Hard to Resist High Tech Toys

Let us be honest about it: most of us love high tech toys and gizmos. Straddling two cultures as I do (I spent the first 20 years of my life in India, the rest of it in the USA), it seems to me the preference for shiny new gizmos is a bit more pronounced in USA (perhaps Europe too, but our European members are better qualified to comment on that).

The topic of this article is CT scans, with or without contrast, PET scans in lieu of CT scans, or why not go for a belt and suspenders approach and do CT scans plus PET scans. Which is a better choice? When should they be done? What are the risks and what do we get for our health-care dollar (as well as unavoidable dose of radiation exposure) when CLL patients get scanned? Does radiation exposure increase risk of getting CLL in the first place?

Almost everyone has their two cents on this issue. Be sure to log in so that you can follow the lively discussion.  Fortunately, we now have some experts weighing in with more than two cents on the subject. If you have CLL, you will face decisions on scans, sooner or later and it helps to be well informed on the subject.

CLL: A Deceptively ‘Simple’ Blood Cancer

CLL is a beast of a different color when compared to solid cancers or even lymphomas. It is not possible to judge the status of, say, breast cancer or lung cancer without doing invasive biopsies or only slightly less invasive CT scans or PET scans. Some day we will have blood tests that can look for very specific and tell-tale markers, that can give us a good handle on all types of cancers and their stage, prognosis etc. Some day, but not today. Even PSA blood test for prostate cancer screening is not without controversy.

CLL is a leukemia. That very word says CLL is a cancer of the blood and therefore reasonably expected to be seen in the blood. But you and I both know that is over-simplification. CLL is a blood cancer, but CLL cells don’t just limit themselves to circulating in the blood, they also hang out in lymph nodes, spleen, liver, bone marrow and just about everywhere that blood and lymph travels – which means everywhere in your body. High tech scanning is obviously necessary to peer at your innards that cannot be felt by mere poking and prodding. Biopsies are necessary to understand what is happening in your bone marrow.

The trick of the game is to learn when you need these invasive procedures - and when you don’t.

CLL Diagnosis

Is it possible to diagnose CLL using only blood tests? More and more, the answer to that important question is YES. Typically an abnormal CBC report with too many lymphocytes (high WBC, high ALC) is the alarm that triggers flow cytometry test to confirm CLL, rule out all the other lymphatic cancers that might confuse the diagnosis. All of the most modern prognostic tests (IgVH gene mutation status, FISH, CD38, ZAP70, B2M etc) are blood tests that cost you no more than a needle prick (and lots of dollars, if you do not have insurance).

Rarely do patients need CT or PET scans or bone marrow or lymph node biopsies just to diagnose CLL. If your local guy asks for any or all of these much more invasive (and expensive) tests just to confirm CLL diagnosis , be sure to ask why, what he hopes to learn from the results. When my husband PC was first (incorrectly) diagnosed back in 2001, we were foolish and naïve and he was put through a CT scan with contrast as well as a lymph node biopsy – for no good reason. The biopsy required full anesthesia and the incision site was painful and took a while to heal. Don’t you make the same mistake. Ask your questions, get satisfactory answers, before you sign on for invasive diagnostics. As always, it is important to understand the true cost of things.

There are some situations where the diagnostic picture is murky, especially if you are ‘blessed’ with atypical CLL. That may need more testing, over and beyond blood tests. People with SLL (small lymphocytic lymphoma) variety of CLL may not have enough of their CLL show up in peripheral blood circulation, these guys have the vast majority of their cancer cells hiding out in lymph nodes. A scan may be necessary to judge the stage of lymphadenopathy (jargon for swollen nodes or glands) and establish a base line for your disease.

CLL Monitoring: Why Do We Ever Need Anything More Than CBC?

While confirming CLL diagnosis and getting most of the prognostic testing requires only blood tests, detailed monitoring of your status as time goes on is not so simple. Most of us get fixated on the regular CBC reports, getting euphoric or devastated because the WBC or some other blood count changed just a tad. Even after we take into account silly stuff like instrument malfunction, built in errors and sensitivity limits, or a lab tech who had partied too hard the night before, there are some obvious limitations of depending too much on the regular CBC for all your monitoring needs.

