Expertise and Survival

Mayo statuesThat is the (short) title of a very recent article published in the journal “Cancer” by the CLL experts at Mayo Clinic, Rochester (MN).  Since CLL is usually a long drawn out process and the disease comes in so many flavors, there is very little doubt in my mind that expertise and knowledge of latest information matters.  Below is the abstract of the Mayo article.  Many of you will recognize the names of the authors, since they are your own physicians.  If you wish to read the full text of the article, send me a personal email and I will help you locate it.

Expertise and Survival: Lessons from Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Tait D. Shanafelt, MD; Neil E. Kay, MD; Kari G. Rabe, MS; David J. Inwards, MD; Clive S. Zent, MD; Jose F. Leis, MD; Susan M. Schwager, Carrie A. Thompson, MD; Deborah A. Bowen, FNP; Thomas E. Witzig, MD; Susan L. Slager, PhD; and Timothy G. Call, MD

BACKGROUND: The impact of physicians’ disease-specific expertise on patient outcome is unknown. Although previous studies suggest a survival advantage for cancer patients cared for at high-volume centers, these observations may simply reflect referral bias or better access to advanced technologies, clinical trials, and multidisciplinary support at large centers.

METHODS: We evaluated time to first treatment (TTFT) and overall survival (OS) of patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) at a single academic center based on whether they were cared for by a hematologist/oncologist who subspecializes in CLL (CLL hematologist) or a hematologist/oncologist with expertise in other areas (non-CLL hematologist).

RESULTS: Among 1309 newly diagnosed patients with CLL cared for between 1999 and 2009, 773(59%) were cared for by CLL hematologists and 536 were cared for by non-CLL hematologists. Among early-stage patients (Rai 0-I), median TTFT (9.2 vs 6.1 years; P < .001) and OS (10.5 years vs 8.8 years; P < .001) were longer for patients cared for by CLL hematologists. For all patients, OS was superior for patients cared for by CLL hematologists (10.5 years vs 8.4 years; P ¼ .001). Physician’s disease-specific expertise remained an independent predictor of OS after adjusting for age, sex, stage, and lymphocyte count at diagnosis. Patients seen by a CLL hematologist were also more likely to participate in clinical trials (48% vs 16%; P < .001).

CONCLUSIONS: Physician disease-specific expertise appears to influence outcome in patients with CLL. To the greatest extent possible, patients should be cared for by a hematologist/oncologist expert in the care of their specific malignancy. When not possible, practice guidelines developed by disease-specific experts should be followed.   Cancer 2011 American Cancer Society.

This study has the strength of large numbers, looking retrospectively at how 1309 newly diagnosed patients fared over their CLL career.  This was the number of patients seen at the Mayo Clinic for a whole decade (1999 – 2009).  That also points out the biggest weakness of the study – it is the experience of a single center, namely the Mayo Clinic.  Would we get similar results if the study had included other CLL centers such as M. D. Anderson, Ohio State University Hospital and UCSD?

The authors paint a compelling scenario:

  • The last decade has seen a tremendous level of improvement in our understanding of CLL as well as how to treat it.  Among the highlights are (1) better prognosis using biologic markers, (2) new drugs  such as Rituxan, ofatumumab, Campath, bendmustine, Revlimid (3) more effective combination of drugs, such as FCR, PCR, FCR Lite, FCO and so on (4) better understanding of the role of mini allo transplants (5) better handle on autoimmune disease complications such as AIHA, ITP (6) role of decreased immunoglobulin levels and infectious complications.
  • Watch & Wait is still useful, and we have better guidelines on when to start therapy.  For example, it does not make sense to start therapy just because the white count is high, if there are no “B-symptoms”
  • Not everyone can handle the most aggressive therapy option available.  Age, comorbidities, prior therapies and prognostic risk category of the patient all play a role in making therapy decisions.
  • Recent large scale studies based on lymphoma patients have shown that whether patients receive their care in rural or metropolitan areas, community oncologists or university based hospitals makes a difference to overall survival.
  • Despite these trends, insurance companies try to control costs by driving patients to the lowest cost provider, rather than the most expert provider.  Really?  They do that?  Who knew.

