The importance of philanthropy for funding cancer research in 2014+

I probably received no fewer than 25 emails  last week asking me to consider donating to a variety of charitable organizations before the stroke of midnight 12/31/13. “There’s still time for that end-of-the-year deduction.” **sigh** Every one of them, no doubt, is worthy, and most were from organizations I had some contact with in the past, either as a member, an alumnus, a prior donor, or some other connection. (The most amusing to me are the requests for donations from the colleges where my kids are currently students, frequently a request that comes by phone. I tell the earnest young men and women who are calling to “verify my address” that I already make regular donations, called tuition payments.)

It’s easy to tune out requests that come in waves at the end of the year, or if you are like me, you may have already made some decisions about where you might be willing to give. But did you know one of the worthiest causes you can donate to is cancer research, specifically to the hospitals and medical centers where you or your loved ones may already be receiving their care? Many people are surprised to find out that much research is funded not only by the Federal government and the pharmaceutical industry, but by donations large and small from grateful patients and family members. While most have heard that Federal dollars for biomedical research have have been drying up in recent years, you should realize how bleak the situation truly is. The American Society of Clinical Oncology (ASCO) has pointed out that the research budget from the National Institutes of Health is almost 25% lower today than 10 years ago when adjusted for inflation. This infographic explains the issue pretty well.

What can you do? I would of course support the idea that as citizens we should work through our elected representatives to send them the message that we can ill afford to continue to mortgage our future in this way, although realistically few of us may be motivated to do that. But you can also make a difference at the local level by donating directly to centers that are doing research and benefiting people in your own community. You don’t have to have millions or thousands or even hundreds. You might be surprised at how welcome and deeply appreciated even a seemingly modest donation to a local doctor or research program would be. Those of us who work in an academic medical center like Johns Hopkins are thrilled when we hear about people who want to help our work by supporting a small (or large) part of it financially. And here’s another thought - instead of remembering your oncologist or his/her office with a Christmas gift or donation of fruit or candy, consider making a donation to the research program that he or she is a part of. While I am always flattered and grateful when a patient buys me a tie or other thoughtful personal item, an even better gift is research support. It may not sound as personal or glamorous, but it is something that will long be remembered.

When I moved from private practice in Sacramento to Johns Hopkins in 2009, quite of few of my California patients wrote me moving personal notes, every one of which I kept. Others bought me small gifts or similar items, again things that I really appreciated and still have. But the one gift I will never forget was from the couple (the husband was one of my patients, and I took care of one of his wife’s family members as well) that donated money in my honor to Johns Hopkins, before I even started working here.  

So let make a very direct “pitch," and I'll be clear I am speaking as an individual,  not as a faculty member of Johns Hopkins University (my employer) or as Editor-in-Chief of ASCO’s Cancer.Net (where I volunteer). I would ask you to consider giving to support research by donating to two worthy causes - the Kimmel Cancer Center at Johns Hopkins and ASCO’s Conquer Cancer Foundation, which in addition to supporting Cancer.Net’s patient education and advocacy efforts, has long supported the careers of gifted physician-scientists by funding their research.

You can learn about opportunities to donate to the Kimmel Cancer Center here (consider designating that your gift be used for breast cancer research) or to the Conquer Cancer Foundation here. Thank you so much for your consideration.

San Antonio Breast Cancer Symposium 2013

This week I was happy to be able to attend my first-ever San Antonio Breast Cancer Symposium, which is probably the largest and most successful scientific conference devoted exclusively to breast cancer research and treatment. The meeting was exciting, intellectually stimulating, and full of great insights into both the basic and translational aspects of the disease and practical management. While I won't give in to hyperbole and say that there were "practice-changing" findings around every corner (a phrase I did hear a few times while there), a number of important research studies were discussed that I know will influence the care I give to breast cancer patients as soon as I return to my practice tomorrow.

As expected, the backchannel of the Twitter stream (using the #SABCS13 hashtag) was very active, despite some annoying WiFi woes in the convention center, with over 5700 tweets and 16+ million impressions. Thanks to the folks at symplur.com, full analytics and a transcript of the tweets can be downloaded here. If you weren't following along live during the meeting, reading the Twitter stream can provide some interesting glimpses into the science that was presented and immediate reactions and commentary.

There was plenty of media coverage from mainstream news sources, as well as specialty media like MedPageToday and the ASCO Post. Don't miss the press releases from the Symposium web site or these helpful audio interviews with some of the speakers.

And finally, I am grateful to Dr. Deanna Attai, breast surgeon and #BCSM Tweetchat co-moderator, for asking Dr. Julie Gralow and me to write blog posts for the BCSM Community site about some of the research findings presented. Rather than wasting electrons by duplicating my post here, I am linking to it here on the BCSM Community blog page. Dr. Gralow's post can be found here. Feel free to comment below on my post or anything else you wanted to share about the Symposium and findings.

