“Just Right” Goldilocks Scenario
By now most of us know that single agent or chemotherapy combinations are rarely given all on one day. Most often they are given over a few days and the process is repeated over a number of cycles. For example, each cycle of FCR is given over three days and the cycle is repeated every month for six months. This standard protocol was developed at M. D. Anderson in their pioneering clinical trials involving many hundreds of patients.
Now that FCR is accepted as the present day gold standard by most CLL practitioners, you are likely to be treated with this regimen as a front-line therapy outside of clinical trials. Come to think of it, you and your oncologist are no longer rigidly locked into the FCR clinical trial protocol. It is possible to consider tweaking the protocol to customize it for individual patients. How much chemo is just right for you?
CLL is such a diverse disease, how is it possible that standardized and rigid protocols defining drug dosage and number of cycles are right for all patients? In this article I would like to discuss the pros and cons of finishing all six cycles of the therapy protocol, as opposed to calling it quits part way through. It is a tricky question and there is plenty of grey area. But a new technology is rapidly gaining acceptance that might make it just a bit easier to make the decision.
Risks and Rewards
Let us all agree on one point: just about every single cancer drug out there has some level of toxicity. Chemotherapy dosages and number of cycles are designed to kill cancer cells – while sparing the healthy cells in your body. Think of it as a window of opportunity, where the drug dosage and its toxicity is enough to kill cancer cells with gusto, but has relatively low toxicity to the healthy cells of your body. The word “relative” is important. It is once again a question of judging whether you get sufficient bang for the buck, without going over the top in terms of toxicity and loss of quality of life.
The problem with CLL is that it presents so differently in different people. Folks with good prognostic indicators, chemo naïve patients who have never had a whiff of chemotherapy earlier on, these guys are likely to respond very well to therapy, getting deep reduction in the number of cancer cells in their bodies right away before they have gone through many cycles. Not so lucky are the patients with refractory disease, poor prognostic indicators and / or prior history of having been around the chemotherapy block a couple of times. So, what is the logic of having the same fixed drug dosage and the same fixed number of cycles no matter which of these two extreme groups you belong to? You don’t want to scald your mouth with too hot porridge, but you don’t want to eat a cold and congealed mess either. You want it just right, thank you very much.
Some Common Reasons Why Patients Do Not Finish All Cycles
With the best of intentions some patients are not able to finish all the cycles prescribed in a given protocol. For them the toxicity becomes too much; important blood counts such as neutrophils, red blood cells and platelets take a dive; or their liver, heart or some other important organ takes too much of a hit; or they are plain unable to tolerate the regimen. For these guys there is no choice, they drop out when they can not handle the therapy any longer. Most of the time they do not get the full benefit of the therapy and have to make-do with less than stellar remissions.
Another subset of patients discontinue therapy before finishing all cycles because they are clearly not responding well. They are not getting much benefit from the therapy in question and there is not much point in beating a dead horse. They are better off regrouping and figuring out what to do next, whether some other therapy option is likely to serve them better.
When You Actually Have A Choice
Let us now focus on patients who have a choice in the matter. Let us assume you are among the lucky ones with good prognostics and this is the first time you are being treated with any kind of chemotherapy. You have completed four of the prescribed six cycles of FCR. Lymph nodes have melted away. A physical exam by your oncologist cannot find any swollen nodes of spleen, no matter how hard he poked around. WBC and ALC are in normal range. But as expected there has been some toxicity and as you went through each cycle your red blood cell counts have taken a hit. Your neutrophil counts have fallen below 1.0K and you are officially neutropenic, increasing your risk of infections and viral reactivations.
Here is the million dollar question: for all practical purposes you are in clinical “CR” (“complete response”), at least once your other blood counts have had a chance to recover. Should you tighten your belt and complete the remaining 2 cycles, or should you quit at this point to avoid further toxicity?
Not All “CR” Responses Are Created Equal
And that is what makes it difficult in deciding when to call it a day and not undergo additional cycles of therapy. The problem is that “complete response” or CR does not mean what you expect it to mean in plain English. It is not complete. Not by a long shot. It just means within the detection capabilities of your oncologist’s trained fingers, there are no swollen lymph nodes, and within the capabilities of the garden variety CBC, the WBC and ALC are within normal ranges, and other blood counts are not too far from normal ranges (or expected to recover reasonably quickly once therapy is completed).
A picture is worth a thousand words. Below is a pictorial representation of the kinds of results we can expect using single agent chlorambucil, or fludarabine, or one of the modern combos such as FCR.
Chlorambucil reduces the total number of CLL cells in your body a hundred-fold, from a trillion cancer cells to a mere ten billion or so, give or take a few. Fludarabine does a better job, taking down the remaining tumor load to just one billion CLL cells. There is no free lunch, you pay for this ten-fold improvement in reduction of remaining cancer cells – in terms of increased toxicity of fludarabine compared to chlorambucil.
