"Researchers mined insurance claims for 3,526 women who had intravenous
chemotherapy for breast cancer and tallied problems serious enough to
require emergency care or a hospital stay."
They found:  "Overall, 16% of women in the new study had at least one of
eight side effects that required emergency care or hospitalization. Side
effects also included blood clots, dehydration, nausea and diarrhea."

An editorial in the same journal issue immediately caught our attention
since the authors, Dr. John K. Erban and Dr. Joseph Lau,  begin with an
affirmation of the Hippocratic Oath.

"Perhaps the most important message is not specific to chemotherapy at all,
but instead is a warning that as we enter the new era of targeted therapies,
we must be especially vigilant for the potential of late adverse effects."

The problem with clinical trials:
"Despite its low sensitivity in detecting harms, the randomized controlled
trial design remains an important source of safety information because it
has the potential to provide the most reliable evidence of relative harms if
the events are relatively frequent and if the study is properly designed to
capture these events. The poor reporting of harms data in clinical trials is
a widespread problem in many areas, including oncology. The need for
standards of reporting of clinical trials harms data is well recognized, and
such standards have been proposed. Effort should be directed at establishing
standards of reporting and collection of this information from future breast
cancer clinical trials."

The sobering informed acknowledgement is as follows:
"Breast cancer treatment recommendations derive largely from
population-based studies. Because the survival benefit of a few percentage
points estimated by these studies may be offset by acute, chronic, and
late-onset toxicities, it is important to be aware that events such as heart
attacks and hip fractures may not emerge for years or even decades after
treatment. The inability of our well-designed studies to detect uncommon
(less than one in 1000) acute yet important, or even fatal, adverse effects
serves as a reminder that clinical trials data are only an estimate of the
worth of a drug and that healthy skepticism and diligent reporting of
potential toxicities should continue even after an agent enters general
use."

The editorial authors then cite a provocative question raised in a 1983
article–"If nothing goes wrong, is everything all right? Interpreting zero
numerators." 
Clinical trials are simply not designed to detect the wrongs that occur long
after the trial termination.
Thus, their conclusion is: "In the case of cancer therapeutics and toxicity
data reporting, the answer must be a qualified "no."

How then, do FDA officials justify their most recent data analysis of
antidepressants and emergent suicidal behavior in clinical trials?
These officials eliminated from their analysis the rock bottom minimal time
frame during which such life-threatening adverse effects occurred. 
Stay tuned for further details.

Contact: Vera Hassner Sharav
veracare@ahrp.org
 
 
http://www.latimes.com/features/printedition/health/la-he-chemotherapy21aug2
1,1,2440078.story?coll=la-headlines-pe-health
 From Reuters 
 Chemo may exact a greater toll
 In a study of breast cancer patients, the side effects are more
serious than earlier thought.
 August 21, 2006
 
 Chemotherapy drugs may cause more serious side effects for breast
cancer patients younger than 64 than once thought, according to a study
released last week.
 
 Researchers mined insurance claims for 3,526 women who had
intravenous chemotherapy for breast cancer and tallied problems serious
enough to require emergency care or a hospital stay. Their review found more
than 8% of women underwent treatment for a fever or infection compared with
less than 2% reported in an earlier review of clinical trials.
 
 Other problems also occurred more frequently than previously
estimated, according to the study, which was conducted by researchers at
Harvard Medical School and the Dana-Farber Cancer Institute.
 
 For example, 5.5% of women were reported to have low blood counts
that could raise the risk of infection or bleeding, the study showed. The
rates were less than 1% or 2% in clinical trials.
 
 Overall, 16% of women in the new study had at least one of eight
side effects that required emergency care or hospitalization. Side effects
also included blood clots, dehydration, nausea and diarrhea. All of the
women were 63 or younger.
 
 Researchers did not see any evidence that the side effects shortened
lifespan, said lead author Dr. Michael Hassett, a researcher at
Dana-Farber’s Center for Outcomes and Policy Research.
 
 But the findings could help women individually weigh risks versus
chances of benefit. Not all women are helped by adding chemotherapy to
surgery and other measures.
 