Unanswered questions

I've been reflecting on the fact that for so many of the common clinical situations I face every week as a breast cancer oncologist, I don't have the answers. Despite great advances in understanding the biology of breast cancer and refining of the diagnostics and therapeutics, there are so many questions that come up in everyday practice that leave me in and my colleagues in the dark:

Which ER positive, node negative patients really need chemo in addition to hormonal therapy?  

How do you predict in advance which patients are going to develop dose-limiting toxicity from breast cancer treatment, like intractable joint symptoms from AI's or neuropathy from Taxol? 

What's the final word on CYP2D6 and tamoxifen? 

How do I help patients lose the weight they gained during adjuvant chemo or hormonal therapy? 

Who should get an MRI or US in addition to mammogram?

What's the best sequence of hormonal therapy for postmenopausal women with metastatic breast cancer?

Is there harm in delaying the start of adjuvant chemotherapy following definitive local therapy more than 4-6 weeks?

Should you give adjuvant trastuzumab to women with HER2 positive cancers less than 1 cm?

Is more than five years of an aromatase inhibitor better than 5 years in the adjuvant setting? 

Is a negative margin following lumpectomy defined as 2 mm, 1 mm, or just no tumor at ink?

Should you do an Oncotype for every healthy patient with an ER positive, node negative tumor between 5 and 10 mm in size or just some?

What's the role for local therapy of the primary tumor in the asymptomatic patient with metastatic disease?

What's the best systemic management for metaplastic carcinoma? 

This list could be endless. These are extremely common scenarios every oncologist who treats breast cancer sees over and over, and we don't know the "right" answer to any one of them. We have some ideas for most of them, and we certainly have plenty of clues as to how to try to figure out many. For some, it's easy to envision that clinical trials may eventually provide an answer, such as the optimal duration of AI's or the management of small HER2 positive tumors, but it will take years. Some of these may become less relevant as technology advances. For example, as we develop more sophisticated imaging, the current dilemmas about false positives with MRI will likely fade. As we develop better predictive markers than Oncotype and Mammaprint (or at least when we learn how to use those two optimally), adjuvant chemotherapy decisions will become much less ambiguous. As we start to understand predictors of toxicity such as which SNPs predispose patients to neuropathy (and we already have some good information for that one), we can be more selective about which patients we expose to drugs like taxanes.

But until then, every week in my clinic, I have to tell my patients that I don't really have answers to these questions. And as distressing as it can be for me as a healthcare professional to constantly repeat the "We don't know" refrain, it is far more than that for the patient and family who are on the receiving end of my non-answer. It is annoying, disconcerting, frightening, frustrating, and maddening, at many levels. And probably quite a few more emotions than that. 

ASCO guidelines for breast cancer follow-up: Solid science & rational skepticism

The American Society of Clinical Oncology (ASCO), the primary professional society representing doctors who care for people with cancer, periodically publishes guidelines for common clinical situations encountered by oncologists. The ASCO guidelines are a summary of best practices based on the latest and most thorough analysis of the scientific evidence currently available. ASCO creates its guidelines using a very rigorous and time-consuming workflow by first identifying and analyzing relevant research findings, crafting them into a format that is practical and accessible for patient care, and then submitting them for multiple layers of editorial review. By comparison, guidelines from the National Comprehensive Cancer Network (NCCN), an alliance of 21 different leading cancer centers, including my own institution Johns Hopkins, are created by panels of disease experts based on their consensus opinion. Both processes have a lot of value and are widely used, and to some extent they complement each other. The NCCN guidelines are much more numerous than ASCO's, and they not only address the treatment of different cancers by primary site but also cancer detection, prevention, risk reduction, and supportive care. NCCN also provides a version of their guidelines for patients. The ASCO guidelines are fewer in number than NCCN and deal with more selective situations, and in part this is due to the different methods used for their creation.

Why are there guidelines for the management of cancer in the first place? The most important reason is that it's a way of standardizing clinical care for common tumors, and since the guidelines are created by recognized experts from respected organizations like ASCO and NCCN, there is usually little controversy that they represent best practices based on the most current knowledge. Here's a good description from an article by Drs. Irwin and Peppercorn in the November 2012 Journal of Oncology Practice entitled "Promise and Perils of Guidelines in Quality Cancer Care:"

Such guidelines are currently used to encourage high-quality, evidence-based management that will increase the use of proven interventions while curtailing use of those that lack evidence or are known to be ineffective.

As the authors point out, some evidence exists that adherence to guidelines improves patient outcomes, although that is harder to prove than you might expect. No doubt, guidelines can serve as a deterrent to inappropriate and/or costly, unnecessary care, and they potentially offer physicians protection against medicolegal risks. The authors also cite some theoretical risks of standardized treatment guidelines, which you can read in the full text of the article.