Notice what happens to the number of cancer cells in your body over time, once the chlorambucil or fludarabine treatments are finished. Gradually over time the numbers creep back up and pretty soon you are back where you started. End of remission, time to think of your next option. Compared to chlorambucil the fludarabine response lasts a bit longer since you got a slightly deeper clean-out of cancer cells.
Modern therapy combinations such as FCR get much deeper responses, going all the way from a trillion cancer cells to begin with to a mere handful, a couple of million or so CLL cells. That is a 100,000 fold reduction! No wonder experts are excited about this and similar chemotherapy combinations. This is the first time in history we are seeing such deep remissions.
What can happen over time to folks who get such deep remissions? We project three possible scenarios. The grey line shows gradual but inexorable increase in cancer cell count, eventual relapse baked in the cake for this scenario. True, even in this bleak scenario the remission lasts a lot longer than the remissions possible with chlorambucil or fludarabine singe agent therapy.
The green line and red line are more interesting. The remaining CLL cell count in the body waffles up and down a bit, the survivors having difficulty regrouping and getting back to full fledged strength. Perhaps your immune system is lending a hand as well, keeping the badly beaten army of cancer cells under control. Our experience to date has been that just about all patients will eventually relapse, even after getting deep cancer cell clearance. But it is reasonable to expect that truly deep remissions are likely to last longer since it will take that much longer for the enemy to regroup. Longer duration remissions are what every patient wants from therapy.
There are two horizontal lines on the graph. The first (higher one) gives us the definition of the NCI “CR”. Even the fludarabine folks get a “CR” by this ‘easy’ criterion. This criteria cannot tell the difference between a ho-hum “CR” after fludarabine or a really deep “CR” after FCR therapy. The second horizontal line is the level of detection accuracy possible with PCR (polymerase chain reaction) technique. It is a hundred times more sensitive. The present day holy grail in response is a “PCR negative remission” – which means that even the most sensitive testing method at our disposal cannot see any CLL cells in your body. It does not mean there are truly no CLL cells left behind in your body. Just that we cannot see any, no matter how hard we looked.
Lessons learned Thus Far
- Not everyone responds the same way to therapy. We need to have customized protocols (outside clinical trials).
- Deeper clean-out of CLL cells is likely to give us longer remission – something that we all desire.
- While higher dosages and longer duration of therapy may yield deeper responses and possibly longer remissions, there is a clear cost to this in terms of toxicity and loss of quality of life.
- We need some way of telling when we have reached the break-even point, when more therapy is not going to improve response but might add to the toxicity side of the equation.
- CT scans with contrast can help look more closely for tell-tale swollen nodes hidden deep in the abdomen. Bone marrow biopsies can look at the level of infiltration. Both of these are invasive procedures that many patients are justly reluctant to undertake. PCR testing is a blood test. But it is expensive, not easy to do and there is not 100% consensus on how exactly to do it.
- We need a simple blood test that does not cost an arm and a leg, that can go much further than the standard CBC in its sensitivity and ability to detect traces of CLL cells, that can shed some light on the status of the bone marrow.
Below are two abstracts of important papers that describe a flow cytometry method that is gaining approval from many experts. As we described in an earlier article, flow cytometry is a blood test. What makes this one special is that it focuses on four crucial markers on CLL cells – hence its name of “Four color flow cytometry”. More and more, it is being used to test for minimum residual disease.
Blood. 2001 Jul 1;98(1):29-35.
Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.
Rawstron AC, Kennedy B, Evans PA, Davies FE, Richards SJ, Haynes AP, Russell NH, Hale G, Morgan GJ, Jack AS, Hillmen P.
Haematological Malignancy Diagnostic Service, Leeds General Infirmary, Leeds, United Kingdom. andy.rawstron@newscientist.net
Previous studies have suggested that the level of residual disease at the end of therapy predicts outcome in chronic lymphocytic leukemia (CLL). However, available methods for detecting CLL cells are either insensitive or not routinely applicable. A flow cytometric assay was developed that can differentiate CLL cells from normal B cells on the basis of their CD19/CD5/CD20/CD79b expression. The assay is rapid and can detect one CLL cell in 10(4) to 10(5) leukocytes in all patients. We have compared this assay to conventional assessment in 104 patients treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H therapy, circulating CLL cells were rapidly depleted in responding patients, but remained detectable in nonresponders. Patients with more than 0.01 x 10(9)/L circulating CLL cells always had significant (> 5%) marrow disease, and blood monitoring could be used to time marrow assessments. In 25 out of 104 patients achieving complete remission by National Cancer Institute (NCI) criteria, the detection of residual bone marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients predicted significantly poorer event-free (P =.0001) and overall survival (P =.007). CLL cells are detectable at a median of 15.8 months (range, 5.5-41.8) posttreatment in 9 out of 18 evaluable patients with less than 0.05% CLL cells at end of treatment. All patients with detectable disease have progressively increasing disease levels on follow-up. The use of sensitive techniques, such as the flow assay described here, allow accurate quantitation of disease levels and provide an accurate method for guiding therapy and predicting outcome. These results suggest that the eradication of detectable disease may lead to improved survival and should be tested in future studies.