 "Our results don’t change the benefits of chemotherapy:. We still
think chemo can improve survival" for many women, Hassett said.
 
 The women in the new study were treated with various intravenous
drugs in families known as alkylating agents, anthracyclines, taxanes and
anti-metabolites. The information came from insurance claims filed between
1998 and 2002, before some newer drugs were available.
 
 Chemotherapy’s side effects can be minimized through steps such as
prescribing blood-cell-boosting drugs or nutritional supplements, said Dr.
Edgar Staren, chief medical officer at Cancer Treatment Centers of America.
"It’s important we make sure [patients] know the various options available."

 The study (Hassett M  ,O’Malley A ,Pakes J,Newhouse J,Earle C;)
Frequency and Cost of Chemotherapy-Related Serious Adverse Effects in a
Population Sample of Women With Breast Cancer, was funded by the Agency for
Healthcare Research and Quality, and published in the Journal of the
National Cancer Institute.

 
http://jncicancerspectrum.oxfordjournals.org/cgi/content/abstract/jnci;98/16/1108
                      
Journal of the National Cancer Institute, Vol. 98, No. 16,
1096-1097, August 16, 2006
 EDITORIAL
 On the Toxicity of Chemotherapy for Breast Cancer-the Need for Vigilance

John K. Erban, Joseph Lau

 Primum non nocere, "First, do no harm" is a central tenet guiding
medical practice. To know whether a prescribed treatment may cause harm and
to assess that quality that has been referred to by the National Surgical
Adjuvant Breast and Bowel Project and others as the "worth" of a treatment,
clinicians depend on well-designed clinical trials. The function of such
trials should be to estimate worth by carefully weighing the difference
between the potential benefit and the potential harm of a treatment.
However, clinical trials in cancer are usually powered to assess endpoints
such as disease-free and overall survival, rather than the toxicities of
interventions. Thus, trial design often precludes precise quantification of
infrequent toxicities. Furthermore, even in well-designed trials, toxicity
reporting is often incomplete, uncertain, or truncated at the reporting of
the primary endpoint.

 The article by Hassett and colleagues (1
<http://jncicancerspectrum.oxfordjournals.org/cgi/content/full/jnci;98/16/10
96#BIB1> ) in this issue of the JNCI describes an important effort to
understand whether toxicity data reported in clinical trials of chemotherapy
for breast cancer therapy reflect the experiences of relatively young women
(?63 years of age) in the general population who undergo similar treatment.
The authors used medical claims and diagnostic codes to determine the
frequencies of various toxicities attributable to breast cancer chemotherapy
and compared the frequencies of these toxicities in a chemotherapy-treated
cohort with those in a propensity score-adjusted cohort of breast cancer
patients who did not receive chemotherapy. Imbalances that might have
influenced the frequency of toxic events were adjusted to the extent
possible, but small differences remained between the two groups. The
frequencies in the treated and untreated cohorts of toxicities that are not
traditionally associated with chemotherapy such as fractures, asthma, kidney
disease, back pain, and thyroid disorders were also compared.

 Not surprisingly, the frequency of chemotherapy-related toxicities
was greater among chemotherapy recipients, but there was no difference in
the frequency of nonrelated toxicities between recipients and nonrecipients.
Increased toxicities in chemotherapy recipients entailed substantial
incremental costs for this group of patients and considerable additional
cost per affected person. Several toxicities appeared to be substantially
more frequent than what was reported previously in randomized controlled
trials (2 ). Adding to the importance of this study is the fact that it is
the first to assess toxicities in a younger population of breast cancer
patients. Younger patients are frequently offered chemotherapy in the
adjuvant setting, and though improvements in survival may be below 5%, women
will often accept chemotherapy for as little as a 1%-2% survival advantage
(3).

