Why Im Not Doing Chemo
Comments
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Again, this is an alternative forum, for those who have reasons for considering nonstandard treatment or a combination of nonstandard treatment and standard treatment.
A.A.
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Ovarian suppression is mentioned in the footnotes of the NCCN guidelines. My doctor didn't even bother plugging in my numbers into adjuvant online.
For sure with drugs like Viagra, propecia and even statins, I can see where consumer demand influences the market. However, I don't think there is a single woman who naively asks for chemo. AA, you are insulting women who think long and hard about their therapy choices.0 -
Btw... Ovarian suppression is not the standard of care here in the United States and is considered alternative treatment. Ditto for Zometa.
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VR:
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Ovarian suppression is one of the goals that chemotherapy tries to reach. Even if choosing to do something like hormonal therapy alone would not be considered standard of care in one's individual situation, one is able to review the alternatives of using no therapy; or hormonal therapy alone; or chemotherapy alone; or combined therapy when looking at Adjuvant Online. They are able to look at it and consider it, even if it wouldn't be considered standard therapy for that patient.
No one has yet explained why there is no option to see how much effect there is with the use of ovarian ablation alone; (or hopefully with version 9.0, with trastuzumab).
Are you saying that ovarian ablation is not being used for you as an effective part of your treatment?
If it is being used as an effective part of treatment, why shouldn't that effect be openly compared as a part of the program just like the other treatments are? Is there a concern that it might show too much effectiveness and would be too competitive with other treatment, such as chemotherapy?
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I don't see any insult to women, whatever choice they make, reluctant or enthusiastically. I am asking them to consider some possible alternative choices, rather than assuming that newbies might be too scared to think for themselves when considering the full range of options in making their choice, including alternatives. I think it is more insulting to women to consider them incapable of making that consideration.
A.A.
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No option to see effect of ovarian ablation alone on Adjuvant on Line, because no or not enough data exists to list it there. Adjuvant online relies on the results of many large trials.
Plus, it is out of date. There are better resources out there for those who choose to research.
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AA - you said "I think it is more insulting to women to consider them incapable of making that consideration" - well some people may not be as smart as others or as well educated and don't understand what's going on. I remember meeting people having chemo and they didn't even know what drug they were having.
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Thanks, orange1.
There are no calculations to include it using lifemath.net either.
Since it is one of the objectives achieved with chemotherapy that is not available through other common therapies, it is a logical question to ask in behalf of those who are interested in not doing chemotherapy but trying to achieve a similar result.
I wonder what the reasoning would be, therefore, for not having enough data (or not doing the research to find out). Does anyone know the answer? Unless, of course, it is not a good idea to ask that kind of logical question when we consider what choices to make?
My thought is that it also would be more available and less expensive for those who don't have access to chemotherapy and all the support drugs for it and all the lab testing required for chemotherapy......as well as the months spent doing treatment and recovering... and perhaps there are those who aren't interested in contributing the creation and use of toxic chemicals for environmental reasons, as well.
AlaskaAngel
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Thank you AA for this comment....I don't see any insult to women, whatever choice they make, reluctant or enthusiastically. I am asking them to consider some possible alternative choices, rather than assuming that newbies might be too scared to think for themselves when considering the full range of options in making their choice, including alternatives. I think it is more insulting to women to consider them incapable of making that consideration.
I don't make claims to being all knowledgeable in regard to the above discussion. If nothing else comes from this discussion hopefully newbies will consider what the importance of checking out further with their oncologist or doctors the discussion posed here. I admit to being a novice, yet in no way do I want to blindly be told what to do without knowing the side effects, risk factors and to given a choice I can live with.
I appreciate that there are those of you who are concerned for me. I am fortunate that I have an intelligent oncologist who is willing to give me herceptin without chemo. If she would not have, I would have looked for another oncologist. I strongly feel that in the end it's my choice...no one elses.
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Here is a study from almost a decade ago. It is interesting reading. (The underlining is mine, not theirs.)
http://theoncologist.alphamedpress.org/content/9/5/507.full
Ovarian Ablation/Ovarian Suppression (OA/OS)
The American perspective: The 2000 U.S. NIH Consensus Development Conference on the Adjuvant Therapy for Breast Cancer concluded that standard adjuvant chemotherapy should be recommended for the majority of premenopausal women with early-stage breast cancer. Women with HR+ disease should also be given adjuvant hormonal therapy in the form of tamoxifen for 5 years, with consideration of ovarian suppression as an alternative to tamoxifen for selected women. The consensus panel determined that there was insufficient evidence at the time to support addition of ovarian suppression to standard adjuvant chemotherapy followed by 5 years of tamoxifen.
The European perspective: The 2003 International Conference on the Adjuvant Therapy of Primary Breast Cancer in St. Gallen, Switzerland, emphasized the primary role of endocrine therapy and concluded that combination endocrine therapy with ovarian suppression and tamoxifen is an acceptable alternative to standard adjuvant chemotherapy followed by tamoxifen in premenopausal women with HR+ breast cancer [67].
Conclusions: ..... In the adjuvant setting, OA/OS monotherapy results in superior DFS and overall survival rates compared to observation in women with HR+ breast cancer, regardless of nodal status. Combined endocrine therapy with OA/OS and tamoxifen yields outcomes comparable to those obtained with adjuvant CMF chemotherapy for premenopausal women with HR+ breast cancer. Some subset analyses suggest that young women who fail to develop chemotherapy-related amenorrhea benefit most from the addition of OA/OS.
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If I did not have health problems that chemo would worsen due to side effects of chemo, I would chose not to do chemo for quality of life. (exceptions for certain types of cancer).
I have a friend, who after being on chemo for six months, had to wear a diaper, used a walker, gained 100 lbs (also took steriods) hair loss, finger nail problems and completely became dependent. She was told that she had 6 months to a yr if she took chemo and a few months if she didn't. She had to take one pill for one side affect, and another pill for the side effect that pill caused, and another for the other pill until she was one big mess. I suggested she didn't have much time to live to get off chemo and live...go on a trip, enjoy her family. She did. Just about a year later, her tumor has significantly shrunk, and her doctors said the recent last mri that her cancer is in remission. After encouraging her to go off chemo she went on alternative treatment plan. I know this person, and she is now her spunky old self.
On the other hand, I know someone who was dx 2 yrs ago with stage 3b cancer. She was on chemo and etc until she died last July. She was sick the whole time.
I spoke with my oncologist therapist. She asked if I was doing chemo. I said no. She agreed with me. She said it really does a trip on the brain. But, wasn't for sure for those who have young children. I said, yes, but would I want my children remembering me in my last days sick or live every moment with them so their last moments are good memories. She thought it was an interesting and reasonable choice.
The only ones I know who are doing well are the ones who post here. There are few whom I've known to make it...and they were stage 1 and as my oncologist said 75% of stage 1 surgery alone is enough. I have another friend stage2b, who was her2+++ who did not have herceptin and after nine yrs no recurrence. ???
So...if I have only a number of days or years to live, I want to live it without being sick. Life for me is not how long I live, rather quality of life. I am not afraid of dying because I believe that my life and times are in God's hands. This of course doesn't mean you do nothing...for me it just means no matter what I do when it's my time to leave planet earth, I'm going. It may not be cancer that takes me out, whatever it is I know that I'm going to a better place. So the choices I make won't include side effects that will worsen my life style. Every day, and every moment for me is important.
Also...it is about risks...no matter what choices we make their are risks...shouldn't it be our choice which risk we can live with? Why is it women dx with cancer, especially those who are older, whose bodies aren't as strong are encouraged to do chemo? I think everyone taking chemo should know the following risks...and for this reason I'm posting it. My own oncologist did not even tell me the risk...just said I should take it.
Managing Chemotherapy Side Effects
http://www.cancer.gov/cancertopics/coping/chemo-side-effects
- Anemia
Practical advice about anemia, tips to help people with cancer feel less tired, and signs to call your doctor about. Read questions to ask your doctor. - Appetite Changes
Practical tips to help people with cancer make eating easier, stay strong during chemotherapy and manage appetite changes. Read questions to ask your doctor. - Bleeding Problems: Managing Chemotherapy Side Effects
Practical steps to help people with cancer prevent bleeding problems during chemotherapy and know what problems to call your doctor about. Read questions to ask your doctor. - Constipation: Managing Chemotherapy Side Effects
Practical tips to help people with cancer prevent or relieve constipation and feel better during chemotherapy. Learn what foods can help and key questions to ask your doctor. - Diarrhea: Managing Chemotherapy Side Effects
Practical information to help people with cancer prevent or relieve diarrhea and feel better during chemotherapy. Learn what foods and drinks may help you feel better and what problems to call your doctor about. - Fatigue (Feeling Weak and Very Tired): Managing Chemotherapy Side Effects
Practical tips to help people with cancer make a plan to feel less tired and fatigued during chemotherapy. Learn what problems you should call your doctor about and read questions to ask your doctor. - Hair Loss (Alopecia)
Practical tips on how others have coped with hair loss (also called alopecia) during chemotherapy. Read questions to ask your doctor. - Infection
Practical advice to help people with cancer lower their chances of getting infections during chemotherapy and problems to call their doctor about. Read questions to ask your doctor. - Memory Changes: Managing Chemotherapy Side Effects
Practical information about what causes memory changes during chemotherapy. Get helpful tips and learn what questions to ask your doctor. - Mouth and Throat Changes: Managing Chemotherapy Side Effects
Practical steps that people with cancer can take if their mouth or throat hurts during chemotherapy. Learn about a mouth rinse that can help, what foods to avoid, and questions to ask your doctor. - Nausea and Vomiting: Managing Chemotherapy Side Effects
Practical tips and advice to help people with cancer prevent nausea and vomiting during chemotherapy. Learn what foods and drinks are easy on your stomach. Read questions to ask your doctor. - Nerve Changes
Practical information about nerve changes (also called peripheral neuropathy) and tips that have helped others during chemotherapy. Learn what changes to call your doctor about and questions to ask your doctor. - Pain: Managing Chemotherapy Side Effects
Practical advice to help people with cancer prevent or manage pain during chemotherapy treatment. Tips to help you track your pain, get the most from your pain medicine, and know when to call your doctor. - Sexual and Fertility Changes in Men: Managing Chemotherapy Side Effects
Practical information and answers to questions from men about sexual problems or fertility changes due to chemotherapy. Learn what questions to ask your doctor before treatment starts. - Sexual and Fertility Changes in Women: Managing Chemotherapy Side Effects
Practical information and answers to questions from women about sexual problems or fertility changes due to chemotherapy. Learn what questions to ask your doctor before treatment starts. - Skin and Nail Changes: Managing Chemotherapy Side Effects
Practical information to help people with cancer care for their skin and nails during chemotherapy and problems to call their doctor about. Read questions to ask your doctor. - Swelling (Fluid Retention): Managing Chemotherapy Side Effects
Practical information for people with cancer about what causes swelling (fluid retention) during chemotherapy, steps to take to prevent it, and when to call their doctor. Learn what questions to ask your doctor. - Urination Changes: Managing Chemotherapy Side Effects
Practical information about how to prevent or manage changes in urination during chemotherapy, problems to call your doctor about, and questions to ask your doctor.
