MS LUKE: This 61-year-old woman was
diagnosed during a routine screening mammogram with a 1.9-centimeter, poorly differentiated invasive ductal carcinoma with
involved margins and one positive lymph
node. The tumor was ER/PR-positive and
HER2-negative. A second surgical intervention was done to clear the margins, and
this was followed by local radiation therapy.
The patient has a family history of breast
cancer, with a 38-year-old daughter diagnosed a few years ago and a paternal aunt
also with a history of breast cancer. She is
an independent, headstrong woman who
made it clear during our first meeting that
she did not want chemotherapy.
DR LOVE: What was that based on?
MS LUKE: She saw her daughter and aunt
go through chemotherapy, and those were
vivid memories for her. Her daughter is still
NED and received AC for four cycles.
DR LOVE: What specifically happened
with her daughter, and what problems
occurred with the chemotherapy?
MS LUKE: Nausea, vomiting, hair loss,
fatigue, a change in her body image and
disassociation from family involvement.
The daughter, at the time, had a two-year-old little girl at home.
DR LOVE: Can you tell us more about the
patient?
MS LUKE: She is married and recently
retired. Her husband was trying to be as
supportive of his wife as he could, while
also expressing the fact that it was difficult
for both of them to have seen their daughter
go through diagnosis and treatment.
DR LOVE: In your practice in these kinds
of situations, do you offer patients specific
numbers about their risk of recurrence and
how that’s affected by therapy? A lot of
people use Peter Ravdin’s Adjuvant! Online
model (Olivotto 2005). Do you generally
use that?
MS LUKE: My colleague and I use Adjuvant! Online, and we went through that
process with this patient.
DR LOVE: Gary, globally, for a patient
with one positive node and ER/PR-positive, HER2-negative disease, what would
you roughly calculate the risk for recurrence to be, and how might that be affected
by chemotherapy and hormonal therapy?
DR LYMAN: Although it’s just barely a T1
tumor, there is a positive node, and she is
clearly at risk, and we would want to offer
her adjuvant options.
In this setting, particularly with strong
reluctance to consider chemotherapy, we
do believe we have a fallback position with
adjuvant hormonal therapy, but I would
present to the patient the real risk of
recurrence.
We give a range of numbers that would
probably incorporate about 20 to 30 percent
risk of recurrence over a five-to 10-year
period, even with hormonal therapy.
I think you have to be honest with patients.
Each one belongs to one of the following
groups: Those who aren’t going to experience recurrence even if they don’t take chemotherapy, those who are going to experience recurrence even if they do take it,
and those who will avoid recurrence by
receiving chemotherapy. We cannot tell her which of these groups she falls into; therefore, you have to offer treatment for the
possibility that she is in the third group.
DR LOVE: What if the patient tried to pin
you down and said, “Okay, you’re saying
it’s a 20 to 30 percent chance of recurrence,
but what will it be if I take chemotherapy?”
DR LYMAN: That cuts right to the chase
and assumes she will receive hormone
therapy. Generally, the benefit of chemotherapy in this situation is small. Depending
on the circumstances, it may be as little as
two to three or four percent.
Is it worth going through four, six, eight
cycles of adjuvant chemotherapy, losing
your hair and going through the various
toxicities for that gain?
Patient surveys suggest that many patients
are willing — in fact, anxious — to be
offered any possibility of preventing recurrent disease, even down to a one percent
margin, despite the toxicities. Some patients
feel that their quality of life will be too
adversely affected and will choose not to
do it.
It sounds as if she may be one of those
patients and has already thought through
some of those issues. You still need to
present a range of numbers and your recommendation, and then, of course, she
makes the choice.
DR LOVE: Chuck, what kind of numbers
would you present to her in terms of risk
of recurrence, despite hormonal therapy,
and how might that be affected by chemotherapy?
DR VOGEL: I have an advantage here
because yesterday I saw a virtually identical
patient for a consultation. She was a 66-year-old woman and had a poorly differentiated tumor. I ran Adjuvant! Online, and I
know the numbers.
DR LOVE: What are they?
DR VOGEL: The numbers are a 57 percent
likelihood of being alive and free of disease
at 10 years with no therapy, so a 43 percent
chance of relapse. We presuppose, of course,
that she will need radiation therapy. I
bypass the tamoxifen part of Adjuvant!
