studies in nsclc based on gender and smoking differences: rationale and outcomes silvia novello...
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Studies in NSCLC Based on Gender and Smoking
Differences: Rationale and Outcomes
Silvia Novello University of Turin Thoracic Oncology Unit
www.oncologiapolmonare.it [email protected]
www.womenagainstlungcancer.eusilvia.novello@[email protected]
Males
Rat
e p
er 1
00,0
00 M
ales
Year of Death
Rat
e p
er 1
00,0
00 F
emal
es
Year of Death1930 1950 1970 1990
Lung & BronchusStomachColon & RectumProstateLiver
1930 1950 1970 1990 2004
LeukemiaPancreas
Females
Annual Age-Adjusted Cancer Death Rates Among Males/Females
for Selected Cancer Types, US, 1930-2004
Colon & RectumStomachOvaryUterusBreastLung & BronchusPancreas
CA Cancer J Clin 2004; 54:9-15
20040
20
40
60
80
100
0
20
40
60
80
100
Lung & Bronchus
Lung & Bronchus
Lopez et al, Tobacco Control 1994
Smoke kills about 50% of smokers: there are 3-4 Smoke kills about 50% of smokers: there are 3-4 decades between prevalence peak and mortality decades between prevalence peak and mortality peak for lung cancerpeak for lung cancer
Model of Smoking Epidemic
Lifetime Probability of Developing Cancer
1997-2001
All sites 1 in 3
Breast 1 in 7
Lung & bronchus 1 in 18
All sites 1 in 2
Prostate 1 in 6
Lung & bronchus1 in 13
Site Risk Site Risk
ACS, 2005
11,3
14,6
9,9
25,5
3,9 3,4
6,78,1
0
10
20
30
Squamouscell
SCLC Adeno-carcinoma
Large cell
Men
Women
Rela
tive R
isk R
ati
oR
ela
tive R
isk R
ati
o
HistologyHistology
Khuder, Lung Cancer, 2001
Meta-Analysis of 28 Lung Cancer Studies*
Relative Risk Ratios for Ever Smokers
Meta-Analysis of 28 Lung Cancer Studies*
Relative Risk Ratios for Ever Smokers
* 27 case-control
Women and Lung Cancer Risk (smokers vs non-smokers)
Author Study Men Women n.cigarettesRisch case- 9.6 27.9 40 packs/yrAm J Epidemiol ’93 control
Zhang case- 11.6 21.4 40 packs/yrJ Natl Cancer Inst ’96 control
Harris case- 24.5 42 40 packs/yrInt J Epidemiol ’93 control
Bach cohort no differenceJ Natl Cancer Inst ’03
Bain cohort no difference J Natl Cancer Inst ‘04
• Female smokers are more likely to develop adenocarcinoma than squamous cell carcinoma Thun MJ et al:JNCI 1997; Fu JB et al: Chest 2005; Patel JD et al: JCO 2005
• Never-smokers with lung cancer have adenocarcinoma and are 2.5 times more likely to be females than males
Wong MP et al: Cancer 2003
• The BAC is two to four times more common among women than among men Thun MJ et al:JNCI 1997; Radzikowska E et al: Ann Oncol 2002; Fu JB et al: Chest 2005
• In some Asian countries never-smokers account for 70% of women with lung cancer Wong MP et al: Cancer 2003
Women and Lung Cancer
• DNA repair capacity
• Gender differences in metabolism of carcinogens
• Differences in proliferation/growth stimulation (GRPR)
• Hormonal interactions
• DNA repair capacity
• Gender differences in metabolism of carcinogens
• Differences in proliferation/growth stimulation (GRPR)