  • As CLL progresses, anywhere from 80-90% of the total tumor burden (i.e., total number of CLL cells in your body) can hide in places other than blood. Basically, trying to get a handle on total tumor load based on a CBC report is like guessing at the size of an iceberg based only on the bit of it you can see poking over the surface of a choppy sea.
  • Most CLL patients develop adenopathy (swollen lymph nodes) as their disease progresses. But it is not uniform across all patients. People with SLL phenotype, people with 12 trisomy or 11q or 17p deletions (FISH results) are more likely to have bulky nodes. A well trained oncologist with calibrated finger tips can judge the size of your nodes quite accurately – that is, the ones he can feel by physical palpation. Not all nodes can be felt, especially those buried deep in your abdomen.
  • But that does not mean physical monitoring of lymph node size is useless. Within limits, it is reasonable to suppose that all nodes are increasing in size at more or less the same rate. Therefore, if that pesky one under your chin or in your groin is growing fast, it is reasonable to think the hidden guys in your gut are growing just as fast. Reasonable, but not guaranteed.
  • Swollen spleens are detectable by trained physicians during a physical exam. Most patients too can tell when their spleens are getting swollen - they get a sense of feeling full after having eaten just a small meal. When you start looking slightly pregnant (lopsided to one side) then it is no longer early stage splenomegaly (jargon for swollen spleen). My husband PC was convinced and swore his spleen was dangerously swollen right after his diagnosis. Turned out it was a beer belly and went away once he got religion about regular exercise.
  • One other important thing that cannot be determined by simple blood tests is the status of your bone marrow. This unique organ in your body is the only place newly minted platelets, red blood cells, neutrophils, etc are created to take the place of old cells worn out and destroyed as part of the natural order of things. The only way to judge the health of the bone marrow is by means of a bone marrow biopsy. Since it involves significant cost and some ‘discomfort’, be sure to get it done some place where they do a lot of them, and the pathologist is qualified and experienced. A biopsy report is only as good as the pair of eyes that looked at the slides. Garbage in, garbage out.

When Are Scans Necessary?

Let us take a simple example. Your CLL has progressed to the point where your oncologist says it is time to start therapy. Of course, the million dollar question is deciding what to use as front-line therapy. You are sort of Bucket B patient, perhaps you have 12 Trisomy and a couple of the other not so good prognostic indicators. You are dithering and can’t decide between the present day “gold standard” FCR chemoimmunotherapy combination versus single agent Campath (alemtuzumab) that has been recently approved by the FDA in that role. How to decide?

If I were in your shoes, I would get a good scan that gives me a look see on what is happening deep in my chest and belly, get a handle on the size of the lymph nodes, before making my decision. Why, you ask? Well, the 12 Trisomy suggests you may be one of the guys with bulky adenopathy. And Campath does not do bulky nodes. In clinical trial after clinical trial, it has been shown that this powerful monoclonal antibody does a good job of clearing the blood and even bone marrow, but if your lymph nodes are bulky (present day definition: bigger than 5cm diameter), you are not going to get enough joy from Campath. If the scan shows you have tennis ball size nodes in your gut, I suggest you look at the FCR option a lot more carefully.

Of course, scans are not the only diagnostic tests you might want to use prior to making therapy decisions. A FISH test may be worth considering. Even if you have had a FISH test at the time of your diagnosis it may be a good idea to repeat the test. Remember “clonal evolution”? FISH status can change over time. If you have managed to “evolve” to a higher risk bucket, perhaps picked up a touch of 17p deletion, that is important information relevant to your therapy choice. Patients with 17p deletion often do not get those squeaky clean pcr negative responses to FCR. Research suggests drugs like Campath and Revlimid (also flavopiridol, a still-experimental drug out of OSU) may be better choices either as single agents or in combination with other drugs.

What the Experts Have to Say

Below is a detailed editorial by Dr. Tom Kipps of UCSD, lead-in to a full length article on the subject by the big guns out of OSU, including our own favorites Drs. John Byrd, Tom Lin etc . Guys, it does not get more credible than that – sort of like Brad Pitt, George Clooney and Matt Damon all in the same movie. (See, I am not just a housebound geeky old lady – I do too know the names of the ‘hot’ guys out there)

I urge you to read the Kipps editorial carefully. It is well written and has a lot of meat on the bones. I highlighted some of the juicy bits for you.

J Clin Oncol. 2007 Dec 10;25(35):5556. Epub 2007 Nov 5.