PMID: 11418459
OK, we buy that four color flow cytometry can tell us much more accurately how many CLL cells are floating around in the blood. Aha, but what about the bone marrow? How can we tell how many CLL cells are lurking there? Do we still need to do a painful / invasive bone marrow biopsy to get a handle on this? The good news is that the authors have shown a very nice correlation between the number of circulating CLL cells in the blood versus the percentage of bone marrow infiltration. Nice correlation, but not perfect – good enough for government work as they say.
The value of this approach was not lost on researchers and there is a rapidly growing consensus on its use. As the abstract below points out, we are now developing international standardized approaches to using this technique with a view to judge MRD status of the patient at different points along the therapy protocol.
Leukemia. 2007 May;21(5):956-64. Epub 2007 Mar 15.
International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia.
Rawstron AC, Villamor N, Ritgen M, Böttcher S, Ghia P, Zehnder JL, Lozanski G, Colomer D, Moreno C, Geuna M, Evans PA, Natkunam Y, Coutre SE, Avery ED, Rassenti LZ, Kipps TJ, Caligaris-Cappio F, Kneba M, Byrd JC, Hallek MJ, Montserrat E, Hillmen P.
HMDS, Leeds Teaching Hospitals, Leeds, UK. andy.rawstron@hmds.org.uk
The eradication of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) predicts for improved outcome. However, the wide variety of MRD techniques makes it difficult to interpret and compare different clinical trials. Our aim was to develop a standardized flow cytometric CLL-MRD assay and compare it toreal-time quantitative allele-specific oligonucleotide (RQ-ASO) Immunoglobulin heavy chain gene (IgH) polymerase chain reaction (PCR).Analysis of 728 paired blood and marrow samples demonstrated high concordance (87%) for patients off-therapy. Blood analysis was equally or more sensitive than marrow in 92% of samples but marrow analysis was necessary to detect MRD within 3 months of alemtuzumab therapy. Assessment of 50 CLL-specific antibody combinations identified three (CD5/CD19 with CD20/CD38, CD81/CD22 and CD79b/CD43) with low inter-laboratory variation and false-detection rates. Experienced operators demonstrated an accuracy of 95.7% (specificity 98.8%, sensitivity 91.1%) in 141 samples with 0.01-0.1% CLL. There was close correlation and 95% concordance with RQ-ASO IgH-PCR for detection of CLL above 0.01%. The proposed flow cytometry approach is applicable to all sample types and therapeutic regimes, and sufficiently rapid and sensitive to guide therapy to an MRD-negativity in real time. These techniques may be used as a tool for assessing response and comparing the efficacy of different therapeutic approaches.
PMID: 17361231
Strange Bed Fellows
I am generally not a big fan of “Managed Care Magazine”. You might say they have a bit of a slanted view of things, a tad more emphasis on saving dollars than me. But for a change their emphasis on dollar cost has a parallel in what is more important to me, toxicity cost to patients. More chemo cycles beyond the optimum point means more health-care dollars. It also means your body takes on more toxicity than is optimum. Hooray, we share a common agenda with the pencil pushers at Managed Care. I have given below some excerpts (highlighting is my contribution). You really should read the full article, it is well written and with little by way of medical jargon. It won’t hurt a bit, I promise.
Four-Color Flow Cytometry Detects Minimal Residual Disease in Leukemia
Should a new (and cheap) test for chronic lymphocytic leukemia be a component of prior-authorization protocols?
Thomas Morrow, MD
- Most managed care decision-makers have focused on the cost of the new therapeutic regimes.
- Even when the polymerase chain reaction is negative, there are probably a number of malignant cells still alive that are undetectable, and sometimes referred to as minimal residual disease (MDR). These residual cells then repopulate, resulting in a relapse. If these few cells are eradicated, we may have a longer disease-free survival
- Scientists have developed a new method to detect these small amounts of cancer cells in patients with B-cell chronic lymphocytic leukemia (B-CLL). This test utilizes a four-color flow cytometry (FC) technology that can detect even a single B-CLL cell in 10,000 white blood cells.
- FC can be used to diagnose a disease as well as to follow post-therapy response.
