Hi again Andrea,
Sorry for the delay in answering your question. As usual, this isn't
a substitute for medical advice or direct professional evaluation and
treatment.
Let me summarize... Your sister is 38 and has breast cancer that was
initially staged as T3N0 infiltrating ductal and DCIS, ER-, PR-, HER2
3+ on immunohistochemistry (IHC). Her initial sentinel axillary lymph
node biopsy was negative. She then underwent chemo and radiation and,
6 months later, was found to have liver metastases. Since then, she
has had 8 months of Herceptin + Navalbin, however, her liver
metastases have not shown a favorable response.
As you likely know, this is a grave situation. One of the best
sources for overview of the latest medical literature is the Cochrane
Evidence Based Medicine Database of Systematic Reviews. Below, I have
referenced the direct Reviews, primarily intended for medical
professionals. You can also find (for free) online "plain language"
versions of these Reviews. Here is the list of topics relevant to
breast cancer:
http://www.cochrane.org/reviews/en/topics/52.html
There are several interesting topics listed at the above site that do
not have links. These are topics that are in progress that are not
yet complete or have not yet completed being reviewed by a panel of
experts. They should appear in the future.
As the authors of one ongoing review state, the literature on this topic is vast:
"There are over 800 references on the Cochrane Breast Cancer Group's
specialised register pertaining to randomised controlled trials of
chemotherapy for metastatic breast cancer. These trials evaluate
various combinations of drugs at varying doses and schedules. There is
a clear need to summarise this information to aid decision making when
chemotherapy is being considered for a woman with metastic breast
cancer."
Although it is an area of intense current research, there is
relatively little conclusive information for patients who have already
received the types of therapy your sister has been through. I will
review what information is available and attempt to tease out relevant
portions of information regarding experimental therapies. Because
your sister has already received chemotherapy, the next step, in terms
of chemotherapy, would be so-called salvage chemotherapy.
________________________
Most people agree that chemotherapy should be offered at some point to
women with metastatic breast cancer. Depending on what actual
chemotherapeutic agents were used in your sister's initial chemo,
there is some evidence to suggest that certain antibiotics with
anti-tumor properties can have some benefit in terms of increasing the
time to progression of the patient's disease. Unfortunately, these
treatment regimens have not been shown to improve overall survival.
"Antitumour antibiotics include the anthracyclines (eg. doxorubicin
and epirubicin); anthracenediones (mitoxantrone/mitozantrone); and
mitomycin-C. This class of drugs, in particular anthracycline-based
FAC (cyclophosphamide, 5-fluorouracil and doxorubicin) and FEC
(cyclophosphamide, 5-fluorouracil and epirubicin) regimens, have been
used in chemotherapy for the management of metastatic breast cancer
for the last three decades "
EBM Reviews - Cochrane Database of Systematic Reviews Lord, S. Ghersi,
D. Gattellari, M. Wortley, S. Wilcken, N. Simes, J. Antitumour
antibiotic containing regimens for metastatic breast cancer.
[Systematic Review] Cochrane Breast Cancer Group Cochrane Database of
Systematic Reviews. 4, 2005.
The most common serious toxicity from this type of treatment was low
white blood cell count (leukopenia), which makes the patient more
prone to infections.
________________________
Because this tumor is ER-/PR-, I will not discuss endocrine therapies.
________________________
A particularly well written article that addresses the latest research
on the treatment of metastatic breast cancer with detailed information
on the various chemotherapeutic agents, as well as therapies on the
frontier, is written by a group at the M.D. Anderson Cancer Center, a
world-renowned institution. Here is the reference:
Esteva FJ, Valero V, Pusztai L, Boehnke-Michaud L, Buzdar AU,
Hortobagyi GN. Chemotherapy of metastatic breast cancer: what to
expect in 2001 and beyond. Oncologist. 2001;6(2):133-46. Review.
Fortunately, you can find the article online free:
http://theoncologist.alphamedpress.org/cgi/reprint/6/2/133
In terms of chemotherapy, the article states that anthracycline plus
taxane regimens are the most effective, but also have the highest
toxicity. The article also discusses agents your sister has already
tried, such as Herceptin for Her2/neu positive tumors that are
ER-/PR-.