• Hormonal interactions
Some Suggested ExplanationsSome Suggested Explanations
DNA Repair Capacity
Host Cell Reactivation Assay
Benzo[a]pyrene
TestLymphocytes
Acetyl -Chloramphenicol
+ .Acetyl CoA
+ Chloramphenicol
+ .Acetyl CoA
+ Chloramphenicol
DRC and Risk of Lung Cancer
DRC (median)> 8.1 1.0 < 8.1 1.5 (1.2,
1.9)Smoking Status
Never 1.8 (1.0, 3.3) Former 1.4 (1.0, 1.9) Current 1.6 (1.2, 2.3)
DRC (median)> 8.1 1.0 < 8.1 1.5 (1.2,
1.9)Smoking Status
Never 1.8 (1.0, 3.3) Former 1.4 (1.0, 1.9) Current 1.6 (1.2, 2.3)
Variable Adjusted OR(95% CI) Variable Adjusted OR(95% CI)
Spitz et al, CEBP, 2003
n = 764 cases and 677 controls
Age (years) < 60 128 7.6 ± 2.8
60 - 69 123 8.2 ± 3.2 0.05 70 65 8.5 ± 3.2
GenderMale 402 8.2 ± 2.8 < 0.001
Female 362 7.5 ± 2.8
Age (years) < 60 128 7.6 ± 2.8
60 - 69 123 8.2 ± 3.2 0.05 70 65 8.5 ± 3.2
GenderMale 402 8.2 ± 2.8 < 0.001
Female 362 7.5 ± 2.8
Variable No Mean % p-valueSD for trend
Variable No Mean % p-valueSD for trend
DNA Repair CapacityLung Cancer Cases
Spitz, CEBP, 2003
Age (yrs)
< 60 109 100.8 ± 94.6 0.05
61+ 112 85.8 ± 83.6
Gender
Male 114 100.1 ± 89.1 NSFemale 107 85.8 ± 89.4
Smoking status Never 21 103.7 ±101.6 NS Former 8587.1 ± 75.0 Current 11595.8 ± 97.0
Age (yrs)
< 60 109 100.8 ± 94.6 0.05
61+ 112 85.8 ± 83.6
Gender
Male 114 100.1 ± 89.1 NSFemale 107 85.8 ± 89.4
Smoking status Never 21 103.7 ±101.6 NS Former 8587.1 ± 75.0 Current 11595.8 ± 97.0
Variable N Mean(%)SD P valueVariable N Mean(%)SD P value
Induced Adduct LevelsLung Cancer Cases
Li et al, Cancer Res 2001Li et al, Cancer Res 2001
Gender differences in metabolism of carcinogens
CYP1A1• CYPA1 codes for an enzyme which activates PAH-
forming DNA adducts. • Significant correlation between CYP1A1 expression
and DNA adduct levels (r= 0.50, p= 0.016)• Female smokers had significantly higher levels of
adducts/pack-year and adducts/cigarette/day than men (1.49 + 1.29 vs. 0.89 + 0.74, P= 0.015)
• Females had higher CYP1A1 levels than males (494 + 334 units vs. 210 + 208 units, P= 0.016)
Mollerup, et al; Cancer Res; 1999: 59: 3317-20
Gender differences in metabolism of carcinogens
Glutathione S-transferase (GST)
Odds ratio for GSTM1 null phenotype and WT
Female (CI)
Male (CI)
Lung cancer2.50
(1.09-5.72)1.40
(0.58 - 3.38)
Lung cancer in smokers
3.03 (1.09 -8.40)
1.42 (.053-4.06)
•GST deactivates carcinogens; the null genotype fails to deactivate carcinogens, resulting in prolonged exposure•GSTM1 null genotype associated with lung cancer (odds ratio: 2.04)
Tang, et al; Carcinogenesis, 19: 1949-1953, 1998
• Gastrin-Releasing Peptide (GRP): plays a role in neoplasia by stimulating cell proliferation. Its effect is mediated mainlythrough the GRPR.
• The gene for GRPR is X-linked, located on chromosome Xp22, near a cluster of genes that escape X-inactivation.
• Women can have two actively transcribed alleles compared with only one in men
• Increased expression of the GRPR gene was noted when human airway cells were exposed to oestrogens.