- FC can be used on peripheral blood, bone marrow aspirate
- Overall, FC is less expensive and much faster (one to two lab hours) to process than IHC (immunohistochemistry)
- Because this new technology detects very low levels of B-cell leukemic cells, it will enable clinicians to cease therapy with a level of clinical certainty unheard of in the recent past, thus potentially preventing unnecessary courses of expensive therapy.
- Common current therapy includes Campath, costing about $64,000 for a three month course, and Rituxan and Fludara, costing about $20,000 for a six-month course. When FC is used to detect MRD, patients avoid the painful, invasive bone marrow biopsy.
- This FC-MRD test retails for about $1,500.
- FC will become a normal part of clinical practice rapidly. How will it be covered? Should FC become a requested component of the prior authorization protocols for various expensive drug regimes?
I am aware that Genzyme does the four color flow cytometry testing for minimum residual disease. Other companies may do so as well. Below is a link to their website and a bit of the information. Please visit their website to get the code numbers etc needed to order the test.
CLL-MRD (Minimal Residual Disease) Testing by Flow Cytometry
This process allows for the differentiation of 1 CLL cell in 10,000 normal B-cells and provides a quantitative measurement of the MRD status of patients with CLL who are undergoing therapy. Patients who achieve CLL-MRD-negative status have improved overall and progression-free survival. This test is not suitable for making primary diagnosis or monitoring untreated CLL patients with a high tumor load.
Specimen Requirements (Peripheral Blood) : 10-20 ml in sodium heparin (green-top) tube.
Turnaround Time: 24-48 hours
Editorial
This article was prompted by three separate cases that came to my attention last couple of weeks, one in the UK and two here in the USA. All three patients have completed some but not all of the six cycles prescribed in the protocols. All three have already achieved what appear to be “CR” responses. In each case, the supervising oncologist did not pro-actively raise the possibility of testing for MRD before going further. However, in the UK case, when requested by the patient his physician agreed to get a four color flow cytometry test done to check for minimum residual disease before progressing to cycles #5 and #6.
As I said, this is not an easy decision to make. The last thing I want is for you guys to chicken out of needed therapy and therefore fail to get full benefit from the chemotherapy option you and your physician have selected. Pulling your punches before you have reached the optimum point would be a shame.
At the same time, more chemo is not necessarily better either. Once again, it is a case of careful weighing of risks and rewards. For a change, technology has given us a great new tool that can help make this process easier. There is no radiation involved as in CT scans, no pain and suffering of a bone marrow biopsy. Just the usual needle prick for a blood sample and away it goes for a quick turn around (2 days!) four color flow cytometry test to evaluate your MRD status. Even your insurance company will be pleased with you, since using this test means dollar cost savings for them.
Will you get some push-back from your oncologist if you ask for a minimum residual disease test (four color flow cytometry) before moving on to remaining cycles? You might, if the oncologist is not up to speed on latest Best Practices in the field. Four color flow cytometry is a new-fangled thing and some people have a built-in objection to new things. It is also much easier to make slam dunk decisions without putting brain in gear first – it saves a whole few minutes of the consultation time! But like the UK consultant I discussed above, most hematologists and oncologists who try to stay abreast of new developments will take your request seriously.
However, if you are in a clinical trial things may be different. There is a huge amount of vested interest in having as many patient – volunteers complete the full course, dot each “i” and cross each “t” of the clinical trial protocol as possible since it makes data interpretation that much easier. Once again we face the ugly possibility of conflict of interest – between that of the dedicated researcher trying to run a well controlled experiment and that of the ethical physician doing the best he can for the individual patient in front of him. It is not always easy wearing two hats.
If you are in the middle of therapy, this is something you should discuss with your doctors with a view to customizing the number of cycles in your case. You agree?
23 comments on "How Much Chemo Is Too Much?"
Chaya,
As usual you have hit the nail firmly on the head. When I was having chemotherapy for my cancer, it was planned that I have 12 courses, but CT with contrast showed no difference between 6 course and 9 so chemo was stopped (thank goodness!). Andy Rawstron and Pete Hillmen have done us a great service by inventing the four color flow test. At $1500 Genzyme are making a huge profit, but even so there is a possibility of saving the patient a lot of suffering.
The other cogent point is that it doesn’t matter how you get to MRD negative. If you can manage it with FC then you don’t need FCR; if FCR-lite will do it then you don’t need full doses. Hence there is a possibility of using less toxic treatment for those with good markers and monitoring with flow.
The other thing I have to say is that I am annoyed about all these abreviations. PCR can mean two things and now FC can mean two things.
Chaya,
Thank you.