Let me give you some information about the therapy your sister is
being offered via clinical trial.
=====================
Xeloda (aka capecitabine)
=====================
This is an oral medication that is metabolized to 5-Fluorouracil
(5-FU), another commonly used chemotherapy agent.
There are a few articles that summarize the current thinking on this
medication, which I have listed below with their abstracts.
Jones L. Hawkins N. Westwood M. Wright K. Richardson G. Riemsma R.
Systematic review of the clinical effectiveness and cost-effectiveness
of capecitabine (Xeloda) for locally advanced and/or metastatic breast
cancer. [Review] [201 refs] [Journal Article. Review] Health
Technology Assessment (Winchester, England). 8(5):iii, xiii-xvi,
1-143, 2004 Feb.
This article is in the process of being reviewed, and is,
unfortunately, not yet available. The abstract is below:
"OBJECTIVE: To examine the clinical effectiveness and
cost-effectiveness of oral capecitabine for locally advanced and
metastatic breast cancer in relation to its licensed indications. DATA
SOURCES: Twenty-three electronic databases and other databases of
ongoing research and Internet resources, bibliographies of retrieved
articles and industry submissions. REVIEW METHODS: Two reviewers
independently screened and assessed all titles and/or abstracts
including economic evaluations. Randomised controlled trials (RCTs)
and observational studies that investigated capecitabine monotherapy,
in patients pretreated with an anthracycline-containing regimen or a
taxane, or capecitabine in combination with docetaxel, in patients
pretreated with an anthracycline-containing regimen, were included.
The economic evaluation was based on data reported in the
manufacturer's submission. RESULTS: For capecitabine monotherapy, 12
uncontrolled observational studies were identified. The methodological
quality of the studies was low. Capecitabine demonstrated antitumour
activity, but was associated with a particular risk of hand-foot
syndrome and diarrhoea. Economic evaluation was hampered by the poor
quality of the published studies, but compared indirectly with
vinorelbine, capecitabine was associated with lower costs and improved
patient outcomes. For capecitabine in combination with docetaxel, one
RCT was identified. Combination therapy was superior to single-agent
docetaxel in terms of survival, time to disease progression and
overall response. Adverse events occurred more frequently with
combination therapy. The economic evaluation demonstrated an overall
improved QALY score for combination therapy with a slight reduction in
costs. CONCLUSIONS: No conclusions could be drawn regarding the
therapeutic benefit of capecitabine monotherapy; RCTs are required.
Capecitabine appeared cost-effective compared with vinorelbine, but
serious doubts remain; the poor quality of the trials may invalidate
this conclusion. Based on limited evidence, combination therapy was
more effective than single-agent docetaxel and likely to be
cost-effective, but was associated with higher incidences of hand-foot
syndrome, nausea, diarrhoea and stomatitis. [References: 201]"
Basically, the article states that randomized controlled trials are
needed to determine if Xeloda might work. This is the type of trial
being offered to your sister.
______
Another article from a group in Canada focuses more on side effects
associated with this drug:
Gerbrecht BM. Current Canadian experience with capecitabine:
partnering with patients to optimize therapy. [Review] [16 refs] [Case
Reports. Journal Article. Review. Review, Tutorial] Cancer Nursing.
26(2):161-7, 2003 Apr.
"Capecitabine (Xeloda) is the first oral chemotherapeutic agent to be
used in Canada for the treatment of metastatic breast cancer and
metastatic colorectal cancer. The home-based administration of this
drug, coupled with the importance of prompt side-effect management,
presents unique challenges to oncology nurses and gives them an
expanded role in optimizing therapeutic outcomes. Fulfillment of this
role involves partnering with patients to help them become educated
active participants in their own treatment, and to ensure that side
effects are prevented, recognized, and managed adeptly. Although well
tolerated, capecitabine, as with all chemotherapy, can require
interventions and dose modification. Hand-foot syndrome, the most
common dose-limiting toxicity, requires particular attention. Drawing
from published articles and interviews with Canadian oncology care
providers, this article reviews the development and safety profile of
capecitabine. Best practices in side-effect management are discussed,
with a particular focus on managing hand-foot syndrome and building
patient partnerships."
