breast and OVARIAN cancer
DR DAVID FENNELLY
CONSULTANT MEDICAL ONCOLOGIST
ST VINCENT’S UNIVERSITY HOSPITAL
DUBLIN
HOW RELEVANT IS ONCOLOGY IN MEDICINE TODAY?
• Cancer is the second leading cause of death worldwide
• Only cardiovascular diseases overcome cancer as cause of death
• Overall incidence of cancer is increasing as a result of improved life expectancy
• The psychological impact of cancer on patients and their relatives is a big part of the “cancer problem” in modern Medicine
TRENDS IN MORTALITY FROM CANCER IN UK (1975-2007)
0
50
100
150
200
250
300
350
400
450
197
5
197
7
197
9
198
1
198
3
198
5
198
7
198
9
199
1
199
3
199
5
199
7
199
9
200
1
20
03
200
5
200
7
Rate
per
100,0
00
Year of diagnosis/death
Persons Incidence Persons Mortality
Age-standardised incidence rates for all cancers and mortality rates for all
BREAST CANCER IN IRELAND: THE FACTS
• Breast cancer is the most common type of malignant cancer among women in Ireland
• Ireland is one of the countries with the highest breast cancer mortality worldwide
• Breast cancer mortality is different with age but represents a substantial cause of death for ages between 40-70
Age-standardised rate (W):
A rate is the number of new cases or deaths per 100 000 persons per year. An age-
standardised rate is the rate that a population would have if it had a standard age structure.
Standardization is necessary when comparing several populations that differ with respect to
age because age has a powerful influence on the risk of cancer.
WHAT HAPPENED OVER THE LAST 20 YEARS?
• Diagnosis at earlier stages (breast, colon, prostate cancer) Role of screening and education
• Improvements in surgical treatments (breast, colon lung cancer, soft tissue sarcoma)
• Improvements in medical treatments for the early stage malignancies (adjuvant therapies)
• Changes in life-style (gastric, lung, cervical cancer)
• But most important…
• BETTER UNDERSTANDING OF MOLECULAR BIOLOGY OF CANCER
An example from clinical practice…
In 1981
• Mastectomy specimen: invasive breast cancer
• 21 mm in size
• 20 axillary lymph nodes negative for metastatic carcinoma
In 2011• WLE specimen: invasive breast cancer
• 21 mm in size
• 2 axillary sentinel lymph nodes negative for metastatic carcinoma
• Grade II
• Lymphovascular invasion present
• Ki-67 (proliferation index)
• ER and PGR positive
• HER2 negative (by IHC and FISH)
• OncotypeDX Recurrence Score: 26
Breast anatomy
Progress of breast surgery(early 1900s to 2000s)
1894
1655
1940s 1970s 1990s
DEFINITIONS OF CANCER
• Clinical definition
• “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change.” (Robbins, 7th
edition)
• Molecular definition
• “Cancer results by the clonal expansion of a single precursor cell that has incurred genetic damage (or mutation) acquired by the action of environmental agents, such as chemicals, radiation, or viruses, or inherited in the germ line. This process, called carcinogenesis, is a multistep process at both the phenotypic and the genetic levels, resulting from the accumulation of multiple mutations.
TNM staging of breast cancer (I)
TNM staging of breast cancer (II)
Epithelial Ovarian Cancer
• The crude incidence of ovarian cancer in the European Union is 18/100.000 women per year, the mortality is 12/100.000 women per year
• The median age at diagnosis is 63 yrs. Incidence increases with age and peaks in the 8th decade. Between age of 70-74 years age-specific incidence is 57/100.000 women per year
* ESMO minimum Clinical Recommendations
Ann Oncol 19 (suppl 2): ii14-ii16, 2008
Five-year Survival in Ovarian Cancer30 years of experience
Vol. Year Cases Ia IV Overall
(n) %
16 1963-68 4588 66.7 5.0 27.3
19 1976-78 6724 72.3 4.5 29.8
21 1982-86 10912 82.3 8.0 35.0
23 1990-92 7059 83.5 11.1 41.6
25 1996-98 4116 89.3 13.4 46.4
26* 1999-01 4911 89.3 18.6 49.7
Int. J Gynecol Obstet 2006 (Suppl 1)
Epithelial Ovarian CancerMilestones
• Surgery according to FIGO guidelines
• At least LNS and peritoneal staging in early ovarian cancer
• Upfront maximal surgical debulking in advanced ovarian cancer
• Chemotherapy evolution
• Introduction of platinum compounds
• Introduction of taxanes
• The set-up of the GCIG in 1997
ARE THERE ANY NEW DEVELOPMENTS IN EARLY OVARIAN CANCER?FIGO I-IIA
• Grade and complete staging are strongest prognostic factors
• Low risk patients do not need chemotherapy as an adjuvant treatment (5-yr survival ≥ 95%)
• High-risk patients do need adjuvant platinum-based chemotherapy: combined analysis of ICON-1 and ACTION trial* showed 5-yr OS 82%vs 74%, p=.008 no significant difference in outcome, but recurrence rate with 6 cycles was 24% lower than with 3 cycles, and significantly more toxicity
*Trimbos et al, JNCI 2003Bell et al, Gynecol Oncol 2006
NEW DATA FOR ADVANCED OVARIAN CANCER