ASCO recently updated their guidelines for the follow-up care of patients with breast cancer who have completed their primary therapy, whether that is surgery, radiation, chemotherapy, or hormonal treatment, or some combination of these. Basically, the population addressed is the very large number of women (and a few men) who have completed the active phase of treatment and who have no evidence of disease, "NED" in oncologist-speak. Generally these are patients who are treated with "curative intent," meaning that their therapy was delivered with the reasonable  expectation that it would result in complete eradication of the cancer. Unfortunately, we know that does not always happen, and recurrence after primary treatment, sometimes many years later, is an unfortunate and feared event. Given how prevalent breast cancer is and how the majority of patients do end up going through one of these life-altering treatments, it is critically important to have some guidance as to the most appropriate follow-up care. These guidelines address such things as how often a patient who has completed all treatment should be seen by her doctors, what lab tests and imaging studies are recommended, and what advice patients should be given. ASCO first created these guidelines in 1997 and updated them in 1999 and 2006; this is the 2012 update. Here are the relevant links:

• The abstract of the early release article from the Journal of Clinical Oncology published online 11/5/12 (shout out to the 3 Johns Hopkins co-authors, Dr. Antonio Wolff, Dr. Tom Smith, and Elissa Bantug, herself a young breast cancer survivor who coordinates our breast cancer survivorship program)
• The full text of the JCO article 
• A summary slide set
• A surveillance flowsheet in Excel format (also available as a PDF)
• Links to Cancer.Net's patient guide on the topic

Let me try to summarize the most important recommendations. The key point is that this 2012 guideline is identical to the 2006 version, which is to say that the ASCO panel, after looking at all of the published literature between 2006 and 2012, did not identify any research findings that warranted a change in their recommendations from 2006. The foundation of follow-up for patients with early stage breast cancer treated with curative intent should be periodic clinical evaluations (i.e., doctors' visits) and mammography. The frequency of recommended follow-up visits decreases as time goes on, from every 3-6 months for the first three years, to once or twice a year for years 4-5, and annually thereafter. The follow-up care should be provided by practitioners experienced in the surveillance of breast cancer (i.e., knowledgeable about the manifestations of cancer recurrence and late effects of the treatment) and comfortable with the physical exam of the breasts, especially the irradiated breast. Note that it doesn't say this has to be an oncologist necessarily, although hand-offs between oncologists and PCP's are discussed, and the practitioner is not required to be a physician, as mid-level providers working with physicians are often quite expert in this role. The guideline gives some recommendations about the frequency of mammograms which you can read at the links above. The importance of educating patients in the signs and symptoms of cancer recurrence is mentioned, as is the importance of regular gynecology follow-up.

As was the case for the identical 2006 version, the part that this 2012 guideline addresses that I think will generate the most interest is what is NOT recommended, which is basically all blood tests (including CBCs, chemistry panels, and tumor markers such as CA 27.29) and all imaging except breast imaging. So specifically all chest xrays, bone scans, CT scans, PET scans, and ultrasounds are not advised. To be clear, the recommendation against performing this type of testing applies to the patient that is in surveillance mode, who is coming in for a regular follow-up visit and who by definition does not have any specific symptoms. ASCO is not suggesting that doctors should forgo this type of testing as a way of evaluating a specific concern like a new symptom (say, back pain) or physical finding (such as an enlarged liver detected by the physician). Good medical practice would dictate just the opposite.

This is not a surprise, and the research supporting this has been around since the mid 1990s. And let me say as a breast cancer oncologist, I support this and have generally been practicing this way for many years. Those studies from the past basically showed that an intensive surveillance strategy of regular imaging studies and labs, when compared with a more conservative approach of periodic physical exams and mammograms alone, did not show any real advantages. The vast majority of recurrences were identified not by imaging tests, but by a symptom the woman herself notes or a physical finding the physician identifies on physical exam. Survival rates were the same between the patients followed more aggressively and those followed more conservatively, and quality of life was not any better. Yes, intensive surveillance and testing did identify more recurrences earlier, usually by no more than a few months, but it did not translate into higher cure rates or even fewer complications. Since metastatic breast cancer is incurable, all the early testing did was identify metastases a few months or so before they declared themselves either by a symptom or a physical finding.

And to take this a step further, this idea of not doing surveillance testing on patients with early stage breast cancer in the follow-up phase made it onto ASCO's Top Five list for the American Board of Internal Medicine Foundation's Choosing Wisely campaign - five commonly used practices that can and should be questioned since they are costly and lack medical justification. I cover this in a blog post from a couple of months ago.