Differences in proliferation/growth stimulationGRP
Shriver SP 2000, JNCI
Differences in proliferation/growth stimulation
EGFR
CharacteristicsPatients with
mutation/total
In unselected pts
Adenocarcinoma
14/182 (8%)
15/152 (10%)
Women with adenocarcinoma
12/83 (15%)
Women non-smokers with adenocarcinoma
18/34 (53%)
ASCO 2004
Hormonal Interactions
• Early age at menopause (≤ 40 yrs) is associated with reduced risk of lung adenocarcinoma (OR=0.3)
• HRT is associated with risk of adenocarcinoma (OR=1.7)
• Interaction between HRT, smoking and the development of lung adenocarcinoma (OR=32.4)
Taioli and Wynder:JNCI 1994
• Late menopause and short menstrual cycles were associated with increased risk of lung cancer
Siegfried JM: The Lancet Oncology 2001
risk of lung carcinoma in women with family history of reproductive cancer
Sellers: Genetic Epidem 1991
β-estradiol inducesproliferation in NSCLC cells and anti-estrogens block this effect
Kiuper, Endocrinology 1997
Oestrogens may be involved in lung tumorigenesis at different levels:• As ER ligands activating cell proliferation
• Via ERs in the plasma membrane causing interactions between ERs and growth factors such as EGF and IGF (in EGFR and ER+ cells)
• Oestrogens may alter metabolic activation of carcinogens (modulations of CY1A1, CY1B1) Stabile: Cancer Res 2005
Hormonal Interactions
Cross-Talk Cascade of ER Activation IGFR
PlasmaMembrane
Cytoplasm
Akt
SOS
P
P
P
P
MAPK
MEK
Nucleus
p90RSK
p160ERER CBP
BasalTranscription
Machinery
ERE
P P P
ER Target Gene Transcription
P
P
P
P
RAS
RAFPI3-K
PP
P
Growth factors
Estrogen
ER
EGFR / HER2
AI
MoAb
TKI
FTI
CCI
CellGrowth
Cell Survival
Tamoxifen
SERD
Johnston, S. 2004
Decreased Cell Proliferation in Lung Tumors Treated with Gefitinib and
Fulvestrant
Rela
tive K
i67 E
xp
ressio
n
0
20
Treatments
control fulvestrant fulvestrant +gefitinib
gefitinib
40
60
80
100
120
*
**
**
Stabile, et al. Cancer Res, 2005
P-value compared to control: *<0.05, **<0.005
UW/UPitt Pilot Study of Gefitinib + Faslodex in Post-menopausal Women with Advanced
Recurrent NSCLC
• Eligibility: 2 or more prior chemo regimens• Treatment: 250 mg gefitinib + 250 mg
Faslodex IM monthly• Objectives: response rate, TTP, survival• Laboratory Objectives:
- ER and EGFr- CYP3A polymorphisms
Traynor AM, Schiller J, JCO 2005
Hormone Replacement Therapy and Lung Cancer Risk
Some positive
Type of Study
NRisk of lung Ca
with HRT95% CI
Taioli, JNCI, 1994
Case control
180 1.7 1.0-2.8
•All studies derived from secondary data or exploratory analysis
Hormone Replacement Therapy and Lung Cancer Risk
Some show no increase in risk
Type of Study NRisk of lung Ca with
HRT95% CI
Adams,Int J Cancer, 1989
Cohort study 23,244 1.3 0.9-1.7
Wu, Cancer Res, 1998
Case control 336 1.3 0.71-1.53
Women's Health Initiative, JAMA, 2002
Cohort 16,690 1.04 0.71-1.53
Blackman, Pharmacoepidemiol Drug Saf, 2002
Case Control 662 1.0
All studies derived from secondary data or exploratory analysis
Hormone Replacement Therapy and Lung Cancer Risk
Some show REDUCED risk of lung cancer with HRT
Type of study
NRisk of lung Ca
with HRT95% CI
Ettinger, Ob Gynecol, 1996
454 0.78 0.04-1.15
Krenzer, 1993
Case control
1723 0.83 0.64-1.09
Olson, Ob Gyne, 1993
Cohort 29,508 0.24 0.08-0.76
Schabath, Clin Ca Res, 2004
Case Control
1008 0.66 0.51 - 0.89