 The conclusions about the frequency and cost of chemotherapy-related
toxicities are important and intriguing, but the methodology used deserves
comment. First, the raw data were derived from employer-provided health
insurance claims and coding information; other sources or direct observation
were not used. Thus, certain socioeconomic groups are likely to have been
excluded outright, and the racial distribution was unknown and unlikely to
represent the population as a whole. Underrepresentation of certain
populations has also been shown to exist within NCI-sponsored trials (4),
and this study does not address this particular question either. The authors
do not comment on the question of whether toxicity incidence and reporting
may differ among ethnic groups. Second, due to the imbalance between the
groups that did or did not receive chemotherapy, equalization by generation
of a propensity score model was required, and the validity of this model is
key to the reliability of the conclusions. Importantly, the authors compared
the data generated by including only those chemotherapy patients for whom
matched controls were available with data generated by including all
chemotherapy patients and found no differences.

 Regardless of these methodologic issues, this study found a much
higher frequency of chemotherapy-related toxicities than did NCI-sponsored
and other well-conducted randomized controlled trials. For this reason,
there are several important messages implicit in this article. One is the
need to continue to develop patient-specific predictive instruments (5)to
focus the use of therapeutic drugs and the supportive treatments that
accompany the drug therapies. As therapy becomes increasingly tailored to
individuals, population-based recommendations will become less widely used,
and thus, the potential for indiscriminate toxicity will be reduced. Another
important message is that trial data are only approximations of risk that
may underestimate the true likelihood of an adverse event.

 Perhaps the most important message is not specific to chemotherapy
at all, but instead is a warning that as we enter the new era of targeted
therapies, we must be especially vigilant for the potential of late adverse
effects. Newer molecular therapeutics are increasingly effective against
breast cancer and less toxic in the short term. Thus, the medical barriers
to their use are coming down. The experience with traztuzumab and aromatase
inhibitors, drugs that are important in the adjuvant setting to prevent
breast cancer recurrence, illustrates these trends. As new drugs of
increasing efficacy and few acute toxicities emerge, the tendency will be to
push them to market, and there will be few incentives for longer term
toxicity studies. After all, the primary endpoints in trials will continue
to be disease-free and overall survival in the shorter term. Without careful
long-term tracking of late adverse effects, there is a risk that very
important toxicity events will occur unnoticed. Moreover, current trial
design is incapable of assessing the toxicities that may occur from rapid
sequential use of novel agents.

 Some in the medical community have already pointed out the potential
for long-term toxicities posed by novel therapeutics. For example, in an
editorial accompanying an article recently published in the New England
Journal of Medicine comparing letrozole to tamoxifen for adjuvant treatment
of hormone receptor-positive breast cancer, Swain emphasizes the need to
continue to be observant for any potential cardiac differences that may
emerge with time (6). For young survivors of breast cancer, cardiovascular
events and bone health are two important areas in which meticulous tracking
of long-term toxicity of new drugs in ongoing trials is necessary if we are
to know how to advise practitioners and patients on best practices for the
future.

 Despite its low sensitivity in detecting harms, the randomized
controlled trial design remains an important source of safety information
because it has the potential to provide the most reliable evidence of
relative harms if the events are relatively frequent and if the study is
properly designed to capture these events. The poor reporting of harms data
in clinical trials is a widespread problem in many areas, including
oncology. The need for standards of reporting of clinical trials harms data
is well recognized, and such standards have been proposed (8) Effort should
be directed at establishing standards of reporting and collection of this
information from future breast cancer clinical trials (7)

 Breast cancer treatment recommendations derive largely from
population-based studies. Because the survival benefit of a few percentage
points estimated by these studies may be offset by acute, chronic, and
late-onset toxicities, it is important to be aware that events such as heart
attacks and hip fractures may not emerge for years or even decades after
treatment. The inability of our well-designed studies to detect uncommon
(less than one in 1000) acute yet important, or even fatal, adverse effects
(9) serves as a reminder that clinical trials data are only an estimate of
the worth of a drug and that healthy skepticism and diligent reporting of
potential toxicities should continue even after an agent enters general use.
Thus, it is useful to remember the provocative question raised by Hanley and
Lippman-Hand with the title of their 1983 article "If nothing goes wrong, is
everything all right? Interpreting zero numerators" (10)In the case of
cancer therapeutics and toxicity data reporting, the answer must be a
qualified "no."

