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7. Case Study
The Clinical Case
Finding a Clinical Trial
Sample Points to Discuss with the Patient Considering a Clinical Trial
Conclusion
Mr. Joe Smith, a 59-year-old African American male, presents to
his primary care physician, Dr. Bob Brown, in rural Wisconsin. He has
been complaining of difficulty with initiating urination and
frequency. He presents clinically with an abnormal rectal exam and an
elevated prostate-specific antigen (PSA) of 8 ng/ml (normal in a
59-year-old Black male is less than 4 ng/ml). Mr. Smith's mass is
biopsied and the results reveal a prostatic tumor. The nearest
comprehensive cancer center is 100 miles away, and Mr. Smith wants to
be treated by Dr. Brown. He says he wants to stay close to his home
and family, and does not want to be cared for by "those big city
doctors."
Mr. Smith decides to undergo a radical prostatectomy at his
community hospital. Surgery reveals a 1.5 cm tumor with clear
margins, negative pelvic node involvement, and unilateral seminal
vesicle involvement, which puts Mr. Smith at high risk for eventual
tumor spread. To complete his clinical staging, a bone scan and CT
scan are completed. Mr. Smith's tumor is formally staged. At his
3-month followup visit, post-operatively, his PSA is 0.2
(undetectable).
Dr. Brown closely follows Mr. Smith. Three years after his surgery
his PSA has slowly risen to 11, but his bone scan and CT scans remain
negative. Dr. Brown informs Mr. Smith that there are many clinical
trials for men with prostate cancer at all stages. He explains that
these trials are being conducted to try to find the best methods for
cancer prevention, early detection, and treatment. At this point in
his disease, Mr. Smith does not wish to consider a clinical trial, so
he continues to receive standard care. Dr. Brown recommends starting
standard treatment with hormone therapy injections monthly. The
patient's PSA drops to less than 0.2 again.
Two years later, the PSA begins to rise to 15 and a bone scan now
shows abnormal uptake in multiple ribs and the thoracic spine. Mr.
Smith is started on an anti-androgen drug and his PSA drops to 10 at
his 3-month followup visit. One year later his PSA has risen to 40,
and he now says he has mild rib pain. Dr. Brown explains to Mr. Smith
that he needs to consult with an oncologist from the cancer center,
Dr. Mary Jones, and that Mr. Smith may need to see her. Mr. Smith
somewhat reluctantly agrees to see Dr. Jones. Dr. Jones recommends
exploring available clinical trials because Mr. Smith is young, is in
good health with mild symptoms, and has a tumor that now appears to
be progressing.
How can Dr. Brown or Dr. Jones find an appropriate clinical trial
for Mr. Smith?
Dr. Jones decides to check NCI's PDQ system, because her center
has no active trials for prostate cancer. The PDQ system will allow
her to see current active clinical trials and their eligibility
criteria. (More information on PDQ.)
Dr. Jones uses the NCI PDQ system to assess what, if any, clinical
trials are available for Mr. Smith. Using the Internet, she accesses
the site as follows:
Enters the clinical trials section of Cancer.gov
Selects "Finding Clinical Trials"
Selects PDQ Search Form
Enters the relevant data; hits search (appropriate
studies will be retrieved)
Reviews the trials
If a physician does not have Internet access, how can he or she
find a trial?
Clinical trial information is always available through NCI's
Cancer Information Service (CIS) at 1-800-4-CANCER
(1-800-422-6237).
After reviewing available trials, Dr. Jones selects a phase 2
trial entitled: A Phase II Randomized Study of High-Dose Ketoconazole
With or Without Alendronate Sodium in Patients With Androgen
Independent Metastatic Adenocarcinoma of the Prostate (2001) to
discuss with Dr. Brown and Mr. Smith.
Mr. Smith is clinically eligible for the study. Participants are
randomized to one of two arms: 1) a single oral dose of ketoconazole
on day 1, and then 3 times daily oral dose beginning on day 8, versus
2) a single oral dose of alendronate sodium on day 1 and a single
oral dose of ketoconazole on day 3 and then daily alendronate sodium
and 3 times daily ketoconazole beginning on day 8. Participants who
experience a clinically complete remission (CR) receive treatment for
an additional 60 days beyond CR. Mr. Smith would have to be willing
to have followup visits at NIH in Bethesda, MD, every 2 months and be
seen in the NIH Cancer Center every 2 weeks for evaluation of
toxicity and drug tolerance.
Randomization
As a health care professional it is often challenging to discuss
the concept of randomization with patients. Patients can feel
threatened knowing that neither they, nor their doctor, can choose
what treatment they will get if they enter a randomized trial. They
may feel that the arm of the study that is standard care or closest
to standard care, is the best option. People may also be concerned
that if they enter a randomized clinical trial they will not receive
treatment; they may receive just a "sugar pill." How can they be
sure?
Dr. Jones began her discussion of randomization with Mr. Smith,
his wife, and their two grown sons by explaining that this study has
an objective group of professionals who monitor the study called a
data and safety monitoring board (DMSB). The DMSB evaluates the data
from the clinical trial to interpret if the therapy or technique
being studied appears to be better (more beneficial) or worse (more
harmful) than standard therapy. A trial can be halted early to allow
all participants access to a clearly more beneficial intervention, or
to protect participants from harm.