0 - Anemia
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Again -- the discussion by and large does not apply to patients who are HR negative, who get more benefit from chemotherapy than HR+ patients do.
From 2009 - the reference is only to the viewpoint about the value of the use of chemotherapy for HR+ patients. There is no discussion of ovarian ablation, but logically if chemotherapy is of little or no value, then hormonal treatments such as OS/OA and/or tamoxifen or an AI would make more sense than using chemotherapy:
http://erc.endocrinology-journals.org/content/16/4/1091.full
Conclusions:
...... However, uncertainty about the benefits of chemotherapy still exists for a substantial proportion of women with hormone receptor-positive breast cancer, which causes subjectivity in using pathological findings in decision making. A recent paper showed that at eight National Comprehensive Cancer Network centers, there was a progressive reduction in the use of chemotherapy in patients with hormone receptor-positive disease from 1997 to 2004 (Hassett et al. 2008). This was interpreted as the acceptance of the concept that chemotherapy may be worthless in a proportion of these women. However, a multivariate analysis of factors associated with chemotherapy revealed that, among other independent predictive factors like tumor size, histological grade, and lymph nodal status, the institution where the patient was treated was also associated with the likelihood of receiving adjuvant chemotherapy. Hopefully, integration of the newer prognostic factors based on multigene expression analysis will help to reduce subjectivity in data interpretation and allow physicians a more objective evaluation of the worth of chemotherapy for each single patient.
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Again...just to note for those of you who find the discussion alternative to chemo not good for newbies...perhaps newbies come here looking for an alternative to chemo. If they don't find a good pro-and con discussion here they will go else where on the Internet without the pro's and cons.
This has been an excellent discussion...again, I appreciate everyone's imput.
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evebarry,
I think your thread here provides a lot of helpful information, and am thankful it offers a place to ask questions and not be afraid to consider them and discuss them politely.
I hope to post as exact as possible for you as an HR+ HER2 positive what I can find that is current about possible choices, plus and minus.
It helped to learn that ovarian ablation for HR+ early stage bc is presently considered professionally equal to CMF chemotherapy, and not inferior to it. In addition, you are addressing the issue of the added risk posed by HER2 positivity with the use of trastuzumab. Here is the most current info I could find for what is really my own personal question about the possibility for the use of ovarian ablation as one aspect for alternative therapy. It provides an understanding of when the use of OA is acceptable.
This ASCO endorsement clearly acknowledges that at present the conclusion is temporary because the clinical trials that are used as a basis for it are still running. I don't know when they will be completed.
"Conclusion: The ASCO review panel agrees with the recommendations as stated in the CCO guideline, with the qualification that ongoing research studies may alter the recommendations of the panel."
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5 hours agoAlaskaAngel wrote:
Here is a study from almost a decade ago. It is interesting reading. (The underlining is mine, not theirs.)
http://theoncologist.alphamedpress.org/content/9/5/507.full
Ovarian Ablation/Ovarian Suppression (OA/OS)
The American perspective: The 2000 U.S. NIH Consensus Development Conference on the Adjuvant Therapy for Breast Cancer concluded that standard adjuvant chemotherapy should be recommended for the majority of premenopausal women with early-stage breast cancer. Women with HR+ disease should also be given adjuvant hormonal therapy in the form of tamoxifen for 5 years, with consideration of ovarian suppression as an alternative to tamoxifen for selected women. The consensus panel determined that there was insufficient evidence at the time to support addition of ovarian suppression to standard adjuvant chemotherapy followed by 5 years of tamoxifen.
The European perspective: The 2003 International Conference on the Adjuvant Therapy of Primary Breast Cancer in St. Gallen, Switzerland, emphasized the primary role of endocrine therapy and concluded that combination endocrine therapy with ovarian suppression and tamoxifen is an acceptable alternative to standard adjuvant chemotherapy followed by tamoxifen in premenopausal women with HR+ breast cancer [67].
Conclusions: ..... In the adjuvant setting, OA/OS monotherapy results in superior DFS and overall survival rates compared to observation in women with HR+ breast cancer, regardless of nodal status. Combined endocrine therapy with OA/OS and tamoxifen yields outcomes comparable to those obtained with adjuvant CMF chemotherapy for premenopausal women with HR+ breast cancer. Some subset analyses suggest that young women who fail to develop chemotherapy-related amenorrhea benefit most from the addition of OA/OS
The study you cite is SO outdated that it is irrelevant. The perspective was developed BEFORE the advent of Herceptin for HER2+ tumors AND genetic testing for ER+ tumors. Back in the stone age of the new millenium, most pre-menopausal ER+ women were recommended chemotherapy. Not any more. Before the development of all of the new genetic tests such as Oncotype DX and Mammaprint, most pre-menopausal ER+ women were recommended chemotherapy despite the fact that doctors knew they were OVER treating the majority of patients. Unfortunately, before these genetic tests were approved, doctors didn't know which women had more aggressive ER+ tumors, so the standard of care, here in the United States, at the time, was to treat EVERYONE. Since the introduction of these genetic tests, the standard of care has CHANGED and more women are spared OVER treatment with chemo. This is the direction that I referred to earlier on this thread...where genetic testing is leading to more personalized and targeted therapies.
Furthermore, more recently (2005), the following trials were commenced:
"Tailored treatment investigations for premenopausal women with endocrine responsive breast cancer: the SOFT, TEXT, and PERCHE (STP) trialsThe STP trials are complementary studies designed to answer three open questions concerning adjuvant treatment for premenopausal patients with endocrine responsive disease: What is the role of ovarian function ablation/ suppression (OFS)? What is the role of aromatase inhibitors? What is the role of chemotherapy? We know that chemotherapy, tamoxifen and OFS are individually effective adjuvant treatment modalities in women under 50 years of age with estrogen receptor-positive breast cancer [5,6]. The addition of 5 years of tamoxifen to adjuvant chemotherapy in this group results in an additional approximately 40% reduction in the odds of recurrence or death [7,8]. These data suggest that adjuvant combination chemo-endocrine strategies can improve results over single modality treatments.Conclusive data on the best approaches to treat this population are scarce because positive results for chemotherapy in the 1970s (mainly for women in their forties) and misleading overview reports on tamoxifen (claimed to be ineffective in younger women) in the 1980s and 1990s, inhibited evaluation of endocrine therapies for younger women. Adjuvant treatment of choice for individual premenopausal women with endocrine responsive disease is largely based upon assessment of risk of relapse and physician's perception on the relative role of endocrine versus cytotoxic approaches. To offer a randomized clinical trial to define a better adjuvant treatment for premenopausal women with endocrine responsive disease, three tailored treatment investigations are being conducted globally by the IBCSG through the Breast International Group and the North American Breast Intergroup.The Suppression of Ovarian Function Trial (SOFT: IBCSG 24-02) is designed to determine the role of OFS and the role of aromatase inhibitors for women who remain premenopausal after surgery alone or after completion of adjuvant and/or neoadjuvant chemotherapy.The Tamoxifen and Exemestane Trial (TEXT: IBCSG 25-02) is designed to determine the role of aromatase inhibitors for women who receive OFS (with triptorelin) from the start of adjuvant therapy. Chemotherapy, if given, should be started with the triptorelin and followed by the tamoxifen or exemestane. Use of chemotherapy is by investigator/patient choice or by randomized assignment in the PERCHE trial.The Premenopausal Endocrine Responsive Chemotherapy Trial (PERCHE: IBCSG 26-02) is designed to determine the role of chemotherapy. It features randomization either to OFS plus tamoxifen or exemestane, or to chemotherapy plus OFS plus tamoxifen or exemestane. Women for whom the role of adding chemotherapy to 'complete estrogen blockade' is uncertain should be offered PERCHE.As of June 30, 2005, 164 participating centers from North America, Europe, Australia, South America, and Africa have randomized patients on these trials, including 243 on SOFT, 432 on TEXT, and 10 on PERCHE. The total required sample size is 3,000, 1,845 and 1,750 patients, respectively."
None of these clinical trials have been completed, as yet. Recall however, that I mentioned the importance of looking back at previous years of NCCN guidelines which provide clues to trends. It is obvious from looking at previous NCCN guidelines and the study you mention that the TREND is moving far, far away from offering chemo as a first line of treatment for early stage ER+ breast cancer.
Likewise, as others have chimed in, the data is NOT included in prognostics tables BECAUSE the therapies are still be investigated.
Regarding the European perspective, their recommendation was made BEFORE the wide use of Herceptin for women with HER2+ tumors. AND the most important point of the perspective you failed to underline. What they said was for premenopausal HER2+ women who did NOT develop chemo related amenorrhea, then O/S was recommended.
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From Clinical Medicine and Research, Nov. 2011, a study on the risks of heart damage with the use of various therapies. It seems the most toxic is chemo + herceptin, followed by herceptin alone, then chemo alone. The link for the full article is at the end of the excerpt.