While there may be a tight correlation between the CLL clone in the blood and the CLL clone in the marrow, I worry that about those of us with 11q and others with big nodes, We may be MRD neg. in the blood and marrow and have no palpable nodes, but still have significant disease in growing nodes hidden in the gut. My CLL recurred in my mesenteric nodes when I still was MRD neg in the blood and bone marrow. For some of us, a CT scan must be carefully considered as part of the mix in assessing when to stop or for that matter, start therapy.
Be well
Brian
Thank you, Chaya, for a most timely report . . most timely for me, anyway. I have just completed round 5 of FCR and my local oncologist has been dropping hints about the possibility of going on to a round 7 or 8. By all indications I am doing very, very well so far with virtually no side effects. I am going to go back and reread the M.D. Anderson protocols for FCR and see when or if going beyond round 6 might ever be warranted. Your report gives me a new tool by which to evaluate it all. Thanks.
Bob
Completed the 6 month FCR Cycle 4 months ago. Results: Complete Remission. The first four sessions were endurable but the 5th and 6th sessions were getting more and more difficult with feeling more of negative effects upon my whole body. It ‘appeared’ that the CLL was in complete remission after number 3, but we continued as my toxcity toleration was not in the negative side of things and the results of my stats were very good. At number #4 I wanted to stop, but pressed on to complete the ‘standard regime’ and have the best possible results. Presently my stats are all normal except for my lymphs that are coming around and approaching normal. Time will tell as to longivity that my CR remains and the success of the 6 stage FCR Treatment regime.
Chaya,
What am I missing with my anti-chemo logic?
I am not a doctor, merely a CLL patient who is doing his best to try and be well informed. When one has chronic lymphocytic leukemia it is important to remember that in almost all cases this cancer is incurable. When your doctor recommends that you begin some form of treatment, such as the intake or infusion of various toxic substances, I recommend that you ask yourself (or him/her) a couple of important questions:
(1) Will taking these drugs mean that my immune system will begin functioning better than it does now? In other words, will my chances of dying from pneumonia or some antibiotic resistant disease this winter be reduced?
(2) Are there peer reviewed studies which show a meaningful extension of lifespan, i.e. survival rate? A longer duration of life; not a few months, but years.
As far as I have been able to find out, all of the current popular therapies appear to have significant side effects. Reduction in the effectiveness of one’s immune system, unusual infections, various degrees of impairment in the proper functioning of one’s kidneys, heart, or liver. I do not give much credence to what I see as “spin phrases” like full remission (usually temporary), good response to the therapy, or minimal residual disease when a physician is discussing therapy options.
When one takes into full consideration the down side risks of these therapeutic agents, one needs to closely look at whether the drugs will make your immune system work better than it does currently; and whether there is reliable and repeatable peer reviewed statistical proof that on average you might expect a meaningful increase in life span by undergoing these toxic treatments which can significantly weaken one’s already rather deficient immune system.
Paul
Another good an informative article from Chaya that us lay folks can understand. I still would like to see some more definitive data on overall survival. I am forever the skeptic on FCR hoping for much more targeted therapies going forward. There are big bucks in these drugs and treating the side effects over time can run into additional hundreds of thousands of dollars and a poor quality of life. I also wonder how many people die from complications and other factors associated with CLL and its treatments but whose cause of death is listed as something else. I remember in the 50s, 60s, and 70s when vast sums were spent on poorly targeted radiation treatments for cancer. If we look back on those 30 years a strong case could be made it did nothing for survival times and may have even shortened them. OS is such a hard statistic to come by because of the long duration of this cancer and would require statistics on 10s of thousands to be accurate. Who is going to fund that? More and more we are recognizing the highly individual nature of CLL.
I’m almost 3 years into an MRD neg (4 color flow) CR following 4 cycles of FCR. My CBC’s bounce around just above and just below normal limts. From what I understand, both the FCR and my cll have caused some marrow destruction that keeps them from getting higher.
So, the threat of infection isnt the consideration when deciding whether to stop early or go the whole 6 cycles. In my case, stopping early has worked out very well.
mschwalm48
This concept of using four color flow cytometry to test for minimum residual disease part way through the full protocol can be applied to any drug regimen, not just FCR. For example, if your preference is R + HDMP, then too it is a question of when to call it quits.
hpgarland:
Seems to me your mind is made up and I will not argue with you. The best therapy choice for you is the one that feels right to you.
Brian:
Four color flow cytometry does not rule out using any other test. By all means include CT scan(s) and /or bone marrow biopsies as they fit into a customized plan for you. My beef is with this unyielding dependence on cook book formulas when we all know CLL is a variable disease and our patients need customized care. It is intellectual laziness not to make the therapy fit the patient – not the other way around!
