promising.

The Hedgehog pathway is normally silent

in the adult pancreas but activated in patients

with pancreatic cancer, contributing to the

desmoplastic stroma that is characteristic of

the disease. This dense stroma is believed to

contribute to resistance to chemotherapy by

presenting a physical barrier to chemothera-

py delivery, said Kim. In addition, Hedge-

hog levels are increased in pancreatic can-

cer stem cells, which drive tumor growth by

generating bulk tumor cells and are par-

ticularly resistant to chemotherapy and

radiation.

Kim and colleagues have achieved some

success in a small number of patients withthe Hedgehog pathway inhibitor GDC-0449

(vismodegib), an oral agent approved for use

in basal cell carcinoma.

In 20 treatment-nave patients with

advanced pancreatic cancer, use of GDC-0449

(as monotherapy for 3 weeks and then in

combination with gemcitabine) led to a

partial response in ve patients and stable dis-

ease in ve patients. Progression-free survivalat 3 months was 50 percent.


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NewsJul-Aug 201239

Arthritis drug to be tested in lymphoma

Christina Lau

Singaporean researchers are planning to

test a Janus kinase 3 (JAK3) inhibitor

in patients with natural killer (NK)/T-

cell lymphoma a very aggressive form of

lymphoma frequently found to harbor JAK3

mutations.

NK/T-cell lymphoma is particularly

prevalent in Asia, accounting for almost half

of all T-cell lymphomas in some parts of theregion, said Professor Bin-Tean Teh of the

National Cancer Center SingaporeVan An-

del Research Institute Translational Research

Laboratory and DukeNational University of

Singapore Graduate Medical School.

Very lile was known about the genetic

and molecular defects causing the aggres-

sive disease before we started our study, he

continued. With no eective treatment, theprognosis of patients with NK/T-cell lympho-

ma is extremely poor.

In their study, Teh and colleagues con-

ducted whole-exome sequencing of NK/T-

cell lymphoma cells from four patients, and

identied JAK3 somatic-activating mutations

in two of them. Further validation was con-

ducted in another 61 patients with Sanger

sequencing and high-resolution melt (HRM)analysis. In total, 23 of 65 cases (35.4 percent)

harbored JAK3 mutations. [Cancer Discov

2012, e-pub 15 Jun]

The mutations enabled NK/T-cell lympho-

ma cell lines to grow in culture without the

normally essential growth factor, interleu-

kin-2 (IL-2). This means that JAK3 mutations

cause dysregulated activation of JAK3, sug-

gesting that JAK3 may be a good drug target.

There is a JAK3 inhibitor [CP-690550

(tofacitinib)] currently in phase III trials fortreatment of rheumatoid arthritis. In our

study, use of CP-690550 in the JAK3-mu-

tant NK/T-cell lymphoma cell lines led to

inhibition of STAT5 [signal transducer and

activator of transcription-5] phosphory-

lation, along with reduced cell viability,

reported Teh. We are in the process of plan-

ning a clinical trial to test the agent as a treat-

ment for NK/T-cell lymphoma with JAK3mutations.

It is tremendously rewarding to have

identied genetic mutations that appear to

have an important role in driving NK/T-cell

lymphoma in a considerable proportion of

cases, he continued. Although relatively

rare in the USA, this form of lymphoma is

responsible for the deaths of a large number

of people in Asia, especially in China and

Korea.


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Meet ing H igh l ightsJul-Aug 201241

Everolimus plus exemestane improves

PFS in advanced breast cancer

Pro.

Schfski

At a sponsored satellite symposium in conjunction with the Asian Oncology

Summit held recently in Singapore, Proessor Patrick Schski, Head o the

Department o General Medical Oncology and the Laboratory o Experimental

Oncology at the University Hospitals Leuven, Catholic University Leuven,

Belgium, reviewed the current treatment options or metastatic renal cell

carcinoma (mRCC). In particular, he highlighted the latest data ocusing on the

angiogenesis inhibitor pazopanib.

Unmet needs in mRCCThe treatment options or mRCC

have been revolutionized over a short

period o time. Since 2005, seven tar-

geted agents have been approved or

use in the treatment o mRCC, either as

rst- or second-line. This has resulted

in improved clinical outcomes or pa-tients with mRCC. However, the more

treatment options we have, the more

dicult and complicated it becomes to

make treatment decisions, said Schski.

The incidence o RCC worldwide con-

tinues to increase by 1 to 2 percent per

year, which may be partly attributed to

improved diagnosis. There is still an un-

met medical need in mRCC, Schski said.The drugs that we have today are not cur-

ing our patients. We are delaying tumor

growth and shrinking metastasis in a large

proportion o patients, but complete re-

sponses are rare.