• NACT an alternative for not optimal resectable FIGO IIIc (Vergote et al, NEJM 2010)
• No benefit from adding a third drug to TC
• No role for consolidation/maintenance cytotoxic CT?1 study positive for PFS (12 vs 3 cycles paclitaxel PFS 28 vs 21 months, p<.005): Markman et al, JCO 2003)
• Dose dense TC superior (JGOG study)Confirmatory studies ongoing
• IP therapy finally recognized
MRC CHORUS
24.5 months
76% 1yr
survival
70% 1yr
survival
22.5 months
Primary sx
Adjuvant chemo
NACT
IDS
Bulky disease
Median age = 65
Treatment
35% OptDebulk
92% home 14/7
StgIII/IV
Surgery outcome OS
N= 550 randomised
25% % Stg IV Same chemo delivery
15% OptDebulk
78% home 14/7
MITO-7 TRIAL DESIGN
Phase I/II trial of weekly taxol MSKCC (fennelly D et al : J Clin Oncol 1996)
Aim of the trial is to compare the quality of life and PFS
1st -line advanced ovarian, tubal and peritoneal cancer
RANDOMISE
Carboplatin AUC 2
Paclitaxel 60 mg/m2
day 1,8 15 - every 21days
Carboplatin AUC 6
Paclitaxel 175 mg/m2
day 1 - every 21days
MITO – 7 PFS
MITO-7 QOL BETTER
MITO-7 OVERALL SURVIVAL
CLASSICAL ANTI-CANCER DRUGS VS NEW TARGETED AGENTS
• The new targeted anticancer agents are designed to target specific molecules which are considered crucial in specific pathways (e.g. growth regulation, DNA-repair, angiogenesis, invasion and metastasis)
Mechanism of action defined before their design
Highly selective therapeutic target
Patients selected for the target
Molecular rationale for associations of different agents
Targeted Therapies in Ovarian Cancer
Target Drug(s)
ErbB kinases Gefitinib, erlotinib, lapatinib, canertinib, cetuximab,
pertuzumab, matuzumab, trastuzumab
MUC1 / PEM Pemtumomab
MUC16 (CA 125) Oregovomab
mTOR / AKT Temsirolimus, everolimus, deforolimus
Apoptosis pathway AEG35156, OGX-011
Angiogenesis Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib
Endothelial cells Combretastatin, Oxi4503
Matrix metalloproteinases BAY 12-9566, marimastat
FIRST-LINE TRIAL OF BEVACIZUMAB IN OVARIAN CANCER (GOG#218)
Stage III°
Optimal and
Suboptimal or
Stage IV
R
A
N
D
O
M
I
Z
E
Paclitaxel/Carbo (PC) + placebo x6
placebo x16
PC+bev* x6 placebo x16
PC+bev x6 bev x16
*Dose of bevacizumab 15 mg/kg q 3 weeks
°Total number of patients 2000
KEY RESULTSTHERE IS CLEAR CLINICAL EFFECT OF BEVACIZUMAB ON PFS
• Per protocol analysis:
• Significant improvement of PFS in Arm III only
• Per protocol analysis: 3.8 mo increase PFS (med)HR 0.717, p <0.0001
• ~ half of all progression events occurred on therapy
Pro
po
rtio
n s
urv
ivin
g p
rog
ressio
n f
ree
Months from randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
+ BEV (Arm
II)
Chemo (Arm I)
+ BEV → BEV maintenance (Arm
III)
• CA 125 censored PFS (sensitivity analysis):
– Similar outcomes (HR 0.645), but 25% fewer events
GOG 218
FIRST-LINE TRIAL OF BEVACIZUMAB IN OVARIAN CANCER (ICON - 7)
Stage Ic - IV°
Excluding those scheduled for further surgery
R
A
N
D
O
M
I
Z
E
Paclitaxel/Carbo (PC)
PC+bev* x6 bev x12
*Dose of bevacizumab 7.5 mg/kg q 3 weeks
°Total number of patients 1500
ICON-7: PFS
http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf
Accessed 15 October 2010
Academic analysis
Number at riskControl 234 205 98 36 14 2Research 231 213 159 56 10 1
PFS: FIGO STAGE III SUBOPTIMAL AND FIGO STAGE IV WITH DEBULKING
1.00
0.75
0.50
0.25
0
Pro
porti
on
ali
ve w
ith
ou
t p
ro
gressio
n
Time (months)0 3 6 9 12 15 18 21 24 27 30
Control
(n=234)
Research
(n=231)
Events, n (%) 173 (74) 158 (68)
Median, months 10.5 15.9
Log-rank test p<0.001
Hazard ratio (95% CI) 0.68 (0.55–0.85)
Restricted mean 13.3 16.5
10.5 15.9
ControlResearch
http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf
Accessed 15 October 2010
Kristensen G. et al, ASCO 2011, abstract #LBA5006
RECURRENT OVARIAN CANCER: IMPORTANT ISSUES
• Presentation (asymptomatic 55-70%; TFI*)
• Realistic goals
• When to treat
• How to treat
• New combinations and compounds
*<6 months; 6-12 months; <12 months
REALISTIC GOALS OF SECOND-LINE THERAPY IN OVARIAN CANCER
• Improve cancer-related symptoms
• Optimize overall quality of life
• Delay time to symptomatic disease progression
• Prolong overall survival
• Achieve an “objective response”
Markman M, 2002
Harries and Gore, 2002
WHEN TO TREAT?
Ovarian Ca…Conclusions
• Upfront surgery followed by 6 cycles of Pt-Tax-based CT is still standard
• Paclitaxel + carboplatin (TC) generally agreed standard arm for trials
• NACT followed by surgery in stages IIIc-IV OC showed the same OS and PFS as PDS with less morbidity in one large randomized GCIG trial.
• A dose-dense therapy approach may be of benefit
• Intraperitoneal chemotherapy suitable for selected patients
• Targeted therapy is promising, in particular anti-angiogenic approaches, however cost effectiveness questions remain.
The Physician’s Dilemma
To standardize? To individualize ?
This is the question!