But if there ever is an issue that I find problematic in my clinical practice, and one that raises delicate issues of patient empowerment and autonomy, physician authority and adherence to evidence-based medicine, and doctor-patient communication, it is this one. This issue about not performing certain tests is one that causes understandable tension with many of my patients, since at face value it seems illogical and inappropriate. Why wouldn't you want to detect cancer earlier? How could it be that would not improve outcome? And even if there was some uncertainty about that, why should ordering a simple blood test be an issue since the harm is perceived as minimal and potential gain great? Let me run through a few aspects of this issue that contribute to making it so challenging:

1. Oncologists used to do this for breast cancer patients. Yes, that is very true. When I was doing my fellowship in the late 80s I think some of the regular testing was starting to wind down, but I do recall that getting annual bone scans and liver ultrasounds - and certainly "routine labs" like chem panels - was accepted without much question.
2. Oncologists do this these days for patients with other cancers. Yes, very true as well. For example, there is very good evidence that monitoring patients with colon cancer who have had primary surgery +/- chemo with CEA blood tests and periodic liver CT scans, improves outcomes by identifying liver metastases early, thereby permitting potentially curative resection of the liver lesions.
3. Some oncologists do this these days for breast cancer patients. Also very true. I see a fair number of patients who receive their care outside of Johns Hopkins, and it is not at all rare when I review their records that I can tell their doctors are ordering CA 27.29 blood tests every few months for monitoring. In fact, a rising tumor marker in the absence of any other positive findings is a common reason for referral to an academic medical center like Hopkins. When I try to diplomatically explain that this was a test that we probably wouldn't have ordered here, the patient is often confused and conflicted, particularly since that fact is irrelevant as far as they are concerned if it suggests that there is a potential problem (which I totally get).
4. The downstream consequences of false positives and enhanced anxiety are not trivial. What is not always easy to appreciate is how a relatively lousy screening test like the CA 27.29, with less than optimal specificity and sensitivity, may open up a whole range of problematic issues - over-interpretation of trivial xray findings, misattribution of physical symptoms better explained in another way to "the cancer," and the endless cycle of repeating scan after scan to follow up on an equivocal abnormality. 
5. Even though patients may intellectually understand #4, many still want these tests done for whatever assurance they can provide, and they are willing to risk the false positives. Again, I am quite sympathetic to this viewpoint which many of my patients articulate to me. But I see how it can go either way - the test can be "negative" which is reassuring for everyone, including me as the oncologist who usually is the one who ordered it, or it can be abnormal or equivocal, leading to more testing. And when the patient now finds herself on the receiving end of the latter, it's much harder to deal with that scenario than it is in the abstract.
6. Patients just want some reassurance that they are ok. The doctor asking you questions and doing regular physical exams, in this modern era of sophisticated imaging and labs, isn't very reassuring. At the completion of adjuvant chemo and radiation, virtually every patient asks me, "How do you know it worked?" In other words, how do you know I am ok? How will I be monitored to know that I remain ok? It's so disconcerting when I have to say that we only really know if chemo didn't work, and we have no way of proving that it accomplished what we wanted it to do. It's very understandable that patients want some objective evidence that they are cancer-free. That's why they are naturally inclined to expect that some type of testing - not the word of the oncologist, even when the trust factor is very high - will offer them that reassurance.
7. A negative test means that based on the performance characteristics of that test there is no evidence of cancer at that time. So a relatively insensitive test (e.g., a chest xray) offers a small degree of reassurance that everything is ok, at least in the lungs, but it is only as good as its ability to discriminate a lesion large enough for it to detect. So a chest xray is likely to miss a 4 mm lung nodule, something that is much easier to see on a CT scan but at the price of a much higher exposure to radiation. But even a CT or a PET scan or whatever the latest imaging test to come will be has a shelf life - a negative PET scan in January does little to reassure anyone in October.
8. It is increasingly being recognized that radiation from diagnostic imaging is not good for you, and it probably increases your risk of cancer a small amount. While this is true, it does seem a little incongruous when an oncologist uses this line in someone that has just gone through 20 weeks of chemo and 6 weeks of radiation which themselves can, ahem, cause cancer. I'm not trivializing the risk, but I understand some patients find this "justification" for not ordering a screening test a bit of an odd juxtaposition.
9. It is possible that a physician ordering a blood test or especially a more expensive study like a PET scan may have a financial stake in the matter, which could theoretically cloud his/her judgment. Doctors who are part owners of facilities that do PET scans or labs that run chemistry panels may benefit financially from these tests, to a greater extent than an employed physician like me, who gets $0 for any test I order. But let me say that having spent the first 17 years of my career in a private practice with an in-office lab, it is hard to believe that even subconsciously that would have influenced my decision to order a chem panel, and of course, if I really followed the guidelines, I would be going against my own financial interest. However, when this potential conflict of interest exists, it does raise the question as to why there are such variances of practice.
10. Where do cost and the ethical principle of justice fit in here? Talk about a thorny issue! When I advise a patient not to undergo a PET scan for the primary purpose of reassuring them that they are ok post-treatment, I am not doing it primarily to save dollars. In fact, that is the furthest thing from my mind in the exam room. In essentially no cases right now (and this will change with ACO's - accountable care organizations) is an insurance company telling me not to do it. At least if they deny coverage, it is transparent and the patient knows right away. But where do you draw the line? It's incredibly easy for me to order a lab test because a patient or family insists, even if I am not convinced it is medically justified. While I have a responsibility to act in good faith, for a cancer patient I can almost always "justify" a lab test for the payer. But should I? If I order a test on every patient who insists on having it done, costs paid by someone will escalate. And if thousands of my colleagues do this all over the country, it will easily be hundreds of millions of healthcare dollars spent. Should those limited dollars be spent on testing that does not improve patient outcomes, like PET scans that identify an incurable lung metastasis 4 months before it declares itself, even though it would not affect treatment decisions one bit? Or should they be spent on something better, like co-pay assistance so people don't go bankrupt paying for potentially curative treatments like Herceptin?
11. Am I really sure of the data? I started this by saying that the ASCO guidelines represented best practice. But evidence-based medicine is hardly static. It changes all the time. While no study to my knowledge has ever shown that periodic measurement of serum markers like CA 27.29 or the Circulating Tumor Cell assay used in some places affect outcome, I am pretty sure these specific issues have not all been addressed in randomized controlled trials in systematic fashion. I noted that none of the 14 manuscripts the ASCO panel looked at to update these guidelines between 2006 and 2012 specifically address these tests as a primary variable. Is it possible that some combination of lab or imaging tests may someday reveal better quality of life or even greater longevity for more heavily screened patients, especially as our treatments improve? Hardly implausible.
12. And finally, doesn't this focus on guidelines impair the trust between the doctor and patient by making the care less individualized? Doesn't the physician's judgment enter in at some point? Do guidelines always have to be followed? My answers are - yes it certainly can and does; absolutely; and absolutely not. No physician should be worshipping at the altar of "guidelines" without a thoughtful examination of their strengths, their flaws, and the needs of the patient in front of you. Medicine and certainly oncology will never be a cookbook science, and the imprecision and variability of some of these issues is as maddening to doctors and patients alike as it is inevitable.