______
Another review from England discusses a Phase II trial of Xeloda,
which is the precursor to a Phase III trial where a drugs
effectiveness is evaluated. Here is the reference for that article:
Talbot DC. Moiseyenko V. Van Belle S. O'Reilly SM. Alba Conejo E.
Ackland S. Eisenberg P. Melnychuk D. Pienkowski T. Burger HU. Laws S.
Osterwalder B. Randomised, phase II trial comparing oral capecitabine
(Xeloda) with paclitaxel in patients with metastatic/advanced breast
cancer pretreated with anthracyclines. [Clinical Trial. Clinical
Trial, Phase II. Journal Article. Multicenter Study. Randomized
Controlled Trial] British Journal of Cancer. 86(9):1367-72, 2002 May
6.
"Background: It is generally accepted that taxanes are among the most
active chemotherapy agents in the management of metastatic breast
cancer.
Objectives: To identify and review the randomised evidence comparing
taxane containing chemotherapy regimens with regimens not containing a
taxane in the management of women with metastatic breast cancer.
Search strategy: The specialised register maintained by the Editorial
Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003
using the codes for "advanced breast cancer", "chemotherapy". Details
of the search strategy applied by the Group to create the register,
and the procedure used to code references, are described in the
Group's module on the Cochrane Library.
Selection criteria: Randomised trials comparing taxane-containing
chemotherapy regimens with regimens not containing taxanes in women
with metastatic breast cancer.
Data collection and analysis: Data were collected from published
trials. Studies were assessed for eligibility and quality, and data
were extracted, by two independent reviewers. Hazard ratios were
derived for time-to-event outcomes where possible, and a fixed effect
model was used for meta-analysis. Response rates were analysed as
dichotomous variables. Toxicity and quality of life data were
extracted where present.
Main results: Twenty one eligible trials were identified of which 12
have published time-to-event data and 16 have reported response data.
The quality of randomisation was generally not described.
An estimated 2621 deaths in 3643 randomised women demonstrate a
statistically significant difference in favour of taxane-containing
regimens with a HR for overall survival of 0.93 (95% CI=0.86-1.00,
p=0.05) and no statistically significant heterogeneity. If the
analysis is restricted to trials of firstline chemotherapy the HR
changes to 0.92 and is no longer statistically significant (95% CI
0.84-1.02, p=0.11). There was also a significant difference in favour
of taxanes in relation to time to progression (overall HR 0.92, 95%CI
0.85-0.99, p=0.02) and overall response in assessable women (overall
OR 1.34, 95%CI 1.18-1.52, p<0.00001) however there was strong
statistical evidence of heterogeneity (P<0.00001), probably reflecting
the varying efficacy of the comparator regimens used in the trials.
Conclusions: When all trials are considered, taxane-containing
regimens appear to improve overall survival, time to progression and
overall response in women with metastatic breast cancer. The degree of
heterogeneity encountered indicates that taxane-containing regimens
are more effective than some, but not all non-taxane-containing
regimens."
======================
Lapatinib (aka GW572016)
======================
This drug inhibits Erb1 and Erb2 tyrosine kinases (enzymes) in cells.
Certain tumor cells require over-expression and activation of these
molecules, which is inhibited by Lapatinib. This generates signals
for the cell to die.
Here are some references that give more details on how this drug works
and how effective it might be:
Spector NL. Xia W. Burris H 3rd. Hurwitz H. Dees EC. Dowlati A. O'Neil
B. Overmoyer B. Marcom PK. Blackwell KL. Smith DA. Koch KM. Stead A.
Mangum S. Ellis MJ. Liu L. Man AK. Bremer TM. Harris J. Bacus S. Study
of the biologic effects of lapatinib, a reversible inhibitor of ErbB1
and ErbB2 tyrosine kinases, on tumor growth and survival pathways in
patients with advanced malignancies. [Clinical Trial. Journal Article.
Multicenter Study. Randomized Controlled Trial] Journal of Clinical
Oncology. 23(11):2502-12, 2005 Apr 10.