Terry:
Thank you! Coming from you that is a huge compliment. I will treasure it.
just a question…can ultra sound be used to measure lymph node loads instead or with palpitation?
bob
bobarmstrong:
As Terry Hamblin pointed out in his answers to questions on this website, ultrasound is not as sensitive as CT scan with contrast. But is ultrasound better than mere physical palpitation? I suppose that depends on the specifics, such as where the node is and how deeply buried it is. Since ultrasound does not carry the same risk as CT with contrast, it may well be a good choice to include this procedure in the MRD determination. I am all in favor of more detailed informtion that can help the decision making process, provided the “cost” side of the equation is not too high. Ultrasound may be a good choice in that regard.
Good call Bob.
Annette
My husband’s onc wants him to do a PET/CT scan ( his lymph nodes are bulky)because his blood creatinine is high (1.54) and on top of the rediation the contrast stuff can harm the kidneys. Is PET/CT as sensitive as CT with contrast ?
Is high blood creatinine part of the CLL package ?
Annette:
High creatinine levels could be due to kidney disease. But there are a host of other causes too, including not drinking enough water! Many of the drugs that CLL patients take (both the prescribed ones as well as over-the-counter variety) can increase the load on the kidneys. You are right to worry about the further load on the kidneys as a result of CT/Contrast.
Below is a link to an article that discusses some of the reasons why creatinine can be high. There are many other such sites on the web. Please discuss your valid concerns about high creatinine levels with your doctors before proceeding with CT scan with contrast. If you believe the recent review we did on the state of the art, combination of PET plus CT+contrast is bit of an overkill under most normal circumstances that CLL patients are likely to encounter. However, there are always exceptions and this too is something your doctor should explain in detail.
http://www.medicinenet.com/creatinine_blood_test/page2.htm
For first line treatment most USA CLL experts recommend going the full 6 cycles (be it FR, FC, FRC,PRC, BR, etc.) to get the most bang for the buck with your first regimen. In the second and third line therapy situation my CLL doc restaged my disease both times after 4 cycles when blood tests and a physical exam indicated good blood response, normal spleen and absense of palpable nodes. While the bone marrow biopsy reviealed low disease involvement, the CT scans indicated abdomimal nodes which were still enlarged. So, when I continued beyond the 4 cycles at least I had the knowledge that there was a good reason to continue rather than stopping early possibly prematurely or proceeding blindly through 6 cycles. Restaging after an apparent good response before completing all cycles increases patient confidence and seems to make good sense to me.
Diane MacKinnon
Thank you Chaya for this informative article.
Stay well,
Monique
Thank you Chaya again for your diligence and affectionate consul on this most insidious disease.
For the record I have been having FCR administered using Dextrose 5% (a sugar) as the vehicle rather then the standard saline solution. The reasoning being is that if one fasts for 12 to 15 hours before undergoing chemo the blood sugar drops and since tumors live on sugars (glucose) they become “hungry” and will absorb the Dextrose quickly along with the FCR. This is proven in PET scan technology.
My history is such; a FNB (fine needle biopsy) was done on swollen lymph nodes and were found to have Diffuse Large B Cell Lymphoma (Richter’s Transformation). I fasted as above and had the oncologist administer the FCR with the Dextrose, by the third day the swelling was gone completely and a CT scan could not detect any other lymph node problem. My doctors reaction was, “This is incredible!” and of course he wished to have a full 5 more treatments given, which I refused and instead have been taking PSP (polysaccharide peptides, Lactobacillus Ramosus GG (mentioned in your article “Let them eat yogurt”) as well as antioxidants. (Note antioxidants should not be taken while undergoing chemotherapy)
After four months of the above oral dosages two components of the immune system (CD3-16 increased by 22% and CD3-56 increased by 46%) others are pending.
I am of the mind that using chemotherapy is essential but in moderation, using the two components above to boost the immune system will perhaps result in better outcomes as the bodies own capacity to defeat the disease must not be compromised and is compromised by chemotherapy destroying the immune systems white and red blood cells.
Mahalo from Hawaii,
RBW
Chaya–Thank you for another excellent analysis and understandable comments.
My case is an encouraging one. I was diagnosed stage 0 in April 09; next test was Aug 09, and I was stage 4, with very bulky nodes in neck and abdomen. I went through 2 cycles of FCR with no side effects in Sept and Oct 2009. All my nodes disappeared. Nov 2009 spent seven days in the hospital with pneumonia, fully recovered. All my blood work is in normal range, as of 12/21/09 and 1/18/10. My onc/hemo is Philip Periman in Amarillo, TX.
Thank you again for publishing this site.
Carter
Thanks again, Chaya.
You gave us important information that can be used now. Having a standard for staging remissions sounds like an excellent plan. I hope it comes about.