Online because I use up-front aromatase
inhibitors (AIs). The AI would give her
17 percent absolute benefit, which would
bring her up to 74 percent chance of being
alive and free of disease.
DR LOVE: Or a 26 percent recurrence rate
even with an AI.
DR VOGEL: Correct. And if you were to
give her AC times four or CMF times six,
you would increase that by two percent. If
you were to give her third-generation chemotherapy, you would increase it by seven
percent.
DR LOVE: So the numbers are similar to
what Gary pulled off the top of his head.
DR VOGEL: Correct.
DR LOVE: We’re going to stay focused on
the issue of chemotherapy, but as a footnote, Gary, has it also been your practice to
switch from using tamoxifen, as a routine,
to aromatase inhibitors in postmenopausal
women receiving adjuvant therapy?
DR LYMAN: Yes, it has. Some low-risk situations may occur in which we’ll continue
to use tamoxifen, particularly if evidence of
bone loss or osteopenia or actual osteoporosis is documented.
In the usual setting for a postmenopausal
woman with one or more significant risk
factors, we do encourage use of an aromatase inhibitor. With proper monitoring, our
experience with the aromatase inhibitors
is favorable.
DR LOVE: Ms Luke, can you talk a little
bit more about how she reacted to some of
these numbers?
MS LUKE: At first, she was shocked
when we reviewed the numbers from the
Adjuvant! Online website (adjuvantonline.com). The interesting twist on the
discussion with this patient was that her
husband insisted she go back and talk to her
daughter and that the three of them discuss
the situation at more length before the
patient made a decision.
DR LOVE: One node doesn’t sound too
bad, but the numbers — a 50-50 chance of
recurrence without treatment — suggest a
high-risk situation.
MS LUKE: Right, and I think she
thought, “Well, with local radiation
therapy, that should be sufficient.”
About a week or so later we got a phone
call from the patient, who said she wanted
to come in with her daughter. In the course
of the discussion with her family, she had
changed her mind.
I think the daughter — having gone
through that experience and now being
on the other side — was able to make the
patient see a different point of view. The
patient is still a young 61-year-old woman
with no comorbid complications, and she
could possibly have another 20 to 30 years
of life.
DR LOVE: So now the patient is open to
receiving chemotherapy, and the question
is, what type? Chuck, what are some of the
options you think would be reasonable in
this situation?
DR VOGEL: Four options are most supportable by studies with Level 1 evidence
(1.1). One is the dose-dense AC followed
by paclitaxel regimen (Citron 2003; Hudis
2005). Second would be TAC, including
docetaxel (Martin 2005a). A third option
would be that of the PACS-01 study from
France, FEC times three followed by
docetaxel times three (Roche 2004). The
fourth option is a newcomer to the field,
and that’s the GEICAM study from Spain.
Miguel Martin presented it at San Antonio,
using FEC followed by weekly paclitaxel
(Martin 2005b).
DR LOVE: Gary, all four of those regimens
have in common a taxane and an anthracycline. We know from our Patterns of Care
studies that patients with node-positive
disease are receiving these kinds of therapies. Is that your practice also?
DR LYMAN: Absolutely. In some low-risk,
node-negative settings, we may just administer four cycles of AC, but for patients
with node-positive disease, we always add
a taxane to the regimen and discuss the
various regimens, all of which are supported by good evidence that they affect
disease-free survival.
DR LOVE: If this woman asks you,
“Which one of the available regimens is the
most likely to prevent me from having a
recurrence?” how do you answer?
DR LYMAN: Head-to-head comparison of
these regimens is limited. They’re all active
and they’re all toxic and will need aggressive supportive care to accompany them.
If she leaves it to our recommendation, we
will go with the ones with which we have
the most familiarity and, therefore, the
greatest comfort.
That’s usually dose-dense ACT or TAC.
Those regimens are being used at my institution at probably a two-to-one ratio, and
both are accompanied by growth factor
support.
DR LOVE: Again from Patterns of Care
studies, we know that, at least right now,
dose-dense
AC
paclitaxel administered
every two weeks with growth factors is the
most common regimen used for patients
with node-positive disease in the United
States.
Chuck, what’s your usual, preferred
regimen in this situation?
DR VOGEL: We published on TAC
and have extensive experience with that
regimen and feel comfortable with it. Some
patients have a hard time with TAC, but in
our hands, those are the minority.