Herceptin plus anthracycline chemotherapy greatly increases risk of heart damage(An excerpt)
A total of 6,420 (46.2%) of the study population received no chemotherapy, 3,857 (28.6%) received anthracycline chemotherapy only, 157 (1.2%) received Herceptin only, 470 (3.5%) were treated with both, and 2,748 (20.4%) received other chemotherapy. A total of 1,041 (7.7%) of the women were diagnosed with heart failure after starting treatment. Anthracycline use alone was found to be associated with 1.19 times the risk of heart failure compared to no chemotherapy. Herceptin alone was associated with 3.02 times the risk of heart failure compared to no chemotherapy; anthracycline plus Herceptin was associated with 6.05 times the risk; and other chemotherapy was associated with 1.36 times the risk. These associations strengthened after excluding women from the analysis who already had heart failure before their breast cancer diagnosis or who were diagnosed with heart failure fewer than 60 days after breast cancer diagnosis. The authors conclude that the combination of anthracycline plus Herceptin, in particular, is associated with an elevated risk of heart failure in the community setting.
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Evebarry,
Your decision is clear from your posts over the past 4 years here on BCO and 21 pages on this thread alone. We get it. You're not doing chemo. You don't need to justify your decisions to any of us. I mean that seriously and sincerely.
BUT. Are you familiar with the term "confirmation bias?" Basically it's cherry-picking facts to support a position that's already determined, and rejecting any facts that don't support it. I know, based on conversations I've had with you here and in PMs), that you think you're being personally challenged and even "bullied" sometimes. However, I hope you can see that for the most part, people are challenging not you personally, but the misinformation and factual errors and conspiracy promotion. I have no problem at all with your personal decisions, but I do admit that I am concerned that you're basing them on factually incorrect assumptions that I see over and over in posts here.
Of course there are incompetent doctors out there. But to imply that many, or most, patients go blindly into chemotherapy wih absolutely no idea that hair loss, chemopause, nausea, anemia, etc are VERY common side effects, that's just plain disingenuous and insulting to both doctors and patients. To say doctors routinely "force" people into treatment or suppress other effective treatment options, or that patients are powerless to participate in their treatment choices - puh-lease. Don't want chemo? Then don't do it. It's pretty simple, and no doctor is going to shackle you into the infusion chair. You're entitled to your decision, as we all are.
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Heart Failure Caused by Molecularly Targeted Therapies for Cancer
Posted: 01/12/2011; Pharmacotherapy. 2011;31(1):92-111. © 2011 Pharmacotherapy Publications
Abstract and Introduction
Abstract
Cancer therapeutics is undergoing a revolution with the advent of new drugs that can selectively target molecules responsible for carcinogenesis and tumor growth. The type and mechanism of these targeting drugs vary. Some are small molecules that specifically target a binding site on a receptor or signal transduction molecule. Antibodies have been engineered to bind to the receptors or the corresponding ligands that mediate a critical cancer activity. In almost all cases, the intent is to inhibit or shut down a specific molecular pathway. Unprecedented activity against the cancer is seen without overt traditional toxicities such as alopecia, nausea and/or vomiting, and cytopenias. Unfortunately, an increase in toxicity has now become evident as more experience accumulates with the use of these drugs. In some cases, unexpected cardiotoxicities have arisen when these new drugs have been added to more conventional chemotherapies. Heart failure is the unfortunate manifestation for many of these toxicities. We outline the scope of this problem and examine the mechanisms of drug-induced heart failure. The distinctive signs and symptoms specific to each drug are described, and the diagnosis and treatment of the condition are discussed. Our aim is to allow the practitioner to recognize the unusual manifestations of heart failure in this setting in order to make a timely diagnosis and begin appropriate treatment measures.
Introduction
Heart failure is a serious and potentially fatal complication of cancer therapy. Much of our knowledge about this adverse effect stems from the collective experience surrounding the agents in therapeutic use as antineoplastic agents. Because cytotoxic chemotherapy was the dominant strategy, the literature about cardiac complications is likewise highly skewed toward these agents. The rapid emergence of new therapeutic agents has given rise to a knowledge gap, as new types of cardiotoxicities have only now become evident.
Treating cancer with chemotherapeutic agents first arose in the 1940s with the advent of nitrogen mustards for chemical warfare and later the discovery of folate antagonists for leukemia.[1-3] Since the 1950s, treatment of cancer has primarily consisted of antineoplastic drugs that target specific cellular functions involved in neoplastic cell growth. Although many of these agents effectively act on cancer cells, the targets are not specific to cancer cells, leading to sometimes severe toxicity in normal cells. From initial nitrogen mustard agents, such as mechlorethamine, to newer chemotherapies, such as epothilones and taxanes, we now have numerous classes of chemotherapies available for treatment today.
In the past 10 years, there has been an accelerating paradigm shift away from classic chemotherapy agents to new agents termed molecularly targeted therapies. These new agents can selectively target specific molecules and receptors responsible for carcinogenesis and tumor growth while theoretically sparing normal host cells, thus limiting severe toxicity and adverse effects. The two dominant strategies within molecularly targeted therapies are the monoclonal antibodies, which have been developed to bind to specific receptors or key ligands, and the tyrosine kinase inhibitors, which target binding sites or signal transduction molecules. Both strategies aim to interrupt one of the many critical cancer pathways.
Much excitement has been generated with these therapies because of their unprecedented anticancer activity, coupled with a lack of overt traditional toxicities such as alopecia, nausea and/or vomiting, and cytopenias associated with cytotoxic chemotherapy. Examples of tyrosine kinase inhibitors are imatinib used in chronic myeloid leukemia and sunitinib used in metastatic renal cell carcinoma. Unfortunately, although classic chemotherapy-associated toxicities are minimal or absent with the targeted agents, there has been an increase in the awareness that cardiotoxicity is an adverse effect of these agents as more experience amasses. Cardiac toxicities reported in clinical trials of molecularly targeted therapies are described in Table 1.[4-19]
[ CLOSE WINDOW ]Table 1. Cardiac Toxicity with Molecularly Targeted Therapies Reported in Clinical Trials
Trial Design No. of Patients Disease Drug Therapy Description of Cardiac Toxicity Phase II (n=17)4 MSTS Bevacizumab + doxorubicin 35% of patients developed grades 2-4 cardiac toxicity Phase III (n=722)5 MBC Bevacizumab ±paclitaxel Grade 3 or 4 left ventricular dysfunction was 0.8% paclitaxel in combination group vs 0.3% with paclitaxel alone Phase III (n=375)6 MRCC Sunitinib 10% had a LVEF decline with grade 3 in 2%; no symptomatic heart failure Phase III (n=299)7 HCC Sorafenib 3% had cardiac ischemia or infarction Phase III (n=451)8 MRCC Sorafenib 3% had cardiac ischemia or infarction Phases I-II (n=75)9 MGIST Sunitinib 8% had symptomatic heart failure Retrospective (n=224)10 Various Sunitinib 2.7% developed symptomatic heart failure Retrospective (n=48)11 MRCC, GIST Sunitinib 15% developed symptomatic grade 3 or 4 left ventricular dysfunction Single-center observational (n=74)12 MRCC Sunitinib or sorafenib 33.8% had a cardiac event; 17.6% had a symptomatic event Retrospective (n=1219)13 MBC Trastuzumab + chemotherapya 9.2% developed cardiac dysfunction Phase III (n=1010)14 MBC Trastuzumab + chemotherapyb 3.5% (4/115) treated with trastuzumab had one or more measurements of LVEF > 15 percentage points less than the pretreatment value; no significant cardiac dysfunction Phase III (n=1677)15 MBC Trastuzumab + chemotherapyc 7.1% had a decreased LVEFd; 1.7% had symptomatic heart failure Phase III (n=1159f)16 MBC Trastuzumab + chemotherapye 14.2% had an asymptomatic decline in LVEF; 4.7% had heart failure or other serious cardiac events Phases I-III (n=3689)17 MBC Lapatinib ±chemotherapy or endocrine therapy 1.4% had a decline in LVEF, 0.2% had symptomatic declines Retrospective (n=1276)18 Hematologic Imatinib ±chemotherapy or other investigational agents 1.7% met Framingham criteria for heart failure during therapy Clinical database of 6 registration trials (n=2327)19 Various Imatinib 0.5% had heart failure possibly or probably related to imatinib MSTS = metastatic soft tissue sarcoma; MBC = metastatic breast cancer; MRCC = metastatic renal cell carcinoma; LVEF = left ventricular ejection fraction; HCC = hepatocellular carcinoma; MGIST = metastatic gastrointestinal stromal tumor.
aChemotherapy agents included cisplatin, doxorubicin + cyclophosphamide or paclitaxel.
bChemotherapy agents consisted of docetaxel or vinorelbine and fluorouracil, epirubicin and cyclophosphamide.
cAdjuvant chemotherapy, neoadjuvant chemotherapy, or both, selected from study-approved regimens consisting of at least four chemotherapy cycles.
dDecrease in LVEF was defined as a decrease in the ejection fraction of 10 percentage points or more from baseline to an LVEF of less than 50% at any time.
eAdjuvant chemotherapy consisting of doxorubicin, cyclophosphamide, and paclitaxel.
f1159 patients with an adequate LVEF after doxorubicin and cyclophosphamide treatment who began treatment with trastuzumab were included.Anthracyclines have classically been the most documented and well-known cause of cardiotoxicity and heart failure among oncologic therapeutic treatment options, with a clear lifetime dose-dependent effect.[20, 21] Other chemotherapies such as cyclophosphamide, taxanes, and 5-fluorouracil have also been reported to cause cardiotoxicity.[22] One of the first targeted agents to cement the idea that cardiotoxicity is a direct consequence of its use was trastuzumab, a human epidermal growth factor receptor 2 (HER2)-targeting antibody that initially received United States Food and Drug Administration (FDA) approval in September 1998 for use against metastatic breast cancer overexpressing HER2.[13, 23] Trastuzumab was the first targeted agent with reported cardiotoxicity, occurring at a rate of 3-5% when used alone and as high as 27% when given concomitantly with cyclophosphamide and an anthracycline.[13, 23] This recognition led to increased vigilance with other targeted therapies. Cardiotoxicities caused by subsequently discovered drugs such as sunitinib, imatinib, and dasatinib were detected partially as a consequence of this heightened awareness.[24-26]
In this review, we examine the extent of this problematic toxicity, define potential mechanisms of drug-induced heart failure, provide practitioners with a guide to recognizing the manifestations of cardiotoxicity, and offer general principles on the treatment of this condition. The discussion is organized around molecular pathways since toxicity is a manifestation of the affected pathway in question.