I appreciated hearing others relate their experiences. My Terry’s oncology appt. is tomorrow regarding CT results and treatment recommendations. The doctor has already said FCR or maybe a lighter dose. I forgot lighter of which element.
A question: Has anyone begun treatment without a BMB? Is it advised?
Thanks,
Linda
Any patient preparation for initial treatment should include an assessment of the immune system’s pretreatment ability to keep infections at bay. A big impression was made on me by an article in CLLTOPICS focusing on the primary cause of death being from infections as a result of degraded immunity from chemo/monoclonal antibody therapy. To some degree the choice and amount of therapy needs to be tailored to the baseline health of the patient beyond the familiar markers we are tested for.
As much as FCR standard therapy is touted to serve the greater statistical number of patients for longer and more durable remissions, far too many fail outright or relapse far too early relative to the toxic risk. Seems likely that more extensive research is needed on basic immune function to develop subtypes of patients.
Response to therapy is highly variable and in my case the RF concurrent protocol for my first cycle gave a dramatic (may be too fast) reduction to the massive tumor burden I was carrying. The creatinine (measure of kidney function) started to slowly and steadily rise from a high normal of 1.4 just after 1st cycle ended to a high of 1.8 just before 2nd cycle began. This concerned me but apparently not my Oncologist or the Physician’s Assistant who proceeded to begin the 2nd cycle without reducing the amount of Fludarabine even though my Glomerular Filtration Rate (GFR) was at 40. This 2nd cycle led to stage four kidney failure in spite of my voicing concern over the creatinine/GFR numbers to the infusion nurse on the first day. I got a “pat-on-the-head” of “Oh, we’re aware of it and we are giving extra saline to deal with it”.
The good news is that my CLL is not drug resistant (yet). The bad news is that I was unable to continue with therapy because of kidney failure from Acute Tubular Necrosis (ATN). A cause for the failure never was clearly defined as it did not occur from classic Tumor Lysis Syndrome (TLS). My onc thought it might have been a rare allergic reaction to the Fludarabine, the volume of debris from the massive cell death or a combo of the two. The copious water drinking and extra saline was not enough to prevent this event.
Several questions have come up in hindsight.
1. How critical, time wise, is it to achieve an optimal remission in CLL for all patient subtypes? In some aggressive blood cancers/lymphomas the timing of drug therapy is to the day and hypercritical to patients dying or being cured.
2. How much more likely is a vital organ, which has suffered previous damage from chemo, to fail when therapy is restarted given a reasonably good functional recovery?
3. Is it meaningful to distinguish between functional and structural recovery?
ATTENTION Annette, I hope you are reading this and consider this advice. Insist your husband gets a Nephrologist involved BEFORE any scanning or treatment is to take place!! It was a real lacking on my part when I failed to have a Kidney Doc brought into my treatment decision making process before my 2nd cycle began. I trusted that my voiced concern to the nurse would be sufficient. Patients cannot trust their Oncologist’s staff on these critical matters. I should have known better but your husband can avoid my mistake as his CLL, without the detail of FISH and other test markers, too closely resembles mine.
Now, I am faced with the difficult decisions of what to treat with and when. Because I am feeling so good, my gut or maybe my kidneys, are urging me to hang in a limbo of Wait & Watch while my intellect is worried about the wisdom of waiting and the treatment choices least likely to further damage my kidneys. It is so good to be enjoying living again that the thought of going back into treatment is not pleasant or free from anxiety given depth of sickness I experienced this past Fall.
Thanks Chaya and Drs Terry Hamblin and Brian for your input.
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Annette
Thank you Waynewells.You bet I will march my husband to the nephrologist. Amazing, he was told to just drink more water and it will go away.
By the way his FISH was “normal” 2 years ago, but his CD38 is 54% ,his ZAP-70 is 56% and B2M 6.8.
And thank you Chaya,I never thought one should even consider not going the full protocol cycle – intelectual laziness as you say – Four color flow cytometry is an amazing discovery for us.
Annette
I was hoping that someone smarter than I would pick up Byron’s post were he was treated for Richter’s Transformation using FCR with a 5% dextrose delivery infusion to comment on. I have never heard of using Dextrose solution as a replacement for saline in giving FCR or RF. PET scanning uses this strategy to get a radio-isotope reading of higher metabolic activity associated with degree of cancer aggression. I believe the isotope is bonded to the sugar for this to work. In the case of FCR, do any of the three agents bond to the sugar? If they don’t, how would this work?
Byron, was this treatment delivery strategy done because of the more aggressive nature of Richter’s Transformation as opposed to the lower metabolic activity of CLL? To your knowledge has this been done before because from what I thought I knew about Richter’s it would be remarkable that FCR would be a treatment choice for CLL transformed to Richter’s.
Were there other considerations or cautions by using the 5% dextrose delivery? I take it one could not be diabetic and considering this path.