Value of Computed Tomography in the Monitoring of Patients With Chronic Lymphocytic Leukemia

Thomas J. Kipps

Moores Cancer Center, University of California, San Diego, CA

In this issue of the Journal of Clinical Oncology, Blum et al1 conducted retrospective analyses of the medical records of patients with chronic lymphocytic leukemia (CLL) to evaluate the relative value of computed tomography (CT) in assessing the response to therapy. Unlike the guidelines for assessing the response to therapy for most other types of non-Hodgkin’s lymphomas (NHL), the widely-used National Cancer Institute–sponsored Working Group (NCI-WG) guidelines for patients with CLL do not incorporate use of CT scans in the response-assessment algorithm.2 Nevertheless, CT scans increasingly are being used, not only to assess the response to treatment, but also for routine disease monitoring, a practice that has been largely discouraged.3 In their study, Blum et al found that the use of CT scans, as per NHL response definitions, had little value over the established NCI-WG criteria for assessing the response of CLL patients to therapy or for predicting post-treatment progression-free survival.

CLL is a systemic disease. Generally, lymphadenopathy detected at one anatomic site also can be found at other locations, giving rise to the notion that the disease can be followed by physical exam, the CBC, and other blood or marrow tests. However, a recent study published earlier in the Journal challenged this notion.4 This study found that CT scans could help stratify patients with early, stage 0 disease into two groups that had significantly different risks for disease progression. Thirty-eight of 140 patients who were not found to have enlarged lymph nodes by physical exam (hence the stage 0 classification) were found to have enlarged lymph nodes by CT scan, albeit of less than 2 cm in diameter except in five patients. Surprisingly, 13 patients (9% of the total) also were found to have splenic enlargement on CT scan that was not appreciated by physical exam.4 Patients who had evidence for lymph node enlargement in this study had a shorter time to initial treatment and poorer survival than did patients without detectable abnormalities on the CT scan. As such, this study challenged the notion that the physical exam for lymphadenopathy or splenomegaly can suffice for accurately staging patients with CLL.

However, an important question that needs to be addressed is whether CT scans can improve on our ability to predict outcome when other diagnostic and laboratory studies are available. In the former study by Muntanola et al,4 a significantly higher proportion of patients who had enlarged lymph nodes detectable only by CT scan also were found to have other known adverse prognostic indicators, such as leukemia cell expression of ZAP-70 or short lymphocyte-doubling times, than did patients without lymphadenopathyon CT evaluation. These other risk parameters also could delineate a subgroup of patients who had a relatively short median time from diagnosis to initial therapy independent of the results obtained by CT scans. In the retrospective study presented in this issue, Blum et alnoted that achievement of either a complete response or partialresponse by NCI-WG criteria had a significant bearing on the ability to predict overall survivalregardless of the results obtained via CT. Moreover, the NHL-CT assessment of response did not perform better than standard NCI-WG criteria in predicting the length of progression-free survival.

More studies are needed to evaluate the relative value of CT scans in monitoring patients with CLL. The need for this is particularly apparent with the advent of therapy with alemtuzumab, an anti-CD52 monoclonal antibody with therapeutic efficacy in inducing complete responses in CLL that appears inversely proportional to the extent of lymphadenopathy, which more often is being assessed with CT scans before therapy. 5 Because of the need for further study, the upcoming revision in the guidelines for treatment-response assessment will suggest that CT scans be performed before and after treatment in clinical trials involving patients with CLL. The prospective analyses of the value of CT scans relative to that of other CLL-associated risk indicators in predicting outcome will be necessary before making recommendations to use, or not to use, CT scans in the routine clinical evaluation and monitoring of patients with this disease.

With that as a lead-in, here is the abstract of the Byrd paper. You can access a free copy of the full text of the paper just by clicking on the link. Even if you don’t read it right away, this paper belongs in your own personal library of important papers. You may need it someday as you discuss these issues with your own oncologist.

J Clin Oncol. 2007 Dec 10;25(35):5624-9. Epub 2007 Nov 5.

Computed tomography scans do not improve the predictive power of 1996 national cancer institute sponsored working group chronic lymphocytic leukemia response criteria.

Blum KA, Young D, Broering S, Lucas MS, Fischer B, Lin TS, Grever MR, Byrd JC.