Larry Norton frequently speaks about
considering dose-dense AC followed by
paclitaxel not as dose-dense but as “toxicity-reducing” therapy. However, there is
a concern about the dose-dense regimen
in this situation, although it’s based on
unplanned, retrospective subset analyses.
This patient has ER-positive disease, and
a diminishing rate of effectiveness seems
to occur with the dose-dense regimen in
ER-positive patients, with all of the caveats
about retrospective and subset analyses.
DR LOVE: The ER-positive status of this
patient’s tumor is one of the interesting
issues with this case and one of the biggest
controversies going on right now in adjuvant chemotherapy. Gary, we’re hearing
more and more about this issue of trying to
evaluate the effect of chemotherapy based
on estrogen receptor status. What’s your
take on that at this point?
DR LYMAN: I agree with Chuck and think
it is a reason for continued follow-up of
these patients. We still recommend dose-dense treatment in this setting. It does have
some advantages, particularly the low rates
of toxicity, so that’s still one of our main
front-line regimens, even in the ER-positive group of patients.
DR LOVE: What about the use of growth
factors with TAC? How do you approach
that, Chuck?
DR VOGEL: I’ve never used TAC without
growth factor support. From the beginning,
when we first presented our data, a 24
percent rate of febrile neutropenia was just
not acceptable, so I’ve always used growth
factor support.
With the current availability of pegfilgrastim, it’s a “no-brainer” to prescribe it.
We now know from Miguel Martin’s analysis of a node-negative TAC versus FAC
study that by giving prophylactic white-cell
growth factor support, the febrile neutropenia rate can be reduced from 24 percent
to, in his study, 3.5 percent.
DR LYMAN: I wanted to make an additional point about TAC and growth factor
support. We’ve been following — through
our national prospective registry that was
instituted in 2002 — the use of supportive
therapies on various adjuvant regimens.
A comparative group in Europe has been
running the same registry across six major
countries, and use of growth factor support
with TAC there is in the range of 80 to
90 percent. We don’t find those numbers
in the United States. When we began our
registry, only about 25 percent of patients
receiving TAC were reported to receive
growth factor support.
Now that has increased to the range of
40 to 50 percent, but it’s certainly not 80
to 100 percent, as you’d think would be
the case given the high level of toxicity
with that regimen. Obviously, emphasis
on growth factor support is increasing, but
many patients appear to be receiving TAC
adjuvantly without growth factor support in
the United States.
DR LOVE: Chuck mentioned the issue of
the cost of using growth factors. What do
we know about the financial “play-out” of
using growth factors? For example, with
TAC, obviously, you’re preventing febrile
neutropenia hospitalizations. Has that been
evaluated?
DR LYMAN: We’ve done a number of economic analyses, most recently focusing on
pegfilgrastim (Cosler 2005). Our earlier
analyses go back almost a decade.
Our more recent analysis in the adjuvant
setting demonstrates a break-even cost
threshold — at which you begin to save
money with growth factor support — with
a febrile neutropenia risk in the area of 20
percent. Reducing hospitalizations counterbalances the cost of the growth factors.
These data, of course, were fed into the
National Comprehensive Cancer Network
(NCCN) guidelines process (NCCN
Practice Guidelines in Oncology Version
2.2005).
A year ago, when we generated the NCCN
myeloid growth factor guidelines (1.2), the
group decided that the economic data were
supportive, but they felt the main reason
they needed to define a threshold was based
on evidence of clinical benefit.
Chuck’s study of primary pegfilgrastim
prophylaxis in patients with breast cancer
demonstrated that with a regimen with
a risk around 20 percent — I think the
actual risk was about 17 percent — the risk
of febrile neutropenia was dramatically
reduced if patients received primary prophylaxis with growth factors. So it’s clinically effective in that range.
Our economic numbers just provide a
little “icing on the cake” that you’re not
spending too much when you do that
because you are preventing a costly, life-threatening toxicity with these growth
factors. I should mention that ASCO is still
going through revisions of their guidelines, which have been in place for about a
decade.
So, in terms of up-to-date guidelines,
we have the NCCN guidelines (Lyman
2005a). The EORTC will be coming out
with guidelines early this year that will
probably be similar to the NCCN, which
says that higher than 20 percent consider
primary prophylaxis routinely (1.2).