All studies derived from secondary data or exploratory analysis
Sex as a predictive factor
Study N Unfavorable in
Multivariate Analysis
Radzikowska (1995-98) 20,561 Male, poor PS, advancedPolish population, all stage, non surgical
treatment, >50 yrs, SCLC
Ouellete (1988-90) 208 Male, advanced stageFrench population, cohort
Moore (1974-98) 7,613 Male, age >65, advancedSingle institution, all stage, large cell, no surgery
Visbal (1997-2000) 4,618 Male, older age, high grade,Single institution, advanced stage, treatment,consecutive cohort adenocarcinoma**smoking status/dose, comorbidy interaction with cause of death, not significant
Relative risk (RR) of death for MEN = 1.15 (p=0.001)
NO differences in overall mean survival
BUT women lived longer at each stageOverall median survival 12.4 mo vs 10.3mo (p<.001) and survival advantage for all stages
RR for MEN= 1.2
NSCLC: completely resected diseases
NSCLC: completely resected diseases
Author # Women Survival
MinamiR (#1242 consec.1984-1998)
[adavntage also for st I &III,adenoca & > 60yrs]
FergusonR (#451)
1980-1998
AlexiouP (#833)
UK 1990-2000
337
186
252
5yr 69% p<.005
st I OS 109vs50 mo p .008
5yr 48%vs36.5% p<0.01
OS p 0.0006
NSCLC: completely resected diseases
Bouchardy, et al. Cancer, 1999
EVEN CONSIDERING OTHER DEATH
CAUSES
2.1
ALPI Multivariate AnalysisALPI Multivariate Analysis
Variable HR 95% CI P Value
Age (5-yr interval)
1.06 1.00-1.12
.051
Stage II III
2.003.15
1.6-2.52.6-3.9
.0001
.0001
Histology-Squamous
0.86 0.7-1.0 .094
Gender – Male(86%)
1.32 1.0-1.7 .034
Complete Dissection
0.89 0.8-1.1 .164
Chemotherapy 0.96 0.8-1.1 .566
Scagliotti GVS, JNCI 2003Similar Data from UFT, Kato et al.
NSCLC: locally advanced disease
Werner WasikR (RTOG)- #1,999- 9 studies
OS 11.4 vs 9.9 mo
AlbainP (SWOG)- #126- st IIIA, IIIB
OS 21 vs 12 mo (p0.08)
AlbainP (RTOG 93-09)-#429 (35%)- st IIIA
> OS in women(p=0.051)
NSCLC: advanced disease*
Favourable factors inGroup N Stage multivariate analysis
MemorialR 378 IIIB/IV Women, normal LDH ,(O’Connell et al) good PS, no bone mts, ≤ 2 sites mts
ECOGR 893 IV Women, PS 0, no bone mts,
(Finkelstein et al) no liver mts,
7 trialsno weight loss,
non-large cell istol.
SWOGR 2,290 IV Women, PS 0-1, (Albain et al) “cisplatin-based”
therapy,13 trials age ≤ 70 yrs
male female P Value
MULTIVARIATE
median survival 8.8 mo 12.4 mo 0.001
*first and second generation chemotherapy
male female P ValueMULTIVARIAT
E
1 yr survival rate
16% 26% 0.005
Women is a strong indipendent factor for improved survival
ECOG 1594
Study # PtsSt. IV,
%ORR,%
MST (mos.)
G4ANC,
%
G4Plts,
%
G> 3Neuro,
%
ECOG 1594DDP-TAXDDP-GEMDDP-TXTCb-TAX
292288293290
9121.32117.3
15.3
8.18.17.48.3
57 394943
22912
59510
HA Wakelee JTO 2006
Patient outcomes for ECOG 1594
N=1157Women (433)
Men (726) P value
Response rate (%)Median PFS (mo)Median survival time (mo)
193.8
9.2 mo
193.57.3
0.990.0220.004
- Separately for each arm, trend for improved survival mantained; statistical significance was LOST
HA Wakelee JTO 2006
Toxicity all grade in ECOG 1594
N=1157Women (431)
Men (726)
P value
Nausea (%)Vomiting (%)Alopecia (%)Neurosensory (%)Neuropsychiatric (%)Cardiac Toxicity ≥ g3 (%)
83656449224.1
70525342147.6
<0.0001<0.00010.00030.020.0010.02
HA Wakelee JTO 2006
Bevacizumab in Advanced NSCLC: Efficacy by Gender
Brahmer et al. J Clin Oncol. 2006;24(No 18S):373s. Abstract 7036.