Dr. Jones explained that there are three phases for clinical
trials and that randomization is generally seen in phase 3 studies
where researchers are unsure whether a new intervention is better
than the currently accepted standard therapy for a specific cancer
type. She discussed how patients entering a phase 3 trial (and, as in
this case, some phase 2 trials) are randomly assigned to groups
(called randomization) and that neither the patients nor their
doctors choose which therapy or technique they will receive. This is
done because if physicians determined which therapy participants
would receive, there could be an unconscious bias in their
assignments. They could tend to assign patients with a more hopeful
prognosis to the experimental therapy group and make the new therapy
seem more effective than it really is. Similarly, if patients were
allowed to choose which therapy they would receive, the results could
also be influenced. Patients with a less hopeful prognosis could tend
to pick the experimental treatment, for example, which may lead that
treatment to look less effective than it really is.
Myths
Mr. Smith and his family have many questions regarding what they
have heard and read about clinical trials. How would you answer these
questions?
1. How do I know I am really safe if I enter this trial? You and I
both know there are bad feelings in our community about research.
Fact: Tragedies have occurred in the past related to
clinical trials. The African American community most notably
remembers the infamous Tuskegee syphilis study, which followed,
but did not treat, African American men with syphilis. There are
now strong safeguards in place to protect research participants
from the notorious human rights abuses of the past which include:
Government oversight and regulations
Institutional review board (IRB) review and approval
of a clinical trial before it begins and annually while it is
in progress
An informed consent process which gives potential
participants the information they need to decide about
participation, including foreseeable risks and benefits
Data and safety monitoring boards which ensure
minimization of risks, integrity of trial data, and oversight
to end a trial early if clear benefit or harm arises from the
intervention being studied (usually used in phase 3
studies)
2. Aren't these clinical trials only for dying cancer
patients?
Fact: Clinical trials are not just for patients with the
most advanced disease. In fact, many newly diagnosed cancer
patients participate in clinical trials. If only the sickest
patients participated in treatment trials, researchers would not
know how to treat patients with earlier stages of cancer. Phase 3
treatment includes all stages of cancer, from the most advanced to
the most localized. These trials enroll hundreds or thousands of
patients. Phase 1 and 2 cancer clinical trials, which enroll fewer
than 100 patients, seek people with few treatment options or
people who have exhausted all the current treatment options, which
is Mr. Smith's case.
3. Aren't people who join clinical trials just "guinea pigs" for
research?
Fact: People who decide to take part in a clinical trial
are called participants, and strict guidelines are in place to
ensure that these volunteers are treated as such:
A participant has the right to withdraw from a
trial at any time. The participant's decision does not
jeopardize his or her future treatment and he or she may
discuss further treatment options with the study physician or
be referred back to a primary care provider for standard care.
Although people fear that trial participants are
treated like guinea pigs, reports from actual trial
participants disagree. According to a Harris Poll conducted in
2000, the vast majority of trial participants said their
overall experience was positive. Ninety-seven percent said they
were treated with dignity and respect and that the quality of
care they received was "excellent" or "good." More than 80
percent said they did not receive more tests than they felt
were necessary and 86 percent said their treatment was covered
by insurance.
4. Mr. Smith's wife is very concerned that cancer patients who
join clinical treatment trials get a sugar pill (placebo) instead of
really being treated. Will my husband really get treatment?
Fact: In phase 3 cancer treatment trials, participants
with cancer get either a new treatment or the best standard
treatment. In phase 2 trials, like the one Mr. Smith is
considering, different schedules and combinations of two drugs are
being evaluated for their effectiveness. It is unethical to
deprive any person with a serious illness or condition of the best
available treatment. There would be no placebo involved in Mr.
Smith's treatment.
5. His oldest son is wondering if only people who have cancer can
participate in a clinical trial. Aren't my brother and I at higher
risk now?
Fact: Treatment and diagnostic trials are designed for
people who already have cancer; however, genetics, prevention, and
screening trials are designed for persons at risk of developing
cancer. This is relevant for Mr. Smith's sons who now have an
increased risk for prostate cancer. Dr. Jones suggests that the
sons make an appointment to discuss a cancer prevention clinical
trial.
Insurance
Dr. Brown is wondering whether participating in this cancer
clinical trial will cost Mr. Smith more than standard treatment. Will
insurance cover the costs?
The costs of new treatments for different cancers vary. Some
treatments under study cost no more than standard therapies. Others,
such as bone marrow transplants, are very expensive. There are
hundreds of insurance companies and managed care organizations in the
United States and each has a different policy about covering clinical
trial costs. In general, most companies have contract language that
prohibits coverage for "experimental therapies." However, decisions
are often made on a case-by-case basis, and costs for patient care in
clinical trials are often covered.
The best way to evaluate each situation is to ask questions such
as the following:
What will the total patient care costs be?
What parts of the treatment, if any, does the study
provide free of charge?
What parts of treatment must be paid for by the
participant or the participant's insurer?
What is the situation for people who have no health
insurance?
Will total patient charges be higher for a clinical
trial
than for standard care?
How often have insurers reimbursed all costs of the new
therapy?
Are there other resources or organizations that might
help cover the fees or provide services, such as free
transportation?
Another option is to discuss reimbursement issues with the
insurance company ahead of time. The company is unlikely to promise
coverage before the fact, but it may give information about general
policies and trends. In considering costs of out-of-town treatment or
follow-up care, patients should remember to include travel-related
costs. The research team conducting the study will know how many
times participants will need to visit, for how long, whether housing
or stipends will be provided, and whether participants will be
hospitalized during their stay.
After meeting with Dr. Jones and discussing their concerns, the
Smith family met with Dr. Brown to discuss his view of the trial. Mr.
Smith decided to enter the trial. After four months and his second
evaluation, his PSA has decreased to 14 ng/ml, and he has no bone
pain. He will continue for another cycle of therapy and be
reevaluated in 2 months. After his initial apprehension eased and
treatment began, Mr. Smith was able to verbalize satisfaction in both
his decision to enter the trial and in the level of care and
attention he received.
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