In the 10 to 20 percent range, the intermediate-risk range, the NCCN guidelines
emphasize how important it is to evaluate
and assess risk factors for these complications in individual patients. Usually, the
thresholds are determined by the published
risk in a given regimen, but we know that
TAC and other regimens behave differently
in different patients.
If you have a regimen with which you’re
in that intermediate-risk area, it is important to consider the individual patient. If
the patient is elderly, is frail and has various
comorbidities, she is not likely to do well
with febrile neutropenia, and you may want
to use growth factor prophylaxis in regimens with published risk in the 10 to 20
percent range.
At less than 10 percent, which we considered low risk, these growth factors play no
routine role, but in the 10 to 20 percent
range, the primary emphasis is on individualization of care. We hope in the future to
base these assessments on objective models
that we’re working on and attempting to
validate (Lyman 2005b; Wolff 2005).
As with Adjuvant! Online, you can plug in
the patient’s characteristics and come out
with an individualization of risk and an
objective quantification of that risk.
DR LOVE: Putting aside the cost and the
social implications of the cost, how would
you respond to a healthy, younger person
who is about to receive AC and asks you
about the chance of developing febrile neutropenia if she receives growth factors?
DR LYMAN: We don’t know. At ASCO,
we presented an updated meta-analysis of
all the prophylactic growth factor trials —
approximately 17 trials — and we don’t see
a bottom risk below which growth factors
don’t work (Kuderer 2005; [1.3]). Historically, filgrastim risk reduction has been
around 50 percent, but Chuck’s data with
pegfilgrastim demonstrated more than a 90
percent relative risk reduction. It may be
that the longer-acting growth factors are
somewhat more potent.
I’m sure risk is reduced, whether it’s from
10 percent to five percent or three percent
or two percent. But the counterargument is that 90 percent of those patients
are receiving growth factor support, and
they wouldn’t develop febrile neutropenia
anyway.
DR LOVE: Chuck, can you talk about your
study? It has certainly changed the way
people view chemotherapy in the adjuvant
setting.
DR VOGEL: The study involved first-cycle use of docetaxel and open-label pegfilgrastim (Vogel 2005; [1.4]). The results
were striking. They showed a 17 percent
risk of febrile neutropenia if you didn’t
receive pegfilgrastim and a one percent risk
if you did receive it, and they showed a 14
percent versus a one percent risk of hospitalization. It was a gratifying result.
DR LOVE: What percentage of those
patients received therapy for metastatic
disease versus adjuvantly?
DR VOGEL: It was 30 percent adjuvant, 70
percent metastatic.
DR LOVE: For AC followed by docetaxel,
when docetaxel is used in the adjuvant
setting, it is generally dosed at 100 mg/m2.
In that situation, do you think that growth
factor support should be used during the
docetaxel?
DR VOGEL: Definitely.
DR LOVE: What about growth factors
with AC?
DR VOGEL: We haven’t had much of a
problem with febrile neutropenia during
AC. A tendency has emerged, based on
the dose-dense experience, to say, “Well, if
we’re going to administer AC, we can dose
densify it, add a dose of pegfilgrastim and
administer it every two weeks.”
For those people who are using AC followed by docetaxel — which, incidentally,
has no Level 1 evidence behind it at the
moment — you could use it that way. The
BCIRG 005 trial, randomizing between
TAC and AC followed by docetaxel, should
provide an answer (Eiermann 2005).
DR LOVE: Do you offer growth factors to
your patients who receive AC?
DR VOGEL: I do because I usually dose
densify AC.
DR LOVE: Let’s hear some more about
what happened with this patient.
MS LUKE: After the discussion with her
daughter and husband and our going over,
again, the choices that she had for treatment, she chose to go with TAC for six
cycles. I believe her daughter helped her with that decision.
DR LOVE: What was her greatest concern
about the chemotherapy?
MS LUKE: Loss of her hair, nausea and
vomiting. This is a woman who comes
into the office well dressed and well put
together. She values her self-image. I
counseled her right away to get fitted for
a wig, so we could match her hair color
and texture before we started the chemotherapy. Through the American Cancer
Society, I set her up with a support group,
and they have some self-image classes that
she also attended.
DR LOVE: So she got started on the TAC;
then what happened?
MS LUKE: She got started on the TAC
and had some nausea and mild vomiting.