But it can be argued that University based physicians have access to more modern technologies, new clinical trials and hot off the shelves new drugs.  Is this the reason why patients seen at University hospitals do better than those seen by community oncologists, just a matter of better equipment and access?

To answer this question, the researchers came up with an ingenious approach.  All 1309 of the patients in this study were seen at the same institution, namely the Mayo Clinic.  But 59% of them were seen by Mayo hematologists who specialized in CLL, while the rest (41%) were seen by Mayo hematologists who did not specialize in CLL.

In other words, all the patients had the same level of care, all had access to Mayo’s formidable resources, clinical trials etc, all were seen by hematologists (oncologists who take care of blood cancers).  The difference between the two groups is that little more than half of them got to see CLL expert hematologists, while the others saw garden variety hematologists that did not have the single minded focus on CLL.  I am sure you will agree this is a nice approach, since it focuses only on the CLL specific expertise of the physician.

To cut to the chase, here are the details that emerged from the study:

  • Patients treated by CLL expert hematologists were much more likely to have detailed workup of prognostic indicators – you know, all the new fangled stuff such as FISH, IgVH gene mutation status, CD38 and ZAP70.  Patients seen to have more aggressive disease were more likely to get the full prognostic testing.
  • Median time to first therapy (i.e., end of Watch & Wait) was 9.2 years for patients treated by CLL expert hematologists, compared to 6.1 years for those cared for by non-CLL expert hematologists
  • Overall survival of patients treated by CLL expert hematologists was 10.5 years compared with 8.8 years for the other group.
  • Both the time to treatment and overall survival differences between the two groups were statistically significant.
  • Patients seen by CLL expert hematologists were more likely to participate in clinical trials (48% versus 16%)
  • Patients seen by CLL expert hematologists were more likely to be treated by purine analog (fludarabine, pentostatin) based therapies (70% versus 28%).  Non-CLL expert hematologists were more likely to use alkylating agents (cyclophosphamide, chlorambucil), or Rituxan based therapy with or without steroids.

All of this sounds quite reasonable.  I guess I was surprised by the level of the difference between the two groups.  Even when all the patients were seen at a major center such as the Mayo Clinic, the level of CLL specific expertise of the physician taking care of them made a difference.  The two charts below are from the paper and they help drive the point home.  Physician’s level of CLL specific expertise delays the start of therapy and increases overall survival.

Expertise and TTFT, OS

The red lines in the charts above are my contribution, to highlight the median (50%) values for time to treatment and overall survival.  The median overall survival had not yet been reached at the ten year mark for patients seen by CLL expert hematologists.  The paper lists it at 10.5 years.  That is a nice improvement over survival statistics I used to see earlier on.

When to start therapy, and what to use as frontline therapy are two of the most important decisions you and your doctors are likely to make.  All too often, I hear from patients whose local oncologists made the decision to start therapy based solely on elevated white blood count.  It is now pretty much the expert consensus that you do not start therapy just because the white blood count is high.  The NCI Working Group Guidelines clearly spell out the conditions that must be met before therapy should be initiated.  If you are not familiar with these guidelines, I suggest you remedy that right away.  This is an important document and you will most likely need to refer to it frequently.

What constitutes “massive / progressive lymphadenopathy” – since this is one of the criteria for start of therapy?  How about a couple of  ugly looking nodes right under the chin where they are most noticeable?  Patients freak out when they can see the swollen nodes every time they look in the mirror.  But they may not be of compelling diagnostic value.  A trained CLL expert who has seen thousands of patients is more likely not to freak out himself.

W&W is tough on patients.  It is tough on physicians too.  Experience and expertise are what are needed, not knee jerk response to elevated white blood counts and minimally swollen nodes.  Each and every one of the therapy options we have right now has its share of toxicity.  Rushing into therapy does not make sense, not until we get therapy options that tilt the balance in our favor, reduce the toxicity risk while improving the remission rewards.