ParameterMales Females
PC (n=230)
PCB (n=191)
PC(n=162)
PCB(n=190)
OS, mo 8.7 11.7* 13.1 13.3
PFS, mo 4.3 6.3* 5.3 6.2*
RR, % 16 29* 14 41*
No survival benefit for females despite 4-fold increase in RR and statistically significant difference for PFS
A number of potential explanations (eg, statistical chance, imbalance of unmeasured prognostic factors, or a true difference)
*Statistically significant
Survival by Treatment - Males
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
ba
bili
ty
0 6 12 18 24 30 36 42
PC (219 events/ 253 cases)PCB (158 events/ 210 cases)
P = 0.0010
Medians: 8.7, 11.7
J Brahmer ASCO 2006
Survival by Treatment - Females
J Brahmer ASCO 2006
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
ba
bili
ty
0 6 12 18 24 30 36 42
PC (125 events/ 180 cases)PCB (147 events/ 207 cases)
P = 0.87
Medians: 13.1, 13.3
Vandetanib 200 mgVandetanib 200 mgPaclitaxel 200 mg/mPaclitaxel 200 mg/m22
Carboplatin AUC 6 mg/mL·minCarboplatin AUC 6 mg/mL·min(n=15)(n=15)
Randomized PhaseRun-In Phase
Vandetanib 300 mgVandetanib 300 mgPaclitaxel 200 mg/mPaclitaxel 200 mg/m22
Carboplatin AUC 6 mg/mL·minCarboplatin AUC 6 mg/mL·min(n=10)(n=10)
Vandetanib 300 mgVandetanib 300 mg(n=73) (n=73) [discontinued][discontinued]
Vandetanib 300 mgVandetanib 300 mgPaclitaxel 200 mg/mPaclitaxel 200 mg/m22
Carboplatin AUC 6 mg/mL·minCarboplatin AUC 6 mg/mL·min(n=56)(n=56)
PlaceboPlaceboPaclitaxel 200 mg/mPaclitaxel 200 mg/m22
Carboplatin AUC 6 mg/mL·minCarboplatin AUC 6 mg/mL·min(n=52)(n=52)
Vandetanib (ZD6474) With Carboplatin and Paclitaxel
as First-Line NSCLC Therapy: Schema
Objectives:Objectives:Appropriate Dose in Combination Therapy, Appropriate Dose in Combination Therapy, Pharmacokinetics, SurvivalPharmacokinetics, Survival
Fir
st-L
ine
NS
CL
CF
irst
-Lin
e N
SC
LC
Fir
st-L
ine
NS
CL
CF
irst
-Lin
e N
SC
LC
Heymach et al., IASLC 2005, Abstract P-497Heymach et al., ASCO 2007, Abstract 7544
Vandetanib With Carboplatin and Paclitaxel (CP) as First-Line NSCLC Therapy: Efficacy
Vandetanib/CP
n = 56
Placebo/CP
n = 52
HR P Value
ORR 32% 25% - -
Median OS 10.2 months 11.9 months 1.07 .595
Median PFS 24.0 weeks 23.1 weeks 0.76 .098*
Exploratory Analysis (females)
n = 17 n = 15
Median PFS 28.6 weeks 11.7 weeks 0.47 .037
Median OS ≥ 8.6 months 5.8 months 0.52 .113
Heymach et al., ASCO 2007, Abstract 7544*Met prespecified significance level of P < .2
No significant differences in PFS or OS based on histology were observed.