This was interesting and I am just curious.
Thank you Chaya for this new, valuable information. As it looks like I will have to make a decision regarding treatment within a year, I will definitely be discussing this test with my oncologist and the CLL specialist that I will be seeing before signing up for any treatment regimen. I do not want to stress my immune system anymore than necessary but certainly want to get the best possible response the first time around. Having the 11q deletion makes this decision all the more important, I believe. I also appreciate Paul’s comments – I sometimes feel exactly as he does. And, finally, a special thanks to all of you for your willingness to share your stories. You are my support group, as I don’t personally know of anyone suffering from CLL, and it just isn’t usually worth the effort in trying to discuss it with people who just don’t “get it.”
Kathy
Hi Waynewells,
I hope your renal function is returning toward normal. Of all the possible problems during my transplant experience, renal failure was without a doubt the issue that held my greatest concern. A combination of antibiotic treatment with vancomycin (high levels are nephrotoxic)for a Hickman catheter infection, a very high level of cyclosporine (also nephrotoxic), and a day 28 post-transplant CT with contrast provided an almost perfect storm for my kidneys. Prior to that point I had never had a renal issue from CT contrast. My creatinine bumped up to 2.2 with a Glomerular Filtration Rate (GFR) of 30. As you well know, once the damage is done, no amount of forced oral or IV fluids will help. It is only a matter of perhaps hope and faith that eventually the renal function will return to normal. It was very unsettling to ponder a life of progressive renal failure and possible dialysis. It also wasn’t very reassuring to be told that my renal dysfunction was very common in this setting and that it usually resolves over time as the dose of cyclosporine is weaned over the next 6-12 months. Although there is really no scientific support for continued excessive hydration, my team was insistent that I continue to receive an extra liter to a liter and one-half of IV fluid per day on top of the 3 liters of fluid that I drank each day. For 6 weeks it was not only inconvenient but also time consuming. My creatinine dropped to about 1.5 within a couple of days following the scan and did not drop any further until by cyclosporine wean began. The team even admitted that the nephrologists felt that excessive hydration was a waste of time. The important time for hydration is the 2 hours before the contrast is administered.
When it came time for my day 84 post-transplant CT, I was very concerned about the effect the contrast would have on my recovering kidneys. I loaded up with IV and oral fluids before the scan. I also was give a double dose of the mucomyst (acetylcystine) protocol and continued the hydration post-scan. That seemed to do the trick. My renal function remained stable post scan and continued to returned to normal as my cyclosporine levels decreased.
I know my experience was very mild compared to your experienced and the result of a different mechanism, but it was enough of a scare for me to feel very vulnerable and helpless.
With regards to the 5% dextrose infusion and fasting prior to chemotherapy, I do remember reading an article in the news on this subject about two years ago. Since I am not planning to have any chemo in the near future, I have to qualify my response in that I am relying on my memory. I would recommend looking up the source and discussing it with an oncologist prior to any action. I seem to recall that the report was not a peer reviewed scientific article, but more like an abstract or theory that was observed/tried in a small group of patients for a specific chemotherapy/cancer. It was based on the thought that normal cells can alter their metabolic pathways in conditions of starvation where as cancer cells did not have that ability. As a general rule, after a 36 to 48 hour fast, normal cells metabolize ketones and/or amino acids for energy to preserve the supply of glucose for the brain (it only runs on glucose). The normal cells also limit transport of other substances into the cells to preserve energy. Cancer cells do not have this ability and continue transport glucose (fuel) and the other substances into the cell. In theory, the cancer cells will uptake more of the chemo than the normal cells that are limiting active transport in response to the fasting state. The normal cells are exposed to less chemo and therefore the patient experiences less chemo side effects due to the decreased exposure. Normal cells switch back to normal metabolism when glucose levels rise (eating or IV infusion of glucose).
I was about to start my second round of OFAR at the time. I thought I might give it a try since I had experienced a significant amount of nausea and other side effects with the first round of OFAR when compared to my experience with CFAR. However, the approach was not practical on two levels. First, some of the medications to be given with OFAR required mixing in dextrose/glucose so despite the fasting, I would get a bolus of glucose just prior to the chemo and probably revert my normal cells from the fasting condition. Second was the fact that the OFAR protocol required chemo for four days in a row. In the end, fasting for 6 days during a round of chemo out-weighed any theoretical benefit in my mind even if the meds could be mixed in a saline solution rather that one that contained glucose/dextrose.
In the time since the report was first mentioned, I am unaware of a follow up study to advocate this practice.
Thanks Steven for your detailed reply. I have found your account most interesting.
Kidney function is reasonable now with creatinine at 1.27 and GFR at 57.
Good luck and a good future to you!
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