"Purpose: This was a pilot study to assess the biologic effects of
lapatinib on various tumor growth/survival pathways in patients with
advanced ErbB1 and/or ErbB2-overexpressing solid malignancies.
Patients and Methods: Heavily pretreated patients with metastatic
cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly
assigned to one of five dose cohorts of lapatinib (GW572016)
administered orally once daily continuously. The biologic effects of
lapatinib on tumor growth and survival pathways were assessed in tumor
biopsies obtained before and after 21 days of therapy. Clinical
response was determined at 8 weeks.
Results: Sequential tumor biopsies from 33 patients were examined.
Partial responses occurred in four patients with breast cancer, and
disease stabilization occurred in 11 others with various malignancies.
Responders exhibited variable levels of inhibition of p-ErbB1,
p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor
alpha. Even some nonresponders demonstrated varying degrees of
biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred
in patients with evidence of tumor regression but not in nonresponders
(progressive disease). Clinical response was associated with a
pretreatment TUNEL score > 0 and increased pretreatment expression of
ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factor
receptor-1, p70 S6 kinase, and transforming growth factor alpha
compared with nonresponders.
Conclusion: Lapatinib exhibited preliminary evidence of biologic and
clinical activity in ErbB1 and/or ErbB2-overexpressing tumors.
However, the limited sample size of this study and the variability of
the biologic endpoints suggest that further work is needed to
prioritize biomarkers for disease-directed studies, and underscores
the need for improved trial design strategies in early clinical
studies of targeted agents."
The above article also gives a good description, although somewhat
technical, of how Lapatinib is thought to work:
"Lapatinib (GW572016) is an orally active small molecule that
reversibly inhibits ErbB1 and ErbB2 tyrosine kinases, which in turn
blocks phosphorylation and activation of Erk1/2 (p-Erk1/2) and Akt
(p-Akt) in ErbB1- and/or ErbB2-expressing tumor cell lines and
xenografts.11-14 Lapatinib elicits cytostatic or cytotoxic antitumor
effects depending on the cell type.11,12 Because ErbB2-containing
heterodimers exert potent mitogenic signals, simultaneously
interrupting both ErbB1 and ErbB2 signaling is an appealing
therapeutic approach."
______
There has also been a recent Phase I clinical trial to look at the
safety of administering Lapatinib:
Burris HA 3rd. Hurwitz HI. Dees EC. Dowlati A. Blackwell KL. O'Neil B.
Marcom PK. Ellis MJ. Overmoyer B. Jones SF. Harris JL. Smith DA. Koch
KM. Stead A. Mangum S. Spector NL. Phase I safety, pharmacokinetics,
and clinical activity study of lapatinib (GW572016), a reversible dual
inhibitor of epidermal growth factor receptor tyrosine kinases, in
heavily pretreated patients with metastatic carcinomas. [Clinical
Trial. Clinical Trial, Phase I. Journal Article. Randomized Controlled
Trial] Journal of Clinical Oncology. 23(23):5305-13, 2005 Aug 10.
"Purpose: This study (EGF10004) assessed the safety/tolerability,
pharmacokinetics, and clinical activity of daily oral dosing with
lapatinib (GW572016) in patients with ErbB1-expressing and/or
ErbB2-overexpressing advanced-stage refractory solid tumors.
Patients and Methods: Heavily pretreated patients with
ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were
randomly assigned to one of five dose cohorts of lapatinib
administered once daily. Pharmacokinetic samples were obtained on days
1 and 20. Clinical response was assessed every 8 weeks.
Results: Sixty-seven patients with metastatic solid tumors were
treated with lapatinib. The most frequently reported drug-related
adverse events were diarrhea (42%) and rash (31%). No grade 4
drug-related adverse events were reported. Five grade 3 drug-related
toxicities (gastrointestinal events and rash) were experienced by four
patients. Drug-related interstitial pneumonitis or cardiac dysfunction
associated with other ErbB-targeted therapies was not reported. Four
patients with trastuzumab-resistant metastatic breast cancer-two of
whom were classified as having inflammatory breast cancer-had partial
responses (PRs). Twenty-four patients with various other carcinomas
experienced stable disease, of whom 10 received lapatinib for >= 6
months. The relationships between lapatinib dose or serum
concentration and clinical response could not be adequately
characterized due to the limited response data. The incidence of
diarrhea increased with increasing dose, whereas the incidence of rash
was not related to dose.