VEGF-Targeted Agents
Vascular endothelial growth factor (VEGF) is an important subfamily of growth factors, consisting of VEGF-A to VEGF-D, that are believed to be essential for vasculogenesis and angiogenesis in vivo.[27] In the 1970s, the initial hypothesis was that cancerous tumors are absolutely dependent on new blood vessel formation to grow.[28] Proof-of-concept work later[29, 30] laid some of the key foundations that cemented tumor angiogenesis as a dominant therapeutic strategy in oncology. The beginning of the antiangiogenesis era arguably began with the approval of three drugs targeting VEGF, the first being bevacizumab in 2004. Sunitinib and sorafenib were subsequently approved in late 2005 and early 2006, respectively, for the treatment of metastatic renal cell carcinoma. Bevacizumab, a humanized monoclonal antibody, binds to circulating VEGF-A rendering it inactive, whereas sorafenib and sunitinib are small molecules that inhibit multiple tyrosine kinases including the receptor for VEGF.[26, 31, 32]
Although these drugs have drastically changed the treatment landscape for various cancers, they are not without serious adverse effects. Recently, cardiotoxicity became a concern with numerous reports and case series of heart failure. Although the mechanism of this toxicity is unknown, the common hypotheses center around VEGF's crucial role in supporting myocardial angiogenesis and collateral vessel development after an insult to the myocardium.[33]
Bevacizumab
Bevacizumab is a recombinant monoclonal antibody that binds to and neutralizes circulating VEGF-A, thus inhibiting extracellular VEGF's ability to bind to its cell surface receptor and thereby inhibiting its endothelial cell growth stimulation.[31] It is FDA approved for the treatment of metastatic breast, metastatic colorectal, kidney, and non-small cell lung cancers, as well as glioblastoma multiforme.
We found only a few reports of cardiotoxicity occurring in patients receiving active treatment with bevacizumab. The first, a phase II study of doxorubicin in combination with bevacizumab for patients with metastatic soft-tissue sarcoma, reported greater than expected cardiotoxicity.[4] Six (35%) of 17 treated patients had a significant decline in left ventricular ejection fraction (LVEF), with two patients experiencing grade 3 or 4 declines in LVEF, according to National Cancer Institute Common Toxicity criteria (defined below). A case report also described bevacizumab-induced serious heart failure in a patient treated with anthracyclines.[34]
In a phase III study comparing paclitaxel with or without bevacizumab for metastatic breast cancer, the rates of grade 3 or 4 left ventricular dysfunction were 0.3% and 0.8% in the paclitaxel and combination groups, respectively.[5] Toxic effects were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0, as follows: left ventricular dysfunction grade 2-asymptomatic, resting LVEF 40-49%; grade 3-symptomatic heart failure responsive to intervention, LVEF 20-39%; grade 4-refractory heart failure or poorly controlled, LVEF less than 20%, intervention required. In Genentech-sponsored studies according to the prescribing information, grades 2-4 left ventricular dysfunction was reported in 1.7% of patients receiving bevacizumab.[35]
Bevacizumab's influence on the heart may be by direct or indirect mechanisms. A specific example of the latter is the acute development of uncontrolled hypertension that is a known consequence of this drug as it decreases nitric oxide production in the endothelium.[36] The consequential increase in myocardial workload, due to an elevated blood pressure, may result in decompensation of heart function particularly in patients who have risk factors for heart failure. A more direct mechanism of heart failure is the decreased repair of myocardial muscle tissue after a cardiac insult as a result of inhibiting VEGF,[33] since myocardial angiogenesis is a necessary event for full repair. After a myocardial infarction, VEGF is responsible for stimulating myocardial endothelial proliferation and myocardial incorporation of endothelial progenitor cells, which ultimately improves cardiac function by way of neovascularization. This may be particularly important in situations where bevacizumab is used in conjunction with an agent, such as doxorubicin, that independently causes myocardial damage. There is no general consensus on the mechanism of bevacizumab-induced heart failure, but it is likely to be multifactorial.
Currently, there are no standard recommendations for patients developing heart failure while receiving bevacizumab; however, the standard maneuver is immediate discontinuation of the offending agent. In addition, it appears reasonable that rechallenge with bevacizumab should be carried out only after careful consideration of risks and benefits, as there are no data, to our knowledge, on the safety of doing so in such patients. Standard heart failure treatment options (discussed in the Prognosis and Treatment of Heart Failure section) should be started.[37]
Sunitinib and Sorafenib
Sunitinib and sorafenib are small molecules that inhibit multiple tyrosine kinase receptors and most potently inhibit VEGF receptors.[26, 32] For this reason, they are known as VEGF receptor tyrosine kinase inhibitors, but significant "off target" activity occurs. For example, both sunitinib and sorafenib also inhibit c-kit and platelet-derived growth factor (PDGF) receptor, whereas sorafenib also inhibits Raf kinase.[26, 32] This is an important point since the differences in the ancillary pathways inhibited by different tyrosine kinase inhibitors may account for the variability of the clinical manifestation and outcome of heart failure for the individual agents.
These drugs have changed the face of treating metastatic renal cell carcinoma and in the specific case of sorafenib, hepatocellular carcinoma, extending response rates or survival to unprecedented levels compared with any previous chemotherapy or targeted agents.[6-8] Before tyrosine kinase inhibitors, there was very little in the way of effective medical therapy, and these drugs alleviated a significant treatment void in both hepatocellular carcinoma and metastatic renal cell carcinoma. As a result, their use gained rapid acceptance, whereas knowledge of their toxicities emerged more gradually. Within this context, cardiotoxicity surfaced as a serious adverse effect, especially with sunitinib where rates of symptomatic cardiotoxicity are reported at 2.7-15% and are rivaling those seen with doxorubicin.[9-12, 26, 38]
Initial concerns regarding the development of posttreatment heart failure with these agents first became apparent in the phase I clinical trial with sunitinib in which two patients had evidence of symptomatic heart failure.[26] No cardiac events were noted in the phase I trial with sorafenib in solid tumors.[32] Subsequently, phase III trials were begun in a variety of tumor types and better defined the cardiac issues with these drugs. These trials include evaluation of both drugs for metastatic renal cell carcinoma, sorafenib for hepatocellular carcinoma, and sunitinib for metastatic gastrointestinal stromal tumors (GIST).[6-8, 39] In the phase III GIST trial, which included patients with imatinib-refractory disease, there were no reports of any LVEF decline or heart failure.[39] In the phase III frontline use of sunitinib for metastatic renal cell carcinoma multicenter trial, 10% of patients were reported to have an LVEF decline with no evidence of symptomatic heart failure.[6] In two phase III trials of sorafenib for hepatocellular carcinoma and metastatic renal cell carcinoma, each reported a 3% rate of cardiac ischemia or infarction.[7, 8]
In a retrospective review of phases I and II data for all cardiovascular events in 75 patients with imatinib-resistant metastatic GIST, symptomatic heart failure was noted in 6 (8%) of 75 patients.[9] After dosing was temporarily stopped or the dose decreased, 5 of the 6 patients with heart failure were able to resume sunitinib after symptoms resolved. Of note, in patients treated with the current FDA-approved dose of 50 mg/day for 28 days on and 14 days off, 28% of patients had a decline in LVEF of at least 10%, and 19% had a decrease of at least 15%. Subsequent studies have reported rates of sunitinib-induced heart failure of 2.7-15%.[10-12]
More recently, a prospective observational study attempted to establish the true incidence of cardiotoxicity with these agents by a rigorous screening and follow-up system. The authors examined patients receiving sunitinib or sorafenib in the treatment of metastatic renal cell carcinoma.[12] These patients underwent a battery of assessments including coronary artery disease risk factors, history or evidence of coronary artery disease, hypertension, rhythm disturbances, and heart failure. Monitoring included assessment of symptoms, electrocardiograms, and biochemical markers (creatine kinase-myocardial band isoenzyme and troponin T levels). Echocardiography was performed at baseline in selected patients and in all patients who experienced a cardiac event. Among 74 patients deemed assessable, 25 patients (33.8%) experienced a cardiac event, with 7 patients (9.4%) having an event serious enough to necessitate admission to an intermediate or intensive care unit. Of importance, all patients recovered with cardiovascular management and were deemed suitable for further tyrosine kinase inhibitor therapy. The statistical analysis did not reveal a correlation between tumor response and cardiovascular event.
The precise mechanism by which sunitinib and/or sorafenib causes heart failure is unknown, but it is likely multifactorial in nature. One study examined the direct cardiotoxicity of sunitinib in mice and attributed cardiomyocyte toxicity to a combination of cytochrome-c release (an intermediate involved in apoptosis or cell death that is usually released in response to stimuli) and activation of caspase-9 (initiator caspase in the mitochondrial apoptotic pathway) along with concomitant hypertension.[9] Other studies have implicated B cell lymphoma 2-regulated cytochrome-c release, inhibition of PDGF, VEGF, Raf, or KIT, as all are relevant to cardiomyocyte survival.[9, 40-42] Raf kinase activity has been shown to be vital for cardiac hypertrophy and survival in overload pressure, and cardiac interference of c-Raf-1 may induce apoptosis.[41, 43] Platelet-derived growth factor has been described to have a protective role on the heart in response to insufficient blood flow, and KIT may be necessary for recruiting endothelial progenitor cells so that repair can occur when there is myocardial damage.[42]
The data suggest that patients recover after symptomatic heart failure from sorafenib or sunitinib after discontinuation of the offending agent, but this may not continue to hold true as more experience accumulates with tyrosine kinase inhibitors. We previously reported a case of sunitinib-induced heart failure in a patient who subsequently tolerated sorafenib without a recurrence of any cardiovascular problems.[38] In contrast, another report has shown that cardiotoxicity is increased with sorafenib in patients previously treated with sunitinib.[44] In patients with symptomatic heart failure, it appears prudent to stop the offending agent and immediately begin heart failure treatment. Even though it appears that almost all patients recover, serious arrhythmias (e.g., ventricular tachycardia degenerating into ventricular fibrillation) are a known complication of heart failure; thus prompt action seems to be the prudent course. In addition, data on the long-term effects of these drugs are limited. Most patients appear to tolerate reinitiation of the drugs after their heart failure has dissipated, but this is not a predictable occurrence, and criteria for rechallenge have yet to be developed. A strong consideration should be given to rechallenging with the offending drug only if the patient has demonstrated an objective tumor response to the treatment in the setting of limited therapeutic options.