My bottom line - I think the ASCO guidelines being discussed here are rational, reasonable, solid, and as good a blueprint as we can hope for in 2012 for this specific clinical issue. They are also as flawed and incomplete as virtually everything else in clinical medicine. I have used them as a starting point for discussion and education with my patients. Usually that goes well, but it is a process not without its tensions at times. I have tried not to draw a line in the sand, but I can think of a few occasions where there was an impasse that we could not bridge. There are few absolutes here. It's not always as straightforward as simply doing whatever test or procedure the patient wants. That's not patient-centered care. Just as I've failed if my reasoning is dogmatic and opaque to my patient, I've also failed if I do something that my training and judgment tells me is incorrect or improper. I hope and pray I can continue to grow in wisdom to make the best decisions. I need input not just from expert ASCO panelists that create these guidelines, but from the real people - my own patients - who are living with breast cancer and trying to make some sense of the madness. And if any of you have read this far, I would love to hear your comments on this blog post. Your insights are always welcome and instructive.

USA Today article on #bcsm weekly tweetchat

Kudos and thanks to Liz Szabo (@LizSzabo on Twitter) from USA Today for her 10/23/12 article "Breast cancer survivor group is a social movement" about the weekly breast cancer social media (hashtag #bcsm on Twitter) tweetchat and online support group.  Co-founded by two breast cancer survivors/bloggers Jody Schoger (@jodyms) and Alicia Staley (@stales) a little over a year ago, the group has blossomed into a vibrant community of support for breast cancer patients and their families, caregivers, friends, and many other interested folks. If you're unfamiliar with the lingo, a tweetchat is a virtual meet-up on Twitter at a specified time, often repeated weekly or at some other interval, around a predetermined hashtag, which is a type of metadata. The conversation is often organized around questions or topics posted by the moderator, although tweetchats are by definition unstructured and free-flowing. Here's a more detailed explanation. 

The USA Today story emphasizes the power of the community that has arisen out of this online gathering. While it seems improbable that meaningful interaction could really occur over the exchange of 140-character tweets, that is exactly what happens, and the online conversation is deeply-nuanced and powerful. I have been honored to be a guest expert on #bcsm, and I frequently join in the conversation, which occurs most Monday evenings at 9:00 pm Eastern time.

I appreciate Liz Szabo allowing me to be quoted for the article and more importantly for publicizing the existence of the group and the good that it is doing. This is another example of how social media provide opportunities for connection and community that transcends geographical, institutional, and socioeconomic boundaries.

Breast cancer links page

This blog post will be a work in progress, and I'll probably keep updating it. I was motivated to do this to try to put together a list of online references for my own breast cancer patients. I do regret I haven't really done this in quite a few years. I frequently refer patients to the Hopkins Breast Center web site or Cancer.Net, but obviously there are many other choices. I will generally only list institutional, non-profit, or governmental sites, and usually only those with which I am reasonably familiar. While there is much good content on commercial sites and social media sites, it is not my intent to focus on those here.