Conclusion: Lapatinib was well tolerated at doses ranging from 500 to
1,600 mg once daily. Clinical activity was observed in heavily
pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing
metastatic cancers, including four PRs in patients with
trastuzumab-resistant breast cancers and prolonged stable disease in
10 patients."
It's unknown (at least to me) if your sister's tumor expresses ErB1
and ErB2 at high levels. This is something the pathology people may
have (or could) determined from biopsy specimens, and may have some
impact on how efficacious treatment with Lapatinib might be.
======================
Other drugs and drug regimens in clinical trials might also have some
effect on survival. One factor, however, is that most of these trials
are only offered within a limited geographic area. It's actually
quite fortunate that your sister has been receiving treatment at an
institution that offers a clinical trial, rather than having to
transfer her care or even travel to participate in such a trial.
You can find out about ongoing clinical trials at this National
Institutes of Health site:
http://www.clinicaltrials.gov/
Here is the continuously updated listing for metastatic breast cancer:
http://www.clinicaltrials.gov/ct/search?term=metastatic+breast+cancer&submit=Search
The efficacy of most new treatment regimens is not well known. You
can find a great table of the currently known efficacies of various
therapies for salvage chemotherapy at this site from the Moffitt
Cancer Center (see Tables 2 and 3):
http://www.moffitt.usf.edu/pubs/ccj/v6s2/article5.htm
There is also a discussion with experts on their own strategies and
interpretation on how they manage patients following these tables.
======================
You also mentioned an interest in herbal and alternative therapies for
breast cancer. There is a clinical trial that is currently looking at
this, located in San Francisco:
http://www.clinicaltrials.gov/ct/show/NCT00028977?order=11
This trial will be looking at the efficacy of herba scutellaria
barbatae, a type of scullcap
You can read more here, at the California Breast Cancer Research Program:
http://www.cbcrp.org/research/PageGrant.asp?grant_id=2134
The mechanism by which this herb might work is unknown, and is the
subject of current research.
For this trial, patients must have less than 50% involvement of the
liver. As you might guess, the response of most of these new drugs is
unknown, which is why they are being tested in clinical trials. Some
of them may have no effect on cancer cells or, although unlikely, make
a cancer progress faster. This is an inherent risk in any clinical
trial.
You can find more herbalist based information from Herbasin:
http://www.herbasin.com/database/banzhilian.htm
It appears you can purchase mixtures of herbs that contain scutellaria
barbatae from this site:
http://www.quantumxrroid.net/homeopathy/orientalHerb.shtml
See catalog #0166, for example. Like most herbal supplements, the
exact amounts and potency of the herb in this mixture is unknown. I
would also recommend discussing with with your sister's physician,
since certain vitamins and herbs can interfere or interact with
chemotherapy and radiation treatment.
Botanicum claims to sell the unmixed herb at their site for $13.50:
http://botanicum.com/neworder.html
______
The most recent review article looking at herbal and alternative
therapy was written by a group (again) from M.D. Anderson Cancer
Center in Houston:
Navo MA. Phan J. Vaughan C. Palmer JL. Michaud L. Jones KL. Bodurka
DC. Basen-Engquist K. Hortobagyi GN. Kavanagh JJ. Smith JA. An
assessment of the utilization of complementary and alternative
medication in women with gynecologic or breast malignancies. [Journal
Article. Multicenter Study] Journal of Clinical Oncology. 22(4):671-7,
2004 Feb 15.
"Purpose: To describe and assess the current utilization of
complementary and alternative medicines (CAMs) in women with a
diagnosis of either gynecologic or breast cancer and evaluate their
reasons for use.