HER2-Targeted Agents
In 2009, an estimated 190,000 women were predicted to be diagnosed with and 40,000 women were predicted to die from breast cancer in the United States.[45] Anthracyclines have been considered the standard of treatment for early- and advanced-stage breast cancer.[46] A subset of approximately 25% of patients with breast cancer overexpress the extracellular domain of human epidermal growth factor (EGF) receptor-2 (also called HER2 or HER2/neu) cell surface receptor protein.[47] The EGF receptor or HER family of receptor kinases are enzymes that play a vital role in several processes such as cell proliferation, differentiation, and survival.[47] Aberrant HER2 signaling is associated with cancer cell proliferation and survival. In the 1980s, a monoclonal antibody known as trastuzumab was developed and later approved in 1998 for the treatment of metastatic breast cancer.[47] Based on success in adjuvant trials, the agent was approved several years later for this indication as well.[47] Lapatinib, which was approved a few years later, is the first small-molecule kinase inhibitor of the HER2 receptor. The approval of these targeted agents has greatly improved the success of treatment for breast cancer.
Trastuzumab
Trastuzumab is a monoclonal antibody with specific high affinity for the extracellular domain of the HER2 receptor. Its binding to HER2 prevents this receptor from conveying the intracellular signaling that would occur with uninhibited binding of EGF to the receptor. Trastuzumab is approved to treat both HER2-positive metastatic and early breast cancer.[47] Cardiotoxicity was not reported in the preclinical and early-phase clinical trials of trastuzumab, and this toxicity appeared as an unanticipated adverse effect in later-phase clinical trials.[47] Heart failure was seen in some phase II trials, but the frequencies were low, and patients may have been at increased risk from previous anthracycline exposure.
Because of the number of reports of heart failure from the phase III studies, an independent Cardiac Review and Evaluation Committee (CREC) was established to assess the adverse cardiovascular effects from trastuzumab therapy.13 This group analyzed data from seven trials that incorporated 1219 patients. By using a specific set of criteria to identify heart failure, cardiotoxicity was identified in 112 patients (9.2%). These criteria were the following: cardiomyopathy characterized by a decrease in cardiac LVEF that was either global or more severe in the septum; symptoms of heart failure; associated signs of heart failure, including but not limited to S3 gallop, tachycardia, or both; and a decline in LVEF of at least 5% to less than 55% with accompanying signs or symptoms of heart failure, or a decline in LVEF of at least 10% to less than 55% without accompanying signs or symptoms. These results led investigators to incorporate cardiac monitoring that included evaluation of baseline LVEF into future trials of trastuzumab treatment.
The CREC review revealed that New York Heart Association (NYHA) classes III and IV symptoms were more common among patients receiving both an anthracycline and trastuzumab. Approximately 75% of the patients with cardiac dysfunction presented with symptoms. Most patients were treated with diuretics (78%), angiotensin-converting enzyme (ACE) inhibitors (58%), cardiac glycosides (58%), or other inotropes. Seventy-nine percent of patients treated responded to these therapies. Cardiac deaths were rare, being reported in less than 1% of patients from the seven trials reviewed.[13]
Patients who developed cardiotoxicity improved after trastuzumab was discontinued, but potential long-term effects are unknown. One group of authors conducted a study involving 38 patients who developed trastuzumab-induced toxicity during a period of 4 years.[48] The mean ± SD LVEF was 61% ± 13% after treatment with doxorubicin but before treatment with trastuzumab. The LVEF significantly decreased after trastuzumab therapy (p<0.0001), with 52% of the patients experiencing symptomatic heart failure. After withdrawal of trastuzumab, the LVEF increased to just below the starting LVEF (56% ± 11%), with a mean time to recovery of 1.5 months after discontinuation of trastuzumab. Almost all patients (97%) had increases in their LVEF. Sixty-six percent of the patients were treated again with trastuzumab while continuing their regimen for heart failure, with only 12% having recurrence of left ventricular dysfunction. The results of this study show that it may be safe to restart trastuzumab therapy after development of heart failure symptoms. In an attempt to understand if trastuzumab caused changes in the structure of cardiomyocytes, nine patients also underwent endomyocardial biopsy, where ultrastructural changes were not seen.
The best known independent risk factors for trastuzumab-induced cardiotoxicity are advanced age and concurrent or previous anthracycline therapy.[49, 50] Other suspected risk factors are previous cardiac disease and NYHA class II symptoms. The sequence in which chemotherapeutic agents are administered could also affect the development of cardiotoxicity.
The mechanism of trastuzumab-induced cardiotoxicity is largely unknown but may reside within the central role of the EGF receptor signaling pathway in cardiomyocyte homeostasis. The HER2-4 receptor tyrosine kinases activate ligand neuregulins (members of the EGF family), which are mainly expressed in cardiac microvascular endothelial cells and are increasingly expressed under conditions of oxidative stress. Mouse models have demonstrated an important role of HER2 in cardiomyocyte function and development.[51, 52] Augmentation of HER2 signaling in cardiomyocytes may offer protection and improve myocardial function. Trastuzumab blocks the extracellular domain of the HER2 receptor, which may leave the myocardium exposed to the unopposed damaging effects of stress-signaling pathways. An alternative mechanism is related to the role of HER2 signaling on mitochondrial function. Turning off HER2 signaling leads to adenosine 5'-triphosphate (ATP) depletion and can cause contractile dysfunction without significantly changing cardiomyocyte ultrastructure.[42] This result is congruent with the findings of the study discussed above.[48] However, focal vascular changes, pleomorphic mitochondria, myocardial cell hypertrophy, and mild interstitial fibrosis have been detected in endomyocardial biopsies evaluated by electron microscopy.[53]
The American Heart Association-American College of Cardiology (AHA-ACC) recommend detecting heart failure at its earliest, minimally symptomatic stage.[54] Based on the results of studies, the most frequent sign of trastuzumab-induced cardiotoxicity is an asymptomatic decrease in LVEF. In the Herceptin Adjuvant (HERA) trial, an asymptomatic decrease in LVEF occurred in 7.1% of patients, whereas symptomatic heart failure occurred in 1.7% of patients.[15] Also, the combined results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 and the North Central Cancer Treatment Group trial N9831 (which compared adjuvant chemotherapy with or without trastuzumab) showed 14.2% of patients had an asymptomatic decrease in LVEF, and 4.7% of patients had to discontinue treatment because of heart failure or other adverse effects.[16]
The optimal cardiac monitoring strategy for patients receiving trastuzumab remains unknown. Based on the reversibility of trastuzumab-induced cardiotoxicity, it is reasonable to reevaluate left ventricular function at regular intervals. The British Society of Echocardiography has issued a statement recommending measuring left ventricular function before treatment and every 3 months during treatment.[55] The risks and benefits of using trastuzumab in patients with a baseline LVEF less than 50% should be carefully weighed. If new symptoms occur or a patient's LVEF decreases by more than 10%, discontinuing trastuzumab might be required. Information regarding the long-term safety of trastuzumab therapy in patients with cardiac dysfunction is limited.
Lapatinib
Lapatinib is an oral dual-kinase inhibitor targeting both ERB1 and HER2 receptors. The ERB1 is overexpressed in 27-30%, and HER2 is overexpressed in 20-25% of patients with breast cancer, respectively.[56] Lapatinib is FDA approved for use in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer overexpressing HER2 and who have failed previous therapy with an anthracycline, a taxane, and trastuzumab.
Cardiac function was prospectively analyzed at baseline, every 8 weeks during therapy, and at withdrawal of study treatment in 3558 patients with breast and other cancers treated with lapatinib in 18 phases I-III clinical trials.[57] Ten of the trials used lapatinib as monotherapy, and eight trials included lapatinib in combination with either capecitabine, letrozole, paclitaxel, cisplatin, or oxaliplatin-5-fluorouracil. Five hundred ninety-eight patients had received previous therapy with anthracyclines, 759 received trastuzumab concurrently with chemotherapy or after an anthracycline, and 2201 received neither anthracyclines nor trastuzumab.
Despite the fact that lapatinib, like trastuzumab, also targets HER2, lapatinib was found to decrease LVEF in only 1.6% of patients.[57] The mean ± SD LVEF decrease was 18.7% ± 11-32%, with most patients experiencing asymptomatic declines (1.4% asymptomatic, 0.2% symptomatic). Patients with breast cancer were not found to be particularly at higher risk for decreased LVEF compared with those with other cancers. By way of comparison, of the 598 patients who had been pretreated with an anthracycline, but not trastuzumab, only 1.2% had a decrease in LVEF, with 0.3% of those being symptomatic. Of the 759 patients who were pretreated with both trastuzumab and chemotherapy, 1.7% experienced a decrease in LVEF, with 0.1% being asymptomatic. Of the 2201 patients who were anthracycline and trastuzumab naïve, 1.7% had an LVEF decrease, with 0.2% being symptomatic.
The time to onset of LVEF decline occurred within 9 weeks of treatment for most patients. The 0.2% of symptomatic patients presented with dyspnea, palpitations, and signs of heart failure. Fortunately, these patients promptly responded to standard therapy. Thus, lapatinib did not appear to impart a significant cardiotoxic risk in this setting. In fact, this study shows that the percentage of patients who developed a decline in LVEF in the lapatinib trials was lower than that of the general population and those who were treated with trastuzumab.[57] Of the patients who developed symptomatic LVEF decreases, cardiotoxicity resolved in all but 14% of patients.