The Ohio State University, Division of Hematology-Oncology, Starling Loving Hall, Room B324, Columbus, OH 43210, USA. kristie.blum@osumc.edu

PURPOSE: National Cancer Institute-sponsored Working Group (NCI-WG) response criteria for chronic lymphocytic leukemia (CLL) rely on physical examination, blood, and bone marrow evaluations. The widespread use of computed tomography (CT) scans has prompted many to advocate for the incorporation of this test into CLL response criteria. PATIENTS AND METHODS: In a retrospective review of 82 CLL patients treated at the Ohio State University (Columbus, OH), we compared CT assessed response using non-Hodgkin’s lymphoma (NHL) response definitions with NCI-WG response. RESULTS: Responses by NCI-WG criteria included five complete responses (CRs), 32 partial responses (PRs), 21 patients with stable disease (SD), 17 patients with progressive disease (PD), and seven patients not assessable (NA). Responses by NHL-CT criteria included three CRs, 12 unconfirmed CRs (CRus), 16 PRs, 26 with SD, four with PD, and 21 NA. Using NCI-WG criteria, progression-free survival (PFS) was 27.3 months for CR and 11.4 months for PR. With NHL-CT criteria, PFS was 18.4 months for CR, 11.7 months for CRu, and 14.5 months for PR. In multivariate analysis, both NCI-WG and NHL-CT response correlated with PFS (P = .009 and .001, respectively). CONCLUSION: Current NCI-WG CLL response criteria are a significant predictor of PFS in previously treated CLL patients, with no additional benefit from the inclusion of CT scans. Although retrospective, these results highlight the importance of prospective validation of CT scans before routine inclusion in CLL response criteria.

PMID: 17984187

As always with CLL issues, the situation is a little ‘nuanced’, no slam dunk “yes” or “no” answer. But I see the balance tilting definitely in the direction of doing fewer scans, justifying the need for doing them before a knee jerk dependence on the high tech toys.

Which Type of Scan Works Better For CLL?

Below is a very recent ASH2009 abstract that compares the usefulness of CT scans (with or without contrast), PET scans and combination of CT and PET scans, across a spectrum of blood cancers.

Comparison of Contrast-Enhanced CT, PET/CT, PET, and Low-Dose Non-Contrast Enhanced CT Imaging of Diffuse Large B-Cell, Follicular, Small Lymphocytic/CLL, and Marginal Zone Lymphomas

Elise A. Chong, BA1*, Drew A. Torigian, MD, MA2*, Abass Alavi, MD3*, Jakub Svoboda, MD1, Anthony R Mato, MD4*, Sunita Dwvedy Nasta, MD1*, Lisa H. Downs, CRNP1* and Stephen J. Schuster, MD1

1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA

2Department of Radiology, University of Pennsylvania, Philadelphia, PA

3Division of Nuclear Medicine, University of Pennsylvania, Philadelphia, PA

4Hematology and Oncology, University of Pennsylvania, Philadelphia, PA

Introduction: Anatomic imaging using contrast-enhanced computed tomography (CT) is essential for management of lymphomas. Functional imaging using 18FDG-PET (PET) improves detection of certain lymphomas, specifically, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Currently, PET imaging is performed with co-registration of low-dose non-contrast enhanced CT images used for anatomic correlation and attenuation correction of PET images (PET/CT). It has been suggested that the low-dose non-enhanced CT cannot substitute for diagnostic contrast-enhanced CT imaging since the arterialand venous phases of contrast enhancement improve detection of lesions. Given the differential sensitivity for detection of specific lymphomas by PET imaging, we hypothesized that FDG could substitute for intravenous contrast in imaging of certain lymphomas, and that PET/CT or PET imaging could potentially obviate the need for contrast-enhanced CT. To test this hypothesis, we performed an independent and blinded radiology review of these imaging studies in patients (pts) with DLBCL, FL, small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL/SLL) or marginal zone lymphoma (MZL) who had contrast-enhanced CT, PET, PET/CT, and low-dose non-enhanced CT available for retrospective review. Patients and Methods: Ptswith a diagnosis of DLBCL, FL, CLL/SLL, or MZL with PET/CT and contrast-enhanced CT studies performed at the Hospital of the University of Pennsylvania within 6 weeks of each other without intervening therapy were studied. Pts with clinically suspected progression of lymphoma between studies were excluded. Radiologists, blinded to clinical information or other imaging results, separately interpreted image sets of low-dose non-enhanced CT, PET, fusion PET/CT, and contrast-enhanced CT studies. The presence or absence of disease at 44 nodal and 48 (female) or 49 (male) extranodal sites was recorded for each site for each imaging modality. Concordant findings across imaging modalities were defined as positive for involvement by lymphoma; discordant findings were reconciled using all available clinical and radiologic information with follow-up for progression or regression of abnormality, or by biopsy. Results: Between May 2006 and January 2008, 55 pts with either DLBCL (n=31), FL (n=13), CLL/SLL (n=5), or MZL (n=6) had complete images sets available for review. All patients had at least 18 months of clinical follow-up after imaging. A total of 282 sites met criteria for involvement by lymphoma. The rates of detection for specific lymphomas by each imaging modality are shown below:

Conclusions: Our results suggest that combined PET/CT imaging is more sensitive than contrast-enhanced CT imaging for detection of DLBCL and at least as sensitive as contrast-enhanced CT imaging for detection of FL. In comparison, contrast-enhanced CT imaging appears superior to PET/CT imaging for CLL/SLL; while further studies are needed to confirm superiority of contrast-enhanced CT imaging in MZL. The routine use of both contrast enhanced CT and PET/CT modalities for staging of lymphoma may be unnecessary, potentially increasing both the cost of medical care and radiation exposure. Additional studies are needed to determine which imaging modality is optimal for each type of lymphoma.

I have simplified the table from the abstract (just a little, just enough to make it easier to read). Here it is.

Lets look at each of the four options (CT with contrast, low dose CT, PET and PET/CT) in turn, paying special attention to how the CLL/SLL patients benefited from the technology.

No question, CT scans with contrast were the most sensitive technology. Roughly 9 out of 10 times they did a good job. As you would expect, detection accuracy of CT scans was a lot better when looking at the nodal part of the disease, much less effective in the bit that is outside of lymph nodes. What does this mean for us chickens? If you have a more SLL type, if you have the FISH abnormalities (such as 12 trisomy, 11q and 17p deletions) that often go hand-in-hand with bulky adenopathy, CT scans with contrast are more useful in your case. If you are a 13q deleted patient with just about all the CLL cells cruising around in the blood, none of them showing any tendency to settling down and setting up home in the lymph nodes, CT scans with contrast are not going to tell you much. Remember, it is always a case of comparing risks and rewards. If the scan is not going to be all that useful in your case, why get the radiation exposure hit (not to mention health care dollar hit) of a full strength CT scan? Something to discuss with your doctor.

This paper says CT with contrast pretty much blows away all the other technologies. PET scans are of much less use in CLL/SLL patients. Low dose CT scans (without the toxicity and hassle of drinking bottles of contrast) are a tad better – but not quite as good as full strength CT scans with contrast. But if you are allergic to the components of contrast you may not have an option but make do with the lower sensitivity of a low dose CT scan – when and if you need it.

Guys, please don’t fall for the extreme positions. Do not throw the baby out with the bathwater. I cannot in good conscience support or validate your position if you swear you will never, ever, have a CT scan, come hell or high-water. There may be occasions when this is the only way your oncologist can get a good sense of the lay of the land and decide if it is time to treat, what to treat you with and judge how well you are doing so that he can fine-tune dosages etc. Be smart, never say never.

On the other hand, I know a couple of guys who have no-limit health-care insurance and get annual “executive” health check-ups. The latest must have fashion accessory of the super rich are “concierge” doctors who are willing to do whole body CT scans. Why would any healthy person in their right mind get this much radiation exposure just to satisfy their vanity? Don’t fall for the high tech solutions if there is no problem needing a solution.

One More Scenario Where Scans Are Mandatory

This is a tough one.

Many clinical trials call for one or more CT scans to stage patients accurately before, during and after completion of the new drug protocol under study. Sometimes this desire for detailed research information goes a little nuts.  Researchers need to keep in mind that their human subjects are not lab rats with no choices.  People can always vote with their feet.  I remember one plaintive letter I got from the Principal Investigator of a clinical trial who was having tremendous difficulty recruiting patients.  He could not figure why patients were staying away in droves.  Duh! His trial protocol required five CT scans and three bone marrow biopsies.

I am all for increased participation of patients in clinical trials.  No progress is possible without well conducted clinical trials and dedicated volunteers that risk their bodies and lives in order to make things just a bit better for future generations. But, on the other side of the coin, we need researchers who are more sensitive to patient friendly trial designs.  How the heck can they influence us if they can’t hear us, don’t care about our needs, forget to even thank us for participating in their clinical trials? Moral of the story, before you sign on the dotted line for any clinical trial, do ask how many invasive diagnostic procedures (scans, lymph node and bone marrow biopsies) are involved; and whether you have the choice of opting out of any of them.  Some of the data collection tests are optional, a little detail you may not find out unless you ask.  As a savvy customer, be sure to understand what you are buying into, before you buy it.