This is an interesting study and I recommend the full text of the paper – it has a lot more details than I have discussed here.

Are there limitations to this study? You bet.  First, this was a single center study.  Second, it was a retrospective study, looking backwards at patients treated in the past. Third, the study was conducted by CLL specific expert hematologists.  Is there a chance of researcher bias?  May be.

Broadening the discussion to the real world, does it help to be seen by CLL expert hematologists, as opposed to the other end of the spectrum, what I call the local strip mall oncologist?  I think the answer is clear, not just because of this study but because it makes common sense that you would want the best informed and most experienced guy looking after you.  That is particularly true in our present situation, where things are changing awfully fast.  But getting to an expert center may not always be possible, for a variety of reasons.  Travel and time restrictions, cost, insurance issues etc come to mind.

If none of these restrictions are there, if you have the luxury of being seen by whoever you want, is it a slam dunk choice to outsource all of your CLL worries to your CLL expert hematologist?  Since this is the editorial section and I get to speak my two cents, I think you would be foolish to abdicate all your oversight and responsibility.  It is still your body, your life.  The sharp pointy needle hurts you a lot more than it hurts the nurse wielding it or the physician who wrote the script for it. Or the patient advocate who gushed about the cool science.

Everyone has agendas. A while back I wrote about a friend of mine who went to five different expert centers for full workup of his newly minted CLL.  Each center did a great job of doing all the blood work and reading the prognostic tea leaves.  Each center came up with an entirely different therapy suggestion for what ailed him.  In each case, the recommendation was a clinical trial that the center was conducting at that time and were actively recruiting patients for it.  Human nature is what it is.

There is a built in conflict of interest between the two roles that CLL experts play.  On the one hand, they are dedicated researchers anxious to hasten the recruitment process for their pet projects.  Expert reputations are built on successful clinical trials and rapid recruitment is one of the advantages of working at a large institution that has a steady inflow of fresh patients.  On the other hand, they are physicians sworn to do what is right for the single, individual patient in front of them.  Finessing this conflict of interest is not always easy. When your expert looks at you, which hat is he wearing?  The researcher hat or the physician’s hat?  Can you tell the difference?

Some centers are more aggressive than others in their recruitment practices.  Recently, one of our leading expert centers told a patient they were recruiting for Rituxan + CAL-101 trial that his participation in the trial would not change his chemo naive status.  I beg to disagree.  They also told him that participation in this trial would not in anyway impact his chances with something like FCR down the road.  I hope so, but no one has done this research and we have no way of knowing whether or not FCR would work equally well down the road, after a possible CAL-101 relapse.  This is a case of trial recruitment getting ahead of clear and honest discussion of the  risks / rewards.  A recent review of a clinical trial using CFAR regimen in relapsed / refractory patients underlines what can happen, when clinical research gets ahead of patient care – in my opinion.

Everyone has agendas, and everyone has egos. The bigger the expert, chances are the bigger the ego.  Do you have what it takes to listen to the expert and nevertheless make decisions that are right for you, even if they do not match what he is suggesting?  Some experts do not take kindly to patients who do not automatically say “how high?” when they say “Jump”. Local oncologist from round the corner from your home or office may be easier to deal with, especially if you are the type that does not do well in confrontational situations.

Bottom line, as with all things having to do with CLL, no one is more in charge than you, the patient.  No one has more skin in the game.  By all means, expertise is valuable and important.  But only you live within your body.  Only you know what is right for you.  The only way I see that you can do a better job of making good therapy decisions for yourself is to come up the learning curve yourself.  Be well informed.  Be well prepared.  Use your resources wisely, use tact and charm in your dealings with the medical establishment. Listen carefully to what your doctors have to say, ask questions and make sure you understand the answers.  Be good to your friendly and ever so charming and humble patient advocate ( grin), you never know when you may need information in a hurry.  Don’t burn bridges that you may need later. But above all, be very sure you remember, you get to have the final say.