 REFERENCES

  (1) Hassett MJ, O’Malley AJ, Pakes JR, Newhouse JP, Earle
CC. Frequency and cost of chemotherapy-related serious adverse events in a
population sample of women with breast cancer. J Natl Cancer Inst
2006;98:1108-17.[Abstract/Free Full Text]
<http://jncicancerspectrum.oxfordjournals.org/cgi/ijlink?linkType=ABST&journ
alCode=jnci&resid=98/16/1108>

 (2) Shapiro CL, Recht A. Side effects of adjuvant treatment of
breast cancer. N Engl J Med 2001;334:1997-2008.

 (3) Simes R, Coates A. Patient preferences for adjuvant chemotherapy
of early breast cancer: how much benefit is needed? J Natl Cancer Inst
Monogr 2001;30:146-52.

 (4) Murthy VH, Krumholz HM, Gross CP. Participation in cancer
clinical trials. JAMA 2002;291:2720-6.

 (5) Savvides P, Terrin N, Erban J, Selker HP. Development and
validation of a patient-specific predictive instrument for the need for dose
reduction in chemotherapy for breast cancer: a potential decision aid for
the use of myeloid growth factors. Support Care Cancer 2003;11:313-20.[ISI]
<http://jncicancerspectrum.oxfordjournals.org/cgi/external_ref?access_num=00
0183194400007&link_type=ISI> [Medline]
<http://jncicancerspectrum.oxfordjournals.org/cgi/external_ref?access_num=12
720075&link_type=MED>

 (6) Swain SM. Aromatase inhibitors-a triumph of translational
oncology. N Engl J Med 2005;353:2807-9.[Free Full Text]
<http://jncicancerspectrum.oxfordjournals.org/cgi/ijlink?linkType=FULL&journ
alCode=nejm&resid=353/26/2807>

 (7) Trotti A, Bentzen SM. The need for adverse effects reporting
standards in oncology clinical trials. J Clin Oncol 2004;22:19-22.[Free Full
Text]
<http://jncicancerspectrum.oxfordjournals.org/cgi/ijlink?linkType=FULL&journ
alCode=jco&resid=22/1/19>

 (8) Ioannidis JP, Evans SJ, Gotzsche PC, O’Neill RT, Altman DG,
Schulz K, et al. Better reporting of harms in randomized trials: an
extension of the CONSORT statement. Ann Intern Med
2004;141:781-8.[Abstract/Free Full Text]
<http://jncicancerspectrum.oxfordjournals.org/cgi/ijlink?linkType=ABST&journ
alCode=annintmed&resid=141/10/781>

 (9) Ioannidis J, Lau J. Completeness of safety reporting in
randomized trials: an evaluation of 7 medical areas. JAMA
2001;285:437-43.[Abstract/Free Full Text]
<http://jncicancerspectrum.oxfordjournals.org/cgi/ijlink?linkType=ABST&journ
alCode=jama&resid=285/4/437>

 (10) Hanley JA, Lippman-Hand A. If nothing goes wrong, is everything
all right? Interpreting zero numerators. JAMA 1983;249:1743-5.[CrossRef]
<http://jncicancerspectrum.oxfordjournals.org/cgi/external_ref?access_num=10
.1001/jama.249.13.1743&link_type=DOI> [ISI]
<http://jncicancerspectrum.oxfordjournals.org/cgi/external_ref?access_num=A1
983QH56700020&link_type=ISI> [Medline]
<http://jncicancerspectrum.oxfordjournals.org/cgi/external_ref?access_num=68
27763&link_type=MED>

 Affiliations of authors: Division of Hematology-Oncology (JKE) and
Institute for Clinical Research and Health Policy Studies (JL), Tufts-New
England Medical Center, Boston, MA

 Correspondence to: Joseph Lau, MD, Institute for Clinical Research
and Health Policy Studies, Tufts-New England Medical Center, 750 Washington
Street, Box 63, Boston, MA 02111 (e-mail: JLau1@tufts-nemc.org ).

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