Based on these results, it seems that the cardiac adverse effects from lapatinib are reversible and nonprogressive. It may be that the effects of lapatinib are similar to those of trastuzumab in that the cardiotoxicity is mostly reversible, not cumulative or dose related, and ultrastructural myocardial changes may not be seen.[48, 53, 57]
The same group of authors also evaluated 44 phases I-III studies that included 3689 patients receiving lapatinib as healthy volunteers (10%), patients with breast cancer (62%), and patients with other cancers (28%).[17] Lapatinib was studied as monotherapy in 54% of patients, as combination therapy with chemotherapy or endocrine therapy in 41%, and as combination therapy with trastuzumab in 5%. Data on the duration of therapy was available for 68% of patients, with 69% of those being treated for less than 3 months, 20% for 3-6 months, 5% for 6-9 months, 3% for 9-12 months, and 3% for more than 12 months.
The overall analysis of this study showed a low rate of symptomatic (0.2%) and asymptomatic (1.4%) cardiac events. The occurrence of cardiac events and degree of LVEF decline from baseline were similar in patients with and those without a history of receiving anthracyclines or trastuzumab or both. The results of this study do not suggest there is a cumulative dose-related toxicity, and the cardiac events related to lapatinib were also largely reversible.
Based on the similarities between trastuzumab and lapatinib, it is reasonable to extend the Cardiac Guidelines Consensus Committee's guidelines for the management of trastuzumab related heart failure to lapatinib.[58] Based on the consideration that the eligibility criterion for the lapatinib trials was a normal LVEF, baseline LVEF should be checked before patients begin lapatinib therapy. In the clinical trails with lapatinib, if a patient's LVEF declined below the institutions' lower limit of normal by greater than 20% from baseline, lapatinib was withheld and cardiac function reevaluated 1 month later. Final guidelines and recommendations on the frequency of LVEF monitoring do not yet exist, but an evaluation completed at baseline and every 3 months during therapy is appropriate until further data are available.
BCR-ABL-Targeted Agents
Chronic myeloid leukemia develops as a result of an acquired mutation in the hematopoietic stem cells causing a balance translocation between chromosomes 9 and 22. This leads to the fusion of the Abelson (ABL) tyrosine kinase gene from chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22, the BCR-ABL gene. This functions as an oncogenic tyrosine kinase.59 The utility of imatinib, a selective inhibitor of BCR-ABL, in treating this disease proved the dependence of chronic myeloid leukemia cells on BCR-ABL tyrosine kinase activity for their survival. Unfortunately, patients may develop resistance to imatinib and require therapy with second-generation BCR-ABL inhibitors (dasatinib and nilotinib).[60-62]
Imatinib
Imatinib is a selective inhibitor of the BCR-ABL translocation-derived oncogene product, PDGF, and stem cell receptor (c-kit) tyrosine kinases.[18] Imatinib has significantly improved the survival of patients with chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, hypereosinophilic syndrome, and GIST.[18]
The authors of one study evaluated the medical records of patients with a hematologic malignancy treated with imatinib monotherapy or imatinib in combination with chemotherapy or other investigational agents between July 28, 1998, and July 27, 2006.[18] A total of 1276 patients were included, of whom only 22 (1.7%) were found to meet Framingham criteria for heart failure during the course of imatinib therapy. The median age of these patients was 70 years (range 49-83 yrs), and 10 were women. The rate of new-onset heart failure increased with increasing age: 0.3% for ages 45-55 yrs, 1.7% for ages 56-65 yrs, 2.8% for ages 66-75 yrs, and 9.3% for ages 76-85 yrs. No correlation between dose and occurrence of heart failure was found.
Twelve (55%) of the 22 patients with heart failure had received previous interferon alfa for a median of 14 months, and three patients had received anthracyclines (two developed heart failure while receiving anthracycline therapy). Eighteen (82%) of the 22 patients had previous cardiac conditions or other medical conditions that could be considered risk factors for cardiac disease including history of heart failure (27%), diabetes mellitus (27%), hypertension (45%), coronary artery disease (36%), arrhythmia (14%), and cardiomyopathy (5%). The median time to cardiac event from the start of imatinib therapy was 162 days (range 2-2045 days). At the time heart failure was identified, 8 (36%) of 22 events were considered possibly or probably related to imatinib. Only 15 (68%) of the 22 patients had an echocardiogram or multiple gated acquisition (MUGA) scan at the time of the event, and nine had a documented low LVEF (< 50%). Two of these nine patients had LVEF values of 45-50% and 50-59%, respectively, before imatinib therapy.
Eleven (50%) of the 22 patients continued imatinib therapy with dosage adjustments and management of heart failure symptoms without further complications.[18] Of the remaining patients who continued therapy, five patients had dosage reductions and six continued taking the same dosage. The treatment of heart failure in these patients consisted of diuretics, β-blockers, and ACE inhibitors.
Another group of authors retrospectively examined the data of 10 patients who presented with severe heart failure without obvious cause while receiving imatinib.[24] All individuals had normal LVEFs (56% ± 7%) before imatinib treatment, but had NYHA class III or IV heart failure (LVEF 25% ± 8%, p<0.001) after an average of 7.2 ± 5.4 months of therapy. Myocardial biopsy specimens obtained from two patients without preexisting cardiac history provided clues to the mechanism of this adverse effect. Histologic examination revealed prominent membrane whorls within the myocytes. This type of abnormality is characteristic of toxin-induced myopathies and is rarely seen in non-ischemic idiopathic dilated cardiomyopathies. Other abnormalities seen include pleomorphic mitochondria with effaced cristae, scattered cytosolic lipid droplets and vacuoles, and glycogen accumulation in cardiomyocytes; againconsistent with the pathologic diagnosis of toxin-induced myopathy.
Nonhuman experimental data provide a context to this observation. One of the most informative long-term studies involved treating mice with imatinib 200 mg/kg/day so as to mimic blood levels of drug comparable to those in humans.[24] After 304 weeks of therapy, there was a significant reduction in left ventricular mass indexed to body weight associated with deterioration in contractile function and moderate left ventricular dilation. Imatinib produced a dose-dependent collapse of the mitochondrial membrane potential followed by pronounced release of cytochrome-c into the cytosol. There was also a large decrease in cellular ATP content and in the ATP:adenosine 5'-diphosphate ratio. This is particularly important since ATP is the molecular engine that drives myocardial contraction. Although there was evidence of classic apoptosis, there were also markers of necrotic cell death such as pronounced cytosolic vacuolization and loss of sarcolemmal integrity, all of which help account for the loss of myocardial muscle mass.
It appears that the molecular target of imatinib, c-Abl, serves a role in myocardial homeostasis. Work with genetic mutant mice examined whether imatinib-induced death in these mice was due to inhibition of c-Abl, the PDGF receptor, or an unknown target of imatinib unrelated to kinase inhibition. Cardiomyocytes genetically engineered to express the imatinibresistant c-Abl mutation were protected from the imatinib-induced cell death. The results of this experiment show that imatinib-induced inhibition of c-Abl may be important for the observed cardiomyocyte toxicity and that c-Abl has a survival function in cardiomyocytes.[24] It suggests that inhibition of c-Abl also leads to activation of the endoplasmic reticulum stress response ultimately leading to cell death.[18, 24]
Although there is some understanding of the molecular effects of imatinib, the net physiologic effects on cardiac function are much more complex. For example, one study concluded that imatinib was cardioprotective in rats with hypertension.[63] This effect could be due to the inhibition of PDGF effects, thereby blunting the self-destructive responses of the heart to high blood pressure. In addition, imatinib independently induces peripheral fluid retention. This additional workload on the heart can precipitate frank heart failure in susceptible individuals.
Fortunately, heart failure is an infrequent consequence of imatinib use. The Novartis clinical database includes 2327 patients with an average exposure to imatinib of 2.5 years. This database included 12 cases of heart failure that may be possibly or probably related to imatinib.[19] Based on 5595 patient-years of exposure, the incidence was 0.2%/year.
Based on the limited evidence and rare occurrence of true imatinib-induced heart failure, it appears evident that the cardiac complications associated with therapy are manageable. Dosage adjustments, brief treatment holidays until resolution of symptoms, and management of heart failure symptoms should all be considered in patients developing clinically symptomatic events. In our opinion, cardiac complications should not justify lifelong discontinuation of imatinib in patients with serious to life-threatening diseases that readily respond to therapy (chronic myeloid leukemia, GIST), as many of the patients described above tolerated further imatinib therapy without complications.
Dasatinib
Dasatinib is a novel, multitargeted inhibitor of BCR-ABL and SRC family kinases that was designed to overcome the imatinib resistance in cancer cells. In vitro studies have shown approximately a 325-fold greater potency than imatinib against BCR-ABL.[64] Adverse effects associated with dasatinib use include peripheral edema and pleural effusion.[60] The prescribing information lists dasatinib as having a 4% incidence of heart failure or cardiac dysfunction for patients with chronic myeloid leukemia.[25]
Nilotinib
Nilotinib is another multitargeted kinase inhibitor that inhibits the ABL, KIT, and PDGF receptor.[61, 65] Nilotinib has approximately a 20-fold greater potency in vitro than imatinib.[66] Although nilotinib does not have an association with heart failure, it does have other cardiac adverse effects. The drug's labeling has an FDA-mandated black-box warning regarding prolongation of QTc interval and an increased risk of sudden cardiac death.[62] The QTc-interval prolongation is a dose-dependent event caused by prolonged cardiac ventricular repolarization.