Reractoriness to treatment develops in

the majority o cases. Other challenges in

targeted therapy or mRCC include iden-

tication o the most eective sequence

or combination o available targeted

agents to reduce adverse events and pre-

vent or overcome the development o

drug resistance.

Many patients suer rom adverse

events associated with some tyrosine ki-

nase inhibitors (TKIs). Mucositis, atigue,

hand-oot syndrome and gastrointestinalcomplaints such as diarrhea all require ad-

equate assessment and prompt manage-

ment.

In a retrospective study involving ap-

proximately 700 patients with mRCC, a va-

riety o adverse events were reported with

the targeted agents sunitinib, soraenib

or bevacizumab. In general, the adverse

event proles o these drugs varied con-siderably. [Levy A, et al. European Multidis-

ciplinary Cancer Congress 2011. Abstract

7.152]

For sunitinib, the main problem that

we all encounter, and Im seeing it daily

in my own patients as well, is atigue/as-

thenia, apart rom other side eects. For

soraenib, the dominant problem rom

my personal experience is hand-oot


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syndrome and also atigue/asthenia. For

bevacizumab, which is usually combined

with intereron-ala, the rate o atigue/

asthenia has reached 44.4 percent andthis has led to treatment discontinuation

in a considerable number o patients, he

reported.

Fatigue/asthenia is a repeating theme

among patients treated with these tar-

geted agents. In general, treatment-

related adverse events have a negative

impact on the well-being o patients,

and the actual dosing and scheduling odrugs. Drugs are used according to la-

beled instructions, but many patients do

not tolerate ull doses. Any variation to

the prescribed regimens has an eect on

treatment outcomes, Schski warned.

In the study, treatment modications

occurred quite oten. Between 12 to 25

percent o patients had to discontinue

treatment due to adverse events.

Pazopanib in mRCC: Ecacy andsaety

The treatment strategy or mRCC con-

tinues to evolve. Pazopanib a potent

inhibitor o VEGFR-2, the primary me-

diator o angiogenesis is a welcome

addition to the mRCC treatment port-

olio. The drug has a avorable overallrisk:beneit proile and works by inhib-

iting the intracellular tyrosine kinase

o vascular endothelial growth actor

receptor (VEGFR) and platelet-derived

growth actor receptor (PDGFR). In vitro

studies demonstrated that pazopanib

has >6 times greater ainity or VEGFR-2

and is overall more selective than suni-

tinib. Unlike sunitinib, pazopanib also

causes less inhibition o Fit-3, a mediator

o hematopoiesis. (Figure 1)

A phase III trial has demonstrated that

pazopanib improves progression-reesurvival (PFS) and response rates in both

treatment-nave and cytokine-pretreated

patients. In this study, patients were ran-

domized to either pazopanib (n=290) or

matching placebo (n=145). The study al-

lowed or early cross-over rom placebo to

active treatment with pazopanib, without

any impact on PFS.

In the overall study population, PFS wassignicantly longer with pazopanib than

with placebo (9.2 months vs 4.2 months,

p


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cidence and severity. Arterial hyperten-

sion is an uncommon event, but there are

clear guidelines on how to deal with it.

(Figure 4)Fatigue is also less prominent with

pazopanib than with other drugs Ive pre-

scribed beore or my patients. Fatigue can

be bothersome or patients and translates

into poorer outcomes, he remarked.

Schski noted that the ongoing COM-

PARZ (Pazopanib Versus Sunitinib in the

Treatment o Locally Advanced and/or Met-

astatic Renal Cell Carcinoma) trial, whichinvolves a head-to-head comparison o

the two TKIs, is expected to provide more

data to acilitate treatment selection or

individual patients.

Conclusions

Pazopanib is the third TKI and the sixthtargeted therapy approved or the treat-

ment o advanced or metastatic RCC.

Its saety prole is dierent rom other

agents. The drug is clearly manageable,

but it is important to assess and man-

age relevant adverse events such as

hypertension, liver enzyme elevation and

diarrhea. Guidelines are available to help

physicians make sound therapeutic deci-

This drug has

less hematologic toxicity

compared with other

targeted therapies

i

i i i

l

l

l

1.0

0.8

0.6

0.4

0.2

0Proportionprogression-free

Time (months)

60%reduction in

risk of

progressionor death withpazopanib vs

placebo

0 5 10 15 20

Number at riskPazopanib 155 84 39 11 1

Placebo 78 22 7 2

Median PFS

Pazopanib (n=155): 11.1 months

Placebo (n=78): 2.8 months

p


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Exper t Op in ionJul-Aug 201244

Cetuximab rechallenge: Extending

clinical benefits in mCRC

Dr. Hui

While the benets o rst-line chemotherapy plus cetuximab

Oncology Tribune July 2012 HK

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