WHI Trial (Writing Group for the WHI Investigators; JAMA)
What was the main objective of the WHI study?
Assesment of the most commonly used combined hormone preparation in the US for health benefits and risks
When and why was the subject enrollmentstopped early (specific statistical reason)?
After 5.2 years. This was due to harm from the breast cancer.
What was the design of the trial?
16608 postmenopausal women underwent the study over 8.5 years
Who monitored the “double-blind” data? How often?
Safety monitoring board.Monitored semiannually.
How many women: screened, randomized, assigned to either arm?
373092 – Screened, 16606 – Randomized, 8506 – Estrogen, 8102- Placebo
Why was the dose of E 0.625 mg/day and P 2.5 mg/day in a single tablet chosen?
Highest amount without damaging the subjects
Why was an “intact uterus” necessary for entry into the “main” study?
It was the main requirement of the drugs to work.
How was compliance measured?
Regular testing of subjects by the researchers.
At baseline, were there any significant differences between groups noted?
The effects on the trial group were significantly higher than the placebo group
Would you consider the two groups well-balanced?
Yes. Almost equal individuals.
The “Hazard Ratio” (Table 2) is the most important statistic to understand. HR greater than 1.0 means “WHAT”?HR less than 1.0 means WHAT?
Greater than 1 means more damage than benefit. Less than 1 means more benefits than damages.
What important differences in end points due to treatment group assignment were seen in Table 2? (Both “good” and “bad” differences due to E/P treatment.)
The HR for death was less than 1
According to Figure 3, which differences manifest themselvesearlier in the study? .later in the study?
Pulmonary embolism and Stroke
Why are the results of this trial “generally applicable to healthy women in this age range”?
The whole sample was comprised of women in this age bracket.
Which positive outcome, known to be related to HRT use, was expected in this trial? Why?
A balance of risks and benefits for hormone use.
Was the “absolute risk” attributable to HRT usage low or high? Explain.
High.there were more damages by use of HRT than benefits.
Does this study suggest that all postmenopausal women should stop using HRT?
Yes.
MWS - Endometrial and Breast Cancer (Million Women Study Collaborators)
What was the design of this trial?
716,738 postmenopausal women with no previous cancer under hormone replacement therapy over3-4 years.
What percentage of UK residents (of the appropriate age) enrolled for this trial?
1.14%
How did the relative risk of endometrial cancer vary among the 6 treatment groups?
They varied according to the women’s body-mass index.
Which group had the highest risk of developing endometrial cancer?
Obese women
In the group reporting the use of tibolone, what were the greatest (top 10) risk factors for the development of endometrial cancer?
Recency of use
Exclusiveness of Use
Duration of Use
Age at recruitment
Socioeconomic status
Past use of oral contraceptives
Body-mass index
Strenuous exercise
Alcohol consumption
How did obesity affect the incidence of developing endometrial cancer?
It increased the risk of endometrial cancer occurring.
What is believed to be the cause of the increasing incidence of endometrial cancer in obese women?
The higher risk of progenstagens counteracting with oestrogen.
How is “Breast Cancer Risk Related to the Interval Between Menopause and Starting HRT” (Beral et al)
The increase in progesterone-oestrogen increases risk of cancer.
What was the source of data collected in this report?
The clinical trial
How many women in total were recruited for the MWS?
716,738
Were the demographics of the three treatment groups similar?
No. There we differences in socioeconomic status.
Which HRT regimens increased the “RR” for breast cancer? List them in order of increasing RR?
Continuous
Cyclic
What does Figure 2 suggest?
The risk factors identified are significant in HRT among the postmenopausal women.
In terms of the clinical grade and histology of the breast tumors observed, how does treatment with E+P differ from treatment E only?
Progeterone counteracts the effects of oestrogens in the body
In terms of the age of first use, duration, and time between menopause and first use, how does the RR differ between E (only) and E+P treatment?
The earlier the age of use, period and time between menopause and first use, RR increases faster with the use of E than E+P
Is there a BMI influence on the RR between never users, current E, and current E+P users? Describe.
Yes. The BMI influences every aspect of this trial.
What is the “new finding of this study” which has not been investigated extensively, previously?