She felt a little tired, but overall, she felt
fairly well. On day eight of the first cycle
she came into the office for an issue not
related to chemotherapy. My oncologist
colleague decided to do a CBC on her that
day, and we found her to be neutropenic,
with an ANC count of 400/mm3, despite
receiving growth factor support.
DR LOVE: Chuck, what would you have
done?
DR VOGEL: I would put her on prophylactic antibiotics. I know that’s a “no-no” in
a lot of practices, but I would do that. The
question is, should you expect this neutropenia? Pegfilgrastim will not absolutely
abrogate the nadir. It decreases the length
of the nadir.
So I would expect her to have virtually
no white cells on day eight; it’s just that
the duration is short. However, as long as I
knew this lab result, I probably would have
put her on prophylactic antibiotics to try to
keep her out of the hospital.
DR LOVE: How low would the count
have to be for you to use antibiotics in an
asymptomatic patient?
DR VOGEL: Less than 500/mm3.
DR LOVE: Gary?
DR LYMAN: I would have examined her
and, if there were no sign of infection, I
would have told her to go home and to call
me if she develops a fever and wasn’t feeling
well. I wouldn’t have used prophylactic
antibiotics, but some of my colleagues do.
More often, we consider that if they fall
below 200/mm3 of absolute neutrophils.
Even there, I think a real concern remains
about emerging fluoroquinolone resistance.
A recent Italian study published in The New
England Journal of Medicine, albeit with more
patients with leukemia, lymphoma and
transplants, saw significant increases in both
gram-positive and gram-negative fluoroquinolone resistance among those receiving
prophylaxis for infection going through
chemotherapy with a fluoroquinolone
(Bucaneve 2005). So we would often wait
until the ANC fell lower.
I agree with Chuck. This decrease is to be
expected. Patients’ counts fall, and some
become neutropenic. You shouldn’t panic.
You shouldn’t add filgrastim to the regimen
at that point because the pegfilgrastim is
still in the serum. It’s still working, and
hopefully, the duration of neutropenia will
be short.
DR LOVE: Ms Luke, what did you do?
MS LUKE: The patient was examined
and did not have any signs or symptoms of
an infectious process at the time, but we
did treat her prophylactically with antibiotics. By the time she came back for cycle
number two, her neutrophil count had
completely recovered.
DR LOVE: Chuck, at that point, what
would you do in terms of chemotherapy
dosing?
DR VOGEL: I’d readminister at the same
dose level.
DR LOVE: Would you tell her not to get a
white count on day eight?
DR VOGEL: I don’t do interim counts if
I’m giving pegfilgrastim.
DR LOVE: Gary, same question: Would
you continue at the same chemotherapy
dose?
DR LYMAN: I would continue at the
same dose, along with pegfilgrastim, and I
don’t check the counts. I do reiterate to the
patient, “Call me if you develop a fever or
if you feel chilled or if you feel ill, but otherwise, go about your business.”
DR LOVE: We’ve had this concept, Gary,
of the importance of delivering the planned
dose of chemotherapy on time. In the adjuvant setting, we’re going for cure. How
much data do we have supporting the idea
that dose delivered makes a difference?
DR LYMAN: Unfortunately, evidence is
sparse, and I think everybody would agree
with that. Most oncologists believe in the
concept of delivering the planned dose on
time. Even in the metastatic disease setting,
a dose-response relationship exists.
Obviously, in the adjuvant setting, at some
level of dose reduction you lose the benefit
completely. We know adjuvant therapy
works, but we don’t know where the break
point is at which you lose the benefit.
DR LOVE: Ms Luke, can you follow up on
what happened?
MS LUKE: She has now gone through
four cycles of TAC and she’s having a lot of
problems with dry eyes and skin rash. She
continues to receive growth factor support,
as she did on cycle one.
DR LOVE: What’s her state of mind?
MS LUKE: She often calls with many
questions and complaints. She requires a lot
of psychosocial support by the staff.
DR LOVE: Do you think that she regrets taking chemotherapy or is thinking about
wanting to stop it?
MS LUKE: I know for a fact she’s thinking
about stopping the chemotherapy. I don’t
think she’ll go through all six cycles. She
finished cycle four about a week ago, and
she’s almost ready to come in and receive
cycle number five.
I know quality of life is important to her,
so I think we’ll probably end up splitting
the difference at five.
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