Curation of online content - in my humble opinion - is an important role for the 21st century physician. In a perfect world, I would spend part of every visit, or at least every new patient visit, pointing my patients to online references that complement what we covered during the visit and help them further understand their diagnosis, prognosis, and treatment options. The truth is, it is very challenging to find the time to do that. That is not likely to change until we have our EHR fully implemented at Hopkins next spring, with the patient portal in place and automated after-visit summary generated with each visit. I am optimistic that the technology will facilitate this type of educational offering.

I welcome recommendations of other web sites that my readers have found helpful. As mentioned, I intend to focus largely on reputable institutional sites, but I will read every suggestion. Please leave me a comment below or suggest a site to me on Twitter (@rsm2800).

And now the obligatory disclaimer stuff...

The links that I list below are from organizations that are reputable and have a history of producing high quality , credible patient-education information. If I approve a blog comment mentioning other sites/resources, I am sharing it but not necessarily endorsing it. Obviously, all of these sites are from third parties, and I do not control their content. And as I say in the disclaimer on my home page, this blog is not medical advice. Always consult your physician for specific medical questions about your condition.

General Breast Cancer Information

Cancer.Net - Cancer Types>>Breast Cancer

NCCN Guidelines for Patients - Breast Cancer

National Cancer Institute - Breast Cancer Home Page

American Cancer Society - Breast Cancer Overview

Johns Hopkins Kimmel Cancer Center - Breast Cancer Program Home Page

Drug Information

Drug Index - British Columbia Cancer Agency

American Cancer Society - Guide to Cancer Drugs

National Cancer Institute - Cancer Drug Information

WebMD - Drug and Medication List

Clinical Trials

National Cancer Institute - Clinical Trials Search

ClinicalTrials.gov

American Cancer Society Clinical Trials Matching Service

Johns Hopkins Kimmel Cancer Center Breast Cancer Program - Clinical Trials Page

Breast Cancer/General Oncology News

Breastcancer.org Research News

MedPage Today - Oncology/Hematology Information Center

Oncolink - Cancer News

Coping/Supportive Care

National Cancer Institute - Coping with Cancer: Supportive and Palliative Care

Cancer.Net - Coping

Cancercare.org - For Patients and Survivors

Oncolink - Cancer Support and Coping with Cancer

Survivorship

Cancer.Net - Survivorship Page

LIVESTRONG - Cancer Transitions

Johns Hopkins Kimmel Cancer Center - Breast Cancer Survivorship Care

I'm on BlogTalkRadio 9/26/12 5PM EDT with Dr. Richard Just

I'm honored to be asked to appear on Internet radio with San Diego area oncologist and social media triple threat Dr. Richard Just, Wednesday 9/26/12 5:00 pm EDT for a 30 minute chat ranging from social media for oncologists to breast cancer. You can listen in live here. And be sure to check out Dr. Just's lively Twitter stream with the handle @chemosabe1 (wish I'd thought of that one) and blog JustOncology.com.

Duration of adjuvant chemotherapy: How much is enough?

(I've been away this week at the Epic Users's Group meeting in WI as part of my IT role at Hopkins, so I haven't been able to contribute to my blog. Here's another post continuing my series on recently published literature about breast cancer that patients and physicians might find relevant.)

How many cycles of chemo do you need? As a breast cancer oncologist, this question comes up in clinic a lot, particularly since I see a large number of women with early-stage disease who are being referred for my recommendations about adjuvant chemotherapy following lumpectomy or mastectomy. Since many of these patients are going to be cured even without chemo (especially if the cancer is estrogen receptor positive, meaning they will be receiving tamoxifen or an AI drug), minimizing the number of cycles of a toxic treatment like chemotherapy is critically important to achieve the optimal balance between benefits of therapy and side effects and risks. Unfortunately, we rarely have solid scientific evidence about how much is "enough," and I can appreciate how patients must think oncologists are incredibly arbitrary and vague when we advise six cycles of treatment not four, 20 weeks of therapy not 18, etc. And why do the recommendations always seem to be expressed as even numbers? Why not ever 3 or 7 cycles? (Don't ask me to try to answer that one…)

A recent trial published as an Early Release article in the Journal of Clinical Oncology came out online several weeks ago. This was a report of CALGB study 40101, entitled "Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes." If you are a JCO subscriber you can read the full article online. Also, there is a good summary article about the trial in the ASCO Post last week. I won't try to describe the study in detail except to say that early stage breast cancer patients who were either node-negative or had three or fewer positive nodes were randomly assigned to receive chemo with four cycles or six cycles of AC (Adriamycin/Cytoxan, a very widely used adjuvant regimen) or four cycles or six cycles of Taxol. The bottom line is that four-year relapse-free survival and overall survival was virtually identical when comparing the patients who received four cycles of either AC or Taxol with those who received six cycles of the same. Whether Taxol was superior or inferior to the AC was not reported yet, as further follow-up will be required before an answer can be determined. Having said that, the AC combination is a widely-used standard, and in very few situations would Taxol be given by itself as adjutant treatment. But clearly 6 cycles is almost always going to be more toxic than 4 cycles; now we know that it's not better, so in this population of patients (i.e., not necessarily applicable to all breast cancer patients), six cycles should NOT be used routinely.