Patients and Methods: This study included 250 female patients from the
Multidisciplinary Breast Center and 250 patients from the Gynecologic
Oncology Center of The University of Texas M.D. Anderson Cancer Center
(Houston, TX). Patients were selected by having an odd-numbered
medical record number, and they were contacted before their clinic
visit. The goals of the study were explained, and verbal consent was
obtained. Patients who agreed to participate were asked to bring a
written list and the medication bottles of all over-the-counter
prescriptions and CAMs with them to clinic. In clinic, the
investigator obtained a written informed consent and administered the
survey. All patients and surveys were assessable.
Results: The most frequently used herbal products and
megavitamins/minerals were identified from the patient medication
histories. Overall, we found the proportion of patients using CAM to
be 48% (95% CI, 44% to 53%; 241 of 500 patients). CAM use was related
to patients' educational status: 62% had postgraduate degrees, 50% had
college degrees, 56% had some college, and 33% had a high school
education or less. Also, among patients using CAMs, only 53.5% had
spoken to a healthcare provider regarding CAM therapy.
Conclusion: The use of CAM is common among women with cancer. Studies
need to be conducted to establish if there are any potential drug
interactions and/or therapeutic benefit of CAM products. Moreover,
there is a need to educate patients and healthcare providers on
appropriate and safe use of CAM products."
To summarize, 48% of breast cancer patients use alternative therapies.
The group recommends that more research is required to determine how
effective these therapies might be and what side effects and
interactions one can expect so that patients can make informed
decisions about therapies. Most of the patients surveyed weren't
taking supplements that are generally thought to have direct
anti-disease effects (e.g., anti-neoplastic agents), such as is
claimed as a potential benefit of scutellaria barbatae mentioned
above. Among breast cancer patients, the most commonly used agents
were (in order): Glucosamine chondroitin, garlic, CQ10, green tea,
flaxseed, echinacea, cod liver oil, acidophilus, lecithin, grape seed
extract, bee pollen, angelica root, slippery elm (ulmus fulva, rose
hips, igngo biloba), kelp, and others. The most popular vitamins (in
order) were Vitamin E, Vit. C, Vit. B, Vit. A, Quercitin,
Multivitamins, Alpha lipoic acid, Zinc, Boron, and others. There was
no difference in use among those with early versus advanced disease.
You can read another article describing the use of alternative
therapies among women with breast cancer from the Doctor's Guide:
http://www.docguide.com/news/content.nsf/news/05866D6DA7AA4F4185256A8C0058593A
You can find a general discussion of alternative therapies in cancer
patients from this recent article in CA - The Cancer Journal for
Clinicians (from the American Cancer Society), which is available free
online:
http://caonline.amcancersoc.org/cgi/content/full/54/2/110
http://caonline.amcancersoc.org/cgi/reprint/54/2/110
______
You can also find some other opinions about alternative therapies,
targeted at diet, at the A. P. John Institute for Cancer Research:
http://www.apjohncancerinstitute.org/cancer/breast-c.htm
To my knowledge, their treatment protocols have not been backed up by
hard science with regard to metastatic breast cancer. I am a little
dubious about their claims. Their amino acid protocol seems to be
based on a paper published in 1967 in the Journal of the American
Medical Association. If this therapy was significant, I would imagine
that it would be more studied and fine tuned in the literature.
================
Another useful, very accessible resource is the patient version of
UpToDate. UpToDate is an excellent resource that is continuously
updated. The full professional version is a subscription version that
you may be able to access from a medical library. The patient
summaries are available online for free. As new information is
published, the UpToDate articles are continuously updated at regular
intervals, make it something like an evolving textbook. The patient
version is fairly general and I think that the information I have
provided above is more specific and detailed. This might be useful
for a "big picture" overview. Here is the patient article on the
current practice for the treatment of metastatic breast cancer:
http://patients.uptodate.com/topic.asp?file=cancer/5162
================
I hope this information is helpful. I wish you and your sister the
best in this difficult ordeal. Please feel free to request any
clarification prior to rating.
Best,
-welte-ga
============
Search terms:
salvage chemotherapy metastatic breast cancer [on Google Scholar and
Ovid Medline Databases]
alternative "metastatic breast cancer"
(herb OR herbal) "breast cancer"
"clinical trials" |