Oestrogen and Tribolone increase risk of endocrinal cancer
Alendronate and Fracture (Lieberman et al)
What was the design of this study?
Women were treated with placebo or alendronate and the effects observed by measuring bone mineral density.
Entry (inclusion and exclusion criteria) were?
Postmenopausal women with osteoporosis.
Were demographics similar among treatment groups? Describe.
Yes. The groups were random.
How did BMD change during the trial by treatment group at 4 different body locations?
There were no significant changes in all 4 body parts
How did the overall vertebral fracture rate change during the course of the trial? Was there an age covariate? Was the decrease in fracture rate similar in both sub-studies?
It droped by 1%. There was no age covariate. The decrease was uniform.
How was height affected during alendronate treatment?
There was a 3.0 mm average height loss.
So.is daily calcium a treatment for osteoporosis? Did daily treatmentwith calcium alone affect the rate of bone loss? (Be careful and specific)
Caliums is not sufficient on its own. It affected the rate but not to a sufficient level.
Were there trends in the rates of non-vertebral fractures? Describe.
The number reduced in the alendronate group.
Alendronate was the first oral drug approved for the prevention and treatment of osteoporosis. What single, prescribed drug (with little, unproven efficacy) was available prior to the approval of alendronate?
Teraparatide.
Oral Sildenafil for the Treatment of ED (Goldstein et al)
Prior to sildenafil, what were the available treatments for ED?
Alprostadil
Phosphodiesterase type % inhibitors
How does sildenafil (and the other, newer members of this class of drugs) work?
It contains enzymes which catalyze cyclic nucleotides and AMP and GMP.
What is the “Rigiscan”? How does it work? Are the results of the Rigiscan valid as endpoints in a clinical trial?
It measures the rigidity and tumescence of a penis. The measurements are valid in a study.
What were some of the inclusion and exclusion criteria for this study?
Gender: Male
Illness: Erectile Dysfunction
What was the study design?
24 week dose response study on 532 men taking oral sildenafil
Demographically, how did the treatment groups compare?
The demography was similar in all groups.
What is the IIEF? Which questions seemed most useful as endpoints?
IIEF: Inernational Index of Erectile Function.
How the increase or decrease of the dose affected erectile function.
What was the optimal dose for resolving ersctiledysfuction.
The IIEF is organized into 5 domains. How did these domain scores change over the course of treatment? Was the lack of change in the “Sexual Desire” domain expected? Why?
The domains increased across the board with the dose response study and decreased in the dose escalation study.
Yes. The drug in question does not have an effect on the psuchological aspect of desire.
What is priapism? Was it reported in the trial? Is it reported in the sildenafil label?
A state of an erect penis not returning to normal.
No incidence of priapism was reported
What were the major adverse effects observed in this trial?
Nausea and vomiting
Leg pain
Backache
Headache and Dyspepsia
SELECTED RETROSPECTIVE STUDIES
Cancer Statistics (Siegel et al)
Which databases supply the statistics for this publication?
National Cancer Institute of the National Institute of Health
Which are the top five cancers in terms of incidence in men and women?
Lung Cancer
Brain Cancer
Breast Cancer
Cervical Cancer
Prostate Cancer
Which are the top 5 cancers in men and women in terms of highest mortality?
Lung Cancer
Breast Cancer
Panctreatic cancer
Colorectal Cancer
Prostate Cancer
Could Table 2 be utilized for estimating “hot spots” for increased incidence of specific cancers?
Yes, the table could be use for identifying which areas are most affected by specific cancers.
What is the likelihood of a 60 year old women developing breast cancer? a60 yo male developing prostate cancer?
Men: 16.7%
Women: 3.56%
How were the numbers of new breast cancer and new melanoma cases estimated for 2012?
The numbers were estimated through a review of cancer statistics in various regions.
Why did the number of cases of prostate cancer spike upwards in the early 90’s?
Prostate cancer rose in the early 90’s due to an increase in unhealthy lifestyles such as eating junk foods.
Why is lung cancer for males on the decline while lung cancer for women is still rising or just beginning to descend?
Lung cancer for men is on the decline since the predisposing factors such as smoking have received widespread negative marketing. The same is, however, not the same for predisposing factors for cancer in women.