Monitoring of Cardiotoxicity during Treatment
Heightened vigilance and continued monitoring for symptoms of heart failure are critical for patients receiving these therapies. This is important since discontinuation of the offending drug often results in significant improvement and recovery. Common symptoms include dyspnea at rest or on exertion, reduction in exercise capacity, orthopnea, paroxysmal nocturnal dyspnea, nocturnal cough, peripheral edema, scrotal edema, and ascites. Vague, nonspecific manifestations of heart failure are early satiety, nausea, vomiting, abdominal discomfort, wheezing, cough, unexplained fatigue, and confusion or delirium.[54]
No consensus guidelines have yet been established with regard to monitoring patients during treatment. The AHA-ACC recommends detecting heart failure at its earliest, minimally symptomatic stage.[54] The Heart Failure Society of America guidelines do not recommend routine reevaluation of cardiac function by noninvasive or invasive methods.[47] The reversibility of cardiotoxicity caused by some agents would suggest that serial monitoring and withholding the drug and providing treatment are important when left ventricular dysfunction is detected.
Natriuretic peptide is a family of polypeptide hormones secreted by atrial heart muscle cells under conditions of heart failure. Because of its central role in cardiac function, natriuretic peptide is thought to be one of the best candidates for population screening of markers of cardiac dysfunction.[67] However, biologic and assay variability and relatively low specificity of diagnostic cutoffs associated with acceptable negative predictive values are severe limitations that make natriuretic peptide levels unsuitable for general population screening.[67] When heart failure symptoms are present, or under the right clinical scenario, B-type (brain) natriuretic peptide (BNP) and its amino-terminal fragment, NT-pro BNP, have similar accuracy when screening for cardiac dysfunction.[67] Both of these peptides are also independent predictors of longterm mortality in asymptomatic patients, even after adjustment for various clinical and echocardiographic variables.[67] The cost-effectiveness of using these peptides for screening has yet to be evaluated. The Systolic Heart Failure Treatment Supported by BNP (STARS-BNP) study evaluated young, mostly male patients with systolic dysfunction to determine the prognostic impact of treating with the goal of decreasing plasma BNP levels to less than 100 pg/ml.[68] The patients in the BNP group experienced fewer heart failure-related deaths and hospitalizations for heart failure. Thus, monitoring and treating to a goal BNP level might be a good treatment strategy for these patients.
Most studies examining the new targeted therapies evaluated LVEF directly by either echocardiogram or MUGA scan. This typically occurred at baseline before starting the study and at regular intervals or when patients became symptomatic. The British Society of Echocardiography has issued a guideline statement recommending patients receiving trastuzumab have a pretreatment and every third month measurement of LVEF.[55] No other agent-specific recommendations are available at this time.
Data suggest that other screening tests may be able to detect cardiotoxicity in a more sensitive and immediate manner. Measurement of cardiac troponin is a potential tool. Cardiac troponin is a component of the myocardial contractile apparatus that is released into the circulation in the event of myocardial damage with as little as one cycle of chemotherapy.[48] This test becomes increasingly abnormal with each cycle in patients who ultimately develop left ventricular systolic dysfunction.[48] B-type natriuretic peptide is also a potential immediate marker for patients with elevated filling pressures, which often suggests myocardial dysfunction. Both of these markers may be used to provide immediate feedback regarding the risk of development of left ventricular dysfunction.[48] However, the evaluations of these markers suggest that they are better at confirming or following up on a diagnosis, than as an up-front screening tool in asymptomatic patients.
Prognosis and Treatment of Heart Failure
The long-term consequences for patients with cancer who experience heart failure as an adverse effect of therapy are not known. It is also unclear how long patients treated for heart failure will need to take heart failure drugs since some degree of recovery usually occurs once the offending agents are stopped. We found no heart failure-specific outcomes studies in patients who develop heart failure with these therapies to inform us about prognosis. Systolic dysfunction tends to be the most common mechanism by which these agents cause heart failure. Both the pathology underlying heart failure and the reversibility of the condition varies by agent and are distinct from the heart failure that occurs in the general noncancerous population. In the latter, heart failure is usually the consequence of fixed, irreversible factors such as refractory ischemic heart disease, myocyte loss from infarction, or cardiomyopathy. Thus, the existing prediction models for the development of heart failure may not be accurate in patients with heart failure due to targeted therapies. Nevertheless, some of the negative predictors, including advanced age, low LVEF, diabetes mellitus, and renal insufficiency, may also impact targeted therapy-induced heart failure.[67] Given the reversibility of targeted therapy-related heart failure once the offending agent is discontinued, it is interesting to hypothesize that cardiac outcomes may be better than those in the general population who develop heart failure. At this time, however, there are no outcome studies that can help prove this concept.
Patients who develop new-onset cardiac dysfunction and are treated with potentially cardiotoxic chemotherapy agents should have other causes of cardiac dysfunction excluded first (e.g., coronary artery disease, myocarditis, alcohol abuse). The management of cardiomyopathy due to cardiotoxic agents is the same as that of other nonischemic cardiomyopathies.[10, 69] The AHA-ACC guidelines recommend multidrug therapy in the treatment of heart failure to slow cardiac disease progression and improve outcomes.[54] Therapy with diuretics should be started to restore and maintain normal volume status in patients with evidence of fluid overload.
Patients who are considered at high risk of heart failure (stage A) include those without functional or structural heart disorders who have cancer and are treated with potentially cardiotoxic agents. These patients should receive aggressive medical care and management of modifiable cardiac risk factors such as diabetes and hyperlipidemia. Smoking cessation and regular aerobic exercise should also be encouraged in all patients receiving potentially cardiotoxic treatments. If these patients have hypertension, an ACE inhibitor or angiotensin II receptor blocker (ARB) should be used.
Patients who are considered stage B (asymptomatic but with a reduced LVEF) or stages C and D (symptomatic with a reduced LVEF) should be actively treated with an ACE inhibitor or ARB.[10, 69] β-Blocker therapy may also be administered to asymptomatic patients with a decreased LVEF.[54] If patients cannot tolerate an ACE inhibitor or an ARB because of renal insufficiency, for example, then hydralazine and isosorbide dinitrate may be used.[10, 69]
β-Blockers may also be used in the treatment of severe heart failure. Carvedilol, long-acting metoprolol, and bisoprolol have approved indications for the treatment of patients with heart failure. One potential approach is to begin an ACE inhibitor and β-blocker at low doses, and then slowly titrate to the maximum tolerated doses.[69] Aldosterone antagonists (spironolactone and eplerenone) have been recommended in the updated AHA-ACC guidelines for the treatment of patients with symptomatic heart failure.[54] The use of digoxin in patients with heart failure is controversial due to its lack of mortality benefit. Digoxin is particularly useful in patients with atrial fibrillation and left ventricular dysfunction because of the dual benefit of inotropic support and rate control.[69]
Conclusion
In patients with cancer, heart failure from molecularly targeted therapies represents a clinically significant problem that has recently come to the forefront of concern. The risk of heart failure should be considered by practitioners treating patients with these newer targeted therapies. Patients require close monitoring during treatment with these agents, especially patients with preexisting cardiovascular conditions. Counseling regarding the signs and symptoms of heart failure should be stressed when initiating these drugs, which are known to cause heart failure in rare instances. In patients developing heart failure, it appears prudent to discontinue the offending agent and immediately begin appropriate treatment measures for heart failure.
As to whether or not the same agent can be restarted is a controversial topic; however, it appears that in some patients the same or similar agents may be used once symptomatic heart failure resolves. As is always the case with cancer treatment, it is important to consider the risk:benefit ratio for each individual patient. Unfortunately, too little experience exists with these agents to fully understand the long-term consequences of their adverse effects. As the oncology community continues to shift toward the increased use of these agents, it has become evident that more research and work need to be done to elucidate the causes and ultimately aim to prevent cardiovascular events from occurring.
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Dr. Wong's work is supported by the Jennifer Linscott Tietgen Family Charitable Foundation and the Cuvelier Family Foundation.
Pharmacotherapy. 2011;31(1):92-111. © 2011 Pharmacotherapy Publications
Here is some information from the Breastcancer.org website:
Herceptin Side Effects
Herceptin causes flu-like symptoms in about 40% of the people who take it. These symptoms may include:
- fever
- chills
- muscle aches
- nausea
Side effects generally become less severe after the first treatment. Your treatment team will monitor you during your infusions, especially your first dose, and can adjust the infusion if you are very uncomfortable. If you are receiving Herceptin every 3 weeks, you may have stronger side effects.
If you are receiving Herceptin with chemotherapy, you may also experience chemotherapy side effects.
Serious heart side effects
Less commonly, Herceptin can damage the heart and its ability to pump blood effectively. This risk has ranged between 5% to 30%. The damage can be mild and result in either no symptoms or signs of mild heart failure, like shortness of breath. Less commonly, the heart damage is bad enough that people experience life-threatening congestive heart failure or a stroke. The risk of heart damage, especially severe damage, is greater when Herceptin is given along with other chemotherapy medicines known to cause heart damage. Adriamycin is an example of a chemotherapy that can cause heart damage.
Women who experience mild or more serious heart damage can stop taking Herceptin and start taking heart-strengthening medications. This often brings heart function back to normal.
Testing your heart before and during Herceptin treatment
Before starting Herceptin therapy, you should have an echocardiogram or a MUGA (multigated blood-pool imaging) scan to check how well your heart is functioning.
- An echocardiogram uses sound waves to take detailed pictures of the heart as it pumps blood. For this quick test, you lie still for a few minutes while a device that gives off sound waves is briefly placed on your ribs, over your heart. There is no radiation exposure with this test.
- A MUGA scan takes about an hour. In this test, a tiny amount of radioactive material is injected into a vein in your arm. This material temporarily hooks onto your red blood cells. You lie still while a special camera that can detect the radioactive material takes pictures of the blood flow through your heart as it beats.
When you first start taking Herceptin, your doctor might want you to have MUGA scans or echocardiograms every few months to detect any sign of heart failure. But after you've been on Herceptin for a while, you may need a heart-monitoring test only every 6 months or so. This is because heart failure is less likely to occur the longer you take Herceptin.
Notify your doctor immediately or go to the nearest emergency room if you're taking Herceptin and you develop any symptoms of heart failure, such as shortness of breath, difficulty breathing, a fast or irregular heartbeat, increased cough, and swelling of the feet or lower legs.