So why can't we answer the question about duration of chemotherapy for all types of breast cancer patients and in other cancers as well?  Why is it so hard to get this information? Well, it just is, and that is very disappointing for oncologists and patients alike. These studies are very difficult to do, since they require large numbers of patients willing to be randomized and many years of follow-up. Remember that no more then 3-4% of all adult patients in the U.S. participate in cancer clinical trials. This trial enrolled 3171 women over a 6-year period of time, and it was performed in multiple institutions. That means that many thousands more treated in those same institutions either were offered the trial and declined it or were not eligible in the first place. And it took 10 years to get the results. That's because there was only a 1% difference in survival at 4 years for women treated with 6 cycles of chemo vs. 4 cycles - not statistically significant and practically not enough of a difference to justify the misery of increasing the length of the chemo by an additional 4-6 weeks. In a disease like early-stage breast cancer, where most patients do well - overall survival was > 95% - you only see differences in treatments when there is an "event," like a relapse, a death due to breast cancer or another cause, or a side effect so severe that it requires the patient to drop out of the study. In other words, only when something bad happens to a patient in the study do you really learn whether there are differences in treatment. And I should also say that it is not intuitive that four cycles of breast cancer chemo of this type are equivalent to six. It could have gone either way, and there are many other examples in oncology where shorter durations of treatment are definitely inferior to longer. So it requires a clinical trial of this magnitude to answer a question of this type.

Or does it? Maybe I'll save this discussion for another blog post, but researchers have been realizing that the days of these mega-trials, with thousands of patients randomized to different treatments that themselves represent only tiny variations in therapy, are numbered. In this era where more and more of our cancer treatments are becoming more personalized to the individual patient, taking into account the genomic make-up of their cancer and other individual variables, designing more trials like CALGB 40101 will not serve our patients well or give us the important answers we need. Furthermore, the cost of doing such mega-trials is already prohibitive, and our clinical cancer research infrastructure can barely support trials that are much more modest in scope as it is. Unfortunately, we still have few "personalized" treatments for early stage breast cancer, so adjuvant chemotherapy will continue to be used, but stay tuned. I'm confident that in a few years, I will have options to offer my early stage breast cancer patients much more attractive than AC X 4. At least it's not 6.

Surgical margins in lumpectomy: How much is enough?

When it comes to the "surgical margin" required in a breast cancer lumpectomy - the amount of normal tissue surrounding the tumor that must be removed along with the cancer to ensure that there are no residual cancer cells left in the breast - the answer is surprisingly unclear. Dr. Monica Morrow, Chief of Breast Surgery at Memorial Sloan-Kettering Cancer Center in New York, addresses this is a commentary in the New England Journal of Medicine from the July 5, 2012 issue. (Unfortunately, the full text is available only to NEJM subscribers and institutions; however, I covered many of Dr. Morrow's points in my free podcast from Cancer.Net where I summarized her talk on the same subject at the ASCO Annual Meeting June 2012.) Interestingly, published surveys have shown that even surgeons and radiation oncologists themselves cannot agree more than 50% of the time. At Johns Hopkins we tend to prefer 2 mm margins, but at our tumor boards we are always agreeing and disagreeing with that figure, mostly when discussing whether a particular patient should have additional surgery to try to achieve a larger negative margin. And that's the main issue. Should a "negative margin" be defined only as one where the tumor does not cross the inked border of the surgical specimen? Or should an additional amount of normal tissue also be taken out to achieve a wider "negative" margin? What if that requires the patient to undergo a second or even third surgical procedure and compromises the cosmetic outcome of the lumpectomy, an important goal for many patients? Studies have not uniformly shown larger negative margins are associated with a lower risk of local recurrence than a margin in which tumor simply is not touching the inked edge of the surgical specimen. For example, when MRI imaging is used in addition to mammography and ultrasound, additional tumor is frequently found, often resulting in the decision to move to mastectomy rather than lumpectomy; however, even then local recurrence rates and certainly long term outcomes are not uniformly improved.

This is not to say that lumpectomy margins are unimportant or that meticulous surgical technique should somehow not be practiced. Morrow gives some examples of clinical situations where re-excision of a close margin is highly appropriate (e.g., extensive DCIS). It is devastating when a patient undergoing a lumpectomy and radiation told upfront that she has a "good" prognosis breast cancer then goes on to experience a recurrence in the same breast months or years later, usually necessitating mastectomy.

Finally, Morrow points out that surgery and radiation are not the only treatments that reduce local recurrence. Hormonal therapy such as tamoxifen, chemotherapy, and trastuzumab (Herceptin) in HER2 positive patients, have all decreased the rate of recurrence in the breast in the modern era, compared to the 1980's and before (3-6% now vs. 10-15% prior to the wider use of drug therapy post lumpectomy, especially tamoxifen or AI's). When counseling patients it is important to emphasize these up-to-date statistics to counter a common misconception that mastectomy is always a "safer" choice.