Which cancers (incidence and mortality) are significantly trending downward? ..upward?
Cancer of the bladder and pancreas have recorded a downward trend while breast cancer, colorectal cancer and lung cancer have been on the rise.
What issues drive the “regional variations in cancer rate? Explain.
The regional variations in the rate of cancer is influenced by ethnic, geographical and lifestyle factors.
Do different sections of the US have different incidences in specific cancers? Explain.
Different sections of the US have different incidences in specific cancers. For example, breast cancer is more prevalent in areas with larger black population. This difference is as a result of various geographical and cultural factors that are unique to each region.
Should we be worried about more lung cancer in Kentucky versus Utah, or more breast cancer in CT versus AZ?
This should not be a worrying factor since there are various factors in Kentucky and CT which predispose the residents to higher risks of various forms of cancer.
Does ethnicity play a role in cancer mortality? Explain.
Ethnicity plays a role in cancer mortality since it influences a person’s way of life; cancer is referred to as a lifestyle disease.
Are more adults surviving cancer today than in 1977? Explain.
More adults are surviving cancer today than in 1977 because of advances in medical research that allow doctors to detect the disease at its early stages.
Are more children surviving cancer today than in 1977? Explain.
The percentage of children surviving cancer was lower in 1977 than it is today. This is because in 1977, cancer was mainly prevalent among adults and not children.
Retrospective Data Analysis (slide presentation)
What trends may be seen in the NCI lung cancer figure?
The rates increased from 1975 to 1998 for men and then stated to decline.
The increase rate slowed down from 1998 for women but has continued to grow.
Why do the curves for male and female lung cancer mortality differ?
The male curve indicates a decline in number of incidences, while the female curve indicates a continued growth even though at a slower rate than before 1998.
What does the retrospective analysis of incident brain tumors tell us?
Brain tumors occurpredominantlyin adults. Adult non-malignant tumors are more than malignant tumors. Children malignant tumors are more than nonmalignant tumors.
How do adults and children differ in the incident of malignant and non-malignant brain tumors?
Adults have more nonmalignant tumors than malignant ones while the vice versa is true in children
What does the retrospective analysis of “what we eat” tell us?
The food we consume has a contribution to the increase or decrease of incidence of cancer.
The number of road accidents in the US has remained steady from 1990 to 2008
Which age groups in the US population should, perhaps, payhigherinsurancerates? .should perhaps have more driver training? .should perhaps be limited in driving (ie, late age for startingearlier age for stopping driving?
25 - 35 years: pay more insurance
20 - 24 years: More driver training
19 and below: Limited driving
How does the state of Arizona compare with the US in terms of fatalities?..in terms of alcohol-impaired fatalities?
The rate of road accidents in Arizona is above the national average.
Framingham Heart Study home page (http://www.framinghamheartstudy.org/about/history.html)
How did the study start? (Objectives, subjects, location, number of generations in the population, publications,)
Objective: to identify factors and charactersitics contributing to cardiovascular disease.
Subjects : 5209 men and women, Age: 30 – 52
Generations: 3
Location: Framingham, Massachusetts
Publications: 1200 articles
Using the Framingham risk calculators, calculate your risks for developing:
A Fib
Diabetes
Risk of hypertension
Risk of stroke
If your likelihood calculated is considered high, does this mean that you will develop the disease?
No. it is just a probability.
What are your comments on the data produced in the WHI E/P versus Placebo trial?
The data was significant to the research. The data collected from the respondents for the first five years was accurate. This is indicated by the fact that the safety monitoring board used the data to evaluate the status and impact of the study on the subjects. They concluded that the study was damaging to the subjects after analyzing the data collected for over five years.
The study was not completed as intended. As such, the data collection was not completed. Nevertheless, this did not compromise the data that had already been collected. The placebo group data was essential in measuring the effects of the drug in question.
In Jemal's manuscript, any suggestion why the trends for mortality due to lung cancer are so different when males are compared with females over the course of the last 20 years?
The difference in trends can be alluded to the fact that there are more male smokers than female ones. Smoking is identified as one of the leading causes of lung cancer, and hence it predisposes the male population to the illness.