Serious lung side effects
Herceptin can rarely cause two possibly related serious reactions that interfere with breathing. One of these is a reaction during or shortly after Herceptin is being administered. This is like a bad allergic reaction, with symptoms that include hives, as well as wheezing and trouble breathing due to sudden swelling and narrowing of the airways. The other reaction, called pulmonary toxicity, results in swelling of the lung tissue, low blood pressure, and possibly fluid buildup around the lungs (called pleural effusions).
The risk of these life-threatening reactions is rare -- much less than 1%. In most cases, these reactions happen during infusion or within the first 24 hours of the first dose of Herceptin. Less commonly they can happen within a week of the first dose. Only occasionally do these reactions occur with the second or later doses. The lung reaction can be more severe when lung disease, such as asthma or emphysema, already exists, or if the breast cancer has spread significantly into your lungs. If you are currently undergoing treatment with Herceptin and have been tolerating it well, you're unlikely to develop these serious reactions.
Even though the severe side effects are relatively rare, your doctor should check you carefully for any heart or lung problems before starting to treat you with Herceptin. You should also be monitored closely for these serious side effects during treatment
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Heart issues are sometimes a problem with the AC TH (anthracycline) regime, but only extremely rarely with TCH (the regimen given to most very early stage patients.) In the rare case of TCH related heart failure, heart failure virtually always reverses itself and resulted in no deaths in the large clinical trial it was tested in. For data - google "BCIRG 006" select pdf showing 3rd planned efficacy (latest) analysis. The safety data is towards the back of the presentation.
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I admire evebarry for having the intelligence and fortitude to continue to explore her options and to share her exploration here in behalf of others with complicating concurrent disease factors in similar situations, where the cookie cutter approach of standard therapy is less applicable. She is doing so despite the barrage of people posting their impressions (including me).
If this were a forum that was not clearly identified specifically as being for those who are actively interested in the exploration of alternative therapies, the insulting comment that was made to the effect "enough already, evebarry" might be more understandable. If inquiries here such as evebarry's are unwelcome to some, it is not mandatory for those persons to come here and continue to read them.
AlaskaAngel
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WOW...talk about scary. Just reinforces my decision not to do chemo! I already have heart issues, and I wouldn't want to risk my health further by overkill on a small stage cancer.
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Nobody said inquiries like hers were "unwelcome."
What I said was that despite what you or I think, Evebarry doesn't need to justify her decision to anyone. She's comfortable with her decision and I wish her the best.
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Kaara - just wondering.... with a very small grade 1 HR+ tumor and no nodes, did anyone suggest you do chemo? I would think not, unless you had a high oncotype score or perhaps LVI
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Kaara,
Especially with pre-existing heart issues, it's wise to look at the risks versus benefits! It's a great thing that the "standards of treatment" allow for and encourage variation depending on specific circumstances! Chemo is certainly not recommended as a one-size-fits-all, and comorbidities should always be considered and factored in.
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thenewme:
I stand corrected. I don't speak for evebarry. "We get it" can be read to mean "enough already, we don't want to hear it" but that was not what you were saying, and I apologize for taking it that way.
A.A.
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VR:
The study you cite is SO outdated that it is irrelevant.
It was identified by me as being an old study in order not to confuse anyone about that: "Here is a study from almost a decade ago." I may not have made my point clear, but the point of the post was in response to those who have posted out of lack of adequate knowledge where they indicated that OA was not as effective as chemotherapy. It was demonstrated almost a decade ago that indeed OA is as effective as CMF chemotherapy.
Again, this is a forum for those who are exploring the possibilities available for alternative therapies. Some may simply prefer to choose not to do chemotherapy because of the lack of any garantee that treatment will absolutely work for any given patient. Some may be choosing alternative therapy because standard therapy poses significant problems for other disease conditions they also have. Posting the information that an alternative that is comparable to CMF has been identified may be helpful to them in their selection of alternatives. There is a warning given with it that it is old information, and no effort was made to imply that it is considered current standard therapy. The information I provided is not irrelevant in this forum.
"The perspective was developed BEFORE the advent of Herceptin for HER2+ tumors AND genetic testing for ER+ tumors. Back in the stone age of the new millenium, most pre-menopausal ER+ women were recommended chemotherapy. Not any more. Before the development of all of the new genetic tests such as Oncotype DX and Mammaprint, most pre-menopausal ER+ women were recommended chemotherapy despite the fact that doctors knew they were OVER treating the majority of patients. Unfortunately, before these genetic tests were approved, doctors didn't know which women had more aggressive ER+ tumors, so the standard of care, here in the United States, at the time, was to treat EVERYONE. Since the introduction of these genetic tests, the standard of care has CHANGED and more women are spared OVER treatment with chemo. This is the direction that I referred to earlier on this thread...where genetic testing is leading to more personalized and targeted therapies.
Such testing has been approved and is being evaluated with time for its limitations. Evebarry was recommended to do chemotherapy, and my post is in regard to her situation.
None of these clinical trials have been completed, as yet. Recall however, that I mentioned the importance of looking back at previous years of NCCN guidelines which provide clues to trends. It is obvious from looking at previous NCCN guidelines and the study you mention that the TREND is moving far, far away from offering chemo as a first line of treatment for early stage ER+ breast cancer. Evebarry was recommended to do chemotherapy, and my post is in regard to her situation.
Likewise, as others have chimed in, the data is NOT included in prognostics tables BECAUSE the therapies are still be investigated.
My question has been to ask not only why the information has not been available in the prognostic tables, but also why these studies have not been attempted and completed long ago. Science has known for a very, very long time that OA provided benefit to some breast cancer patients -- long before the advent of toxic therapies. As long as they are "still being investigated" the information in the prognostic tables continues to keep breast cancer patients focused on making a choice between hormonal therapy only or chemotherapy or both, even though it has been known for a very long time that OA provides benefit to some breast cancer patients. If patients are blindfolded to that fact by not presenting any information to indicate that OA is actually a known beneficial therapy in the prognostic tables while failing to conduct the trials in a reasonably timely way, then IMHO, the information provided by the prognostic tables is failing to present information objectively. How many studies for chemotherapies have been successfully completed during all those years that studies for OA were not completed?
Regarding the European perspective, their recommendation was made BEFORE the wide use of Herceptin for women with HER2+ tumors. AND the most important point of the perspective you failed to underline. What they said was for premenopausal HER2+ women who did NOT develop chemo related amenorrhea, then O/S was recommended.
As I posted, specific to evebarry:
"It helped to learn that ovarian ablation for HR+ early stage bc is presently considered professionally equal to CMF chemotherapy, and not inferior to it. In addition, you are addressing the issue of the added risk posed by HER2 positivity with the use of trastuzumab."
A.A.
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AA - at present there is no data showing to what degree that use of trastuzumab (Hercptin) alone addresses Her2 positivity without chemo. Apparently a trial is underway in older women, so we will have some idea in a few years, but unfortunately data doesn't exist to help with decisions now.
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AA - thanks, I'm glad I could clarify.
I'm still concerned, though, that although you acknowledge that this is Evebarry's thread and that her doctors recommended chemotherapy for her, you continue to disparage chemotherapy.
I appreciate that you have some unresolved questions about a specific treatment modality that either hasn't been proven yet or maybe hasn't shown enough promise to warrant further research. In any case, it seems neither here nor there with regard to Evebarry's real-life treatment decisions right now. By all means, you should keep asking those questions (although I think you may get more useful information from a different audience). But why here - on this thread? It just seems dangerous and irresponsible to be actively encouraging someone to go against the advice of their doctor with regard to breast cancer treatment. Especially when she has said herself that she struggles with scientific/medical information comprehension. Why not share specific fact-based information that might help her with her decision and then encourage her to discuss it with her doctors?
Why continue to overwhelm with hypothetical and theoretical discussions that really don't help with today's decision (which she's already made)?
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orange1: Very true, we don't know what effect trastuzumab used alone has when used alone (other than that it is showing helpful action as a neoadjuvant treatment when given without chemotherapy initially).
thenewme:
Your question is logical:
"Why continue to overwhelm with hypothetical and theoretical discussions that really don't help with today's decision (which she's already made)?"
The point has been made a number of times here that the guidelines are only guidelines and that oncs make adjustments to their recommendations in consideration of individual patient characteristics. I think that is what happened for evebarry. My comments might be helpful to her and they might not, but my impression is that her onc gave her an initial recommendation that met the guidelines but did not address her concerns about her concurrent issue(s), and then, just as others have mentioned, went on to work with evebarry to better address her total picture.
However, had evebarry not declined the initial recommendation of chemotherapy, it is questionable whether there would have been full consideration of her other issues. This is especially true in regard to receiving trastuzumab without chemotherapy.
Because there are genuinely unknowns involved with such exceptions, it may be helpful to explore the basis for possible alternative therapies -- even if only to provide the info as to why they might be unknown.
A.A.
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Eve - A couple of the Aussie girls have been given FEC chemo x 4 with herceptin owing to existing heart issues. A much less toxic combination. It's the taxol or taxotere that can be hard to tolerate. Have you asked about alternatives to TCH? TCH is the standard but I see more and more women being offered alternative treatment.
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susieq58,
A page or so ago, you pointed out that I did chemotherapy and it might have saved my bacon. At the time I had to choose my treatment, the onc I happened to have -- one that both patients and professionals alike indicated was topnotch and definitely no slouch -- failed miserably to communicate even the most basic information to me -- that I was HER2+++. I never was told by any professional who treated me. I found out by independently getting a copy of the report. As mentioned, at the time I had to choose treatment I went out of my way to try to deal with whatever his problem was, by requesting he provide someone else to talk with me who was more capable than that. The person he provided also did not tell me. I did get a second opinion elsewhere. I was unable to get answers from any professional source as to why my preference for ovarian ablation and tamoxifen would not be sufficient for me as an early stage ER+ PR+ patient. I opted to accept the chemotherapy recommendation. While the chemotherapy may have protected me, ovarian ablation might also have been sufficient for me without all the toxic effects of chemotherapy.
Can you explain why, if HER2+++ is without exception so aggressive, I (and others) have not recurred in spite of never having had trastuzumab?
A.A.
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