ZD6474 plus docetaxel vs docetaxel in previously treated NSCLC
A randomized, double-blind, two-part, multicenter study
2nd
-lin
e N
SC
LC
ZD6474 100 mgDocetaxel 75 mg/m2
n=4
Randomized phase*Run-in phase
2nd
-lin
e N
SC
LC
ZD6474 100 mgDocetaxel 75 mg/m2
n=42
PlaceboDocetaxel 75 mg/m2
n=41
ZD6474 300 mgDocetaxel 75 mg/m2
n=11
ZD6474 300 mgDocetaxel 75 mg/m2
n=44
JV Heymach, ASCO 2006
0.25 0.5 1.0 2.0 4.0
Time to progression
Time to death
Males vs females: exploratory analysis
Hazard ratios and 95% confidence intervals
0.25 0.5 1.0 2.0 4.0
Males
Females
All patients
ZD6474 100 mg + doc (n=42) vs placebo + doc (n=41)
ZD6474 300 mg + doc (n=44) vs placebo + doc (n=41)
ZD6474 100 mg + doc (n=42) vs placebo + doc (n=41)
ZD6474 300 mg + doc (n=44) vs placebo + doc (n=41)
JV Heymach, ASCO 2006
• Work better in women than men
• Gefitinib and erlotinib studies: females RR, more symptom improvement, longer OS (univariate), but no difference in benefit phase III study erlotinib
• Biologic basis for difference by sex complex: interactions with frequency of activating mutations, EGFR+ (by IHC/amplification), adenocarcinoma or BAC histology, non-smoking status
EGFR Tyrosine Kinase Inhibitors Second and Third Line Therapy
EGFR Tyrosine Kinase Inhibitors
• Female sex is predictive of response: - Symptoms improvement: 50% vs 31% (p
0.006) - Radiographic regression: 19% vs 3%
(p=0.001) with 82% of responses among women
Kris MG, JAMA 2003
BR.21 Trial: Overall Survival by Gender
SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0025
Female/OSI-774 Female/PlaceboMale/OSI-774 Male/Placebo
Perc
enta
ge
0
20
40
60
80
100
Time (months) # At Risk(Female/OSI-774) # At Risk(Female/Placebo) # At Risk(Male/OSI-774) # At Risk(Male/Placebo)
0.017383
315160
10.0752711332
20.03292
30.00000
_____ Erlotinib Female
_____ Placebo Female
_____ Erlotinib Male
_____ Placebo Male
Months
Interaction p = n.s.
Shepherd, NEJM, 2005
Is there an interaction between the ER and EGFr pathways?
•EGFR protein expression is down-regulated in response to estrogen
•EGFR protein expression is up-regulated when estrogen is depleted
•Suggests “cross-talk” between these two pathways
Paclitaxel Poliglumex (PPX)
• Macromolecule that combines paclitaxel with poly-L- glutamic acid
• Into the cell broken in its active form by cathepsin B (regulated by estrogen) minimize systemic exposure & prolong exposure to active drug
ELIGIBILITY CRITERIA
chemonaive
advanced NSCLC
PS2
STRATIFIED BY
disease stage
sex
brain mts
geography
STELLAR 3
PPX 210 mg/mq + CBDCA AUC6 Q3w
versus
Paclitaxel 225 mg/mq + CBDCA AUC 6 Q3w
STELLAR 4
PPX 175 mg/mq Q3w
versus
GMC 1200 mg/mq d1,8,15 Q4w OR NVB 30 mg/mq d 1,8,15 Q3w
Ross H, ASCO 2006
-The composite analysis of STELLAR 3 and 4 shows a statistically significant survival benefit for women receiving PPX (p=0.03)
-The presence of estrogen appear to make PPX a more effective drug
-PIONEER (Paclitaxel Poliglumex Investigating Outcomes in NSCLC: Establishig Estrogen Response) study is ongoing
Favourable factors in Group N Multivariate analysis
Danish 443 Cox: women, good PS,
(Osterlind et al) normal sodium e uric acid
CALGB R 1745 Cox: women, good PS, (Spiegelman et al) age <60 yrs
SWOG R 1,316 Cox: women, PS 0-1, caucasian,(Albain et al) conc. CT/RT, LDH
1,137 RPA: women, LDH nn,
no pleural effusion,age<70 yrs
SCLC: limited disease
Albain (10 SWOG trials from 1976 to1988)
male female
MST
LD
ED
17.7mo
no
24.4mo
differences
Singh, S. et al. J Clin Oncol; 23:850-856 2005
Small Cell Lung Cancer Survival by Sex: retrospective review (4 trials)
SCLC: Toxicity and outcomes by sex
• No difference in treatment delivered or toxic deaths, but greater treatment delays in females, with more toxicity (anemia, neutropenia, stomatitis, emesis)
• Greater toxicity females significant in multivariate model
• Females RR higher and overall survival (p<.0001)
1006 Patients (648 m, 358 f)
on 4 trials of similar chemotherapy
Singh, S. et al. J Clin Oncol; 23:850-856 2005
Conclusion• A better understating of the genetic, metabolic, and
hormonal factors in women represents a research priority
• Evidence suggests that the development of lung cancer is different in women compared with men
• Women with lung cancer live longer than men with
lung cancer, regardless of therapy and stage
• Sex as stratification factor in prospective clinical trials