Diabetes, metformin, and breast cancer

A number of interesting connections between obesity, diabetes,  the diabetes drug metformin, and breast cancer have been discovered in recent years. It has been known for some time that obesity is an adverse prognostic factor for breast cancer. For example, obese women have a higher risk of developing breast cancer compared to normal-weight woman, and women who have been treated for breast cancer who gain a lot of weight after treatment have a higher risk of recurrence than those that do not. The exact mechanism is not known, but it is thought that naturally-occurring insulin may play a role, since obese women tend to have higher levels of insulin and have relative insulin resistance. Additionally, women with diabetes who take metformin, a widely used agent to control blood sugar, may have a lower risk of cancer. This was shown in a recently published study in the Journal of Clinical Oncology. A large population-based clinical study called the Women's Health Initiative (WHI) looked at 68,019 women between 50-79 who did not have breast cancer at baseline. Of these 3,401 had diabetes at study entry. Women with diabetes treated with medications other than metformin had a slightly higher chance of developing breast cancer. By contrast women with diabetes treated with metformin had about a 25% lower breast cancer incidence. It is possible that metformin produced this finding by diminishing some of the effects that insulin-related cellular pathways had on cancer cells.

So does this mean that we are ready to prescribe metformin in women without diabetes as a treatment to lower the risk of breast cancer? No. However, this question is being studied in a large international clinical trial called MA.32 in which women without diabetes who have been curatively treated for breast cancer with surgery, with or without radiation, chemo, or hormonal therapy, are randomly assigned either to the drug metformin orally twice a day for 5 years or a placebo for 5 years. Interestingly, in non-diabetic women, metformin does not seem to cause much hypoglycemia (low blood sugar) as you might expect, and thankfully there are not a lot of other side effects. We won't know the results of this important study for a number of years, but if it does show a benefit to metformin in reducing breast cancer recurrence risk further, this old, widely-used, and inexpensive medication may be added to standard cancer therapies. This trial is available at Johns Hopkins for eligible patients.

Neuropathy from taxane-based adjuvant chemo does not correlate with breast cancer outcomes

So I wanted to try something a little different with the blog this week and try to write some brief posts about recently published breast cancer articles that I thought would be of interest to many. The links are to full text versions, and I realize that those without an individual subscription or institutional access may only be able to read the abstract which is less desirable (for many journals, full text can be accessed a number of months after publication, e.g., for JCO after 12 months).

Peripheral neuropathy is a common and often difficult side effect of breast cancer chemotherapy, particularly regimens that include the taxane drugs paclitaxel (Taxol) or docetaxel (Taxotere). In my practice, the majority patients who receive our current institutional standard 3rd generation adjuvant regimen of dose-dense Adria/Cytoxan every 2 weeks x 4 cycles followed by Taxol weekly x 12 develop at least a little bit of sensory neuropathy in their hands and/or feet by week 8-12 of the Taxol portion. For many patients it is only a minor annoyance and unpleasantness which resolves within a few months after end of chemo, but for a significant minority it can greatly affect quality of life by limiting mobility or dexterity and in some cases requiring pain medicines or other treatments. In a small number of patients, it takes many months to improve and occasionally there are residual symptoms at the 12 and 24 month post-treatment point. A recent article from Journal of Clinical Oncology looked at a previously reported (in 2008) clinical trial of adjuvant chemotherapy called E1199 and tried to determine if the women who developed neuropathy from the chemo were more or less likely to develop breast cancer recurrence and/or premature death. Other research had previously suggested that women who received taxanes as adjuvant treatment who then went on to develop neuropathy had a lower chance of recurrence than those that did not develop neuropathy, perhaps because whatever toxic effect the chemo had correlated in some way with great breast cancer cell kill. But this trial failed to show any connection at all with the incidence or severity of neuropathy and breast cancer outcome. In a multivariate analysis, the authors found that there was NO correlation between the development of Grade 2-4 neuropathy (which was as high as 22% in some treatment groups) and disease-free survival or overall survival.

The results are reassuring…sort of. Patients sometimes ask me, "If I did not get as much nausea or hair loss as expected, does that means the chemo didn't work?" Here, it is logical to conclude that women who get taxane-based chemo and who are lucky enough not to get neuropathy are just that - lucky, but not more prone to recurrence than women who have more side effects. In reality it's probably not a matter of luck but rather genes, as other research has shown that some women may have a special genetic predisposition to develop chemotherapy-induced neuropathy. Hopefully we can soon have a commercially-available, validated test which can be performed on all patients for whom taxane-based chemo is being considered, which can be used to predict which patients are more neuropathy prone. And even more importantly, we need to identify what alternatives that group has. Right now, we are not there yet, and it is important to recall that taxane drugs are a critical component of many modern adjuvant breast cancer regimens and cannot easily be dropped without compromising curability.