Every since reading the European regulatory safety recommendations, I have been struggling with the entire risk vs. benefit philosophy that seems to override the significant toxicity of secondary malignancies.
Particularly, since when we look at the trials for Velcade (bortezomib) / dex while we see a significant increase in complete response (CR) and very good partial response (VGPR) there is no improvement in progression-free survival (PFS) or overall survival (OS) as compared to prior conventional therapy.
Thalidomide / dex also double CR, and Revlimid (lenalidomide) can triple CR, but once again there is no increase in PFS or OS ... but there is significantly greater toxicity.
In other words, new agents offer no significant increase in overall survival or progression-free survival ... only greater toxicity.
So the one question is whether using highly active toxic agents early on in newly diagnosed patients is akin to starting a marathon by sprinting the first mile, given that multiple myeloma is a chronic malignancy?
Does the PFS surrogate endpoint serve as a way to enhance revenues by justifying prolonged use due to more newly diagnosed being placed on Revlimid earlier and for maintenance?
If overall survival is not affected by early or delayed treatment, and the risk of toxicity is high, is progression-free survival enough of a benefit?
Shouldn't Revlimid have to demonstrated improvement in overall survival to warrant a toxicity risk of a secondary malignancy?
Complete response in multiple myeloma is not a surrogate for cure but a marker for reduction in tumor. In other words, it is not a true complete response, since patients will relapse in time.
Is it not simply impossible to say whether the individual patient has benefited by achieving a surrogate endpoint and easy to see how the patient is harmed (irreversible neuropathy, pulmonary embolus, second primary malignancies)?
Has treatment of multiple myeloma been hijacked when it comes to overall survival being an endpoint, as a trade off for using the progression-free survival, which is only an interval, but allows drugs to be used repeatedly and for prolonged periods which maximizes profits vs overall survival?
These are questions I am wrestling with as a newly diagnosed patient.
I would greatly appreciate opinions in terms of whether chronic therapy should be aimed at quality of life vs. the high toxicities involved in seeking a complete response.
Somewhat like controlled blood pressure and diabetes with minimum toxicity to the patient.
Forums
Re: Are CR and PFS suboptimal surrogate endpoints?
Suzierose,
Novel agents not demonstrating overall survival benefit have to be attributed to the time limitations involved in the studies. For instance, UAMS TT2 demonstrated an overall survival of 12 years. In TT3, UAMS added Velcade to their trial. The TT3 trial is only a few years old. But, at 5 years, overall survival in TT3 was 82% as compared to 69% at 5 years in TT2. To verify a survival benefit, we would have to wait until the median survival of TT2 (12 years) to analyze the overall survival benefit of Velcade. However, if overall survival is the primary end-point, the goal of speeding progress toward the cure is impossible. Additionally, to say "no overall survival benefit has been demonstrated" is not to say "there is no survival benefit." It simply means the time limitations preclude an absolute answer.
Because of the limitation of a prospective overall survival analysis, depth of response must be the primary end-point. I say this because the significance of the impact on overall survival of complete response in multiple myeloma is well-documented. A Blood article published in April of this year studied multiple myeloma patients diagnosed between 1989 and 1998. At 12 years after diagnosis, the survival numbers correlated to depth of response: CR 35%, nCR 22%, VGPR 16%, and PR 16%. In addition, recent studies have suggested sCR, a deeper response than CR, predicting an even better outcome.
The fact that myeloma patients are living so long makes overall survival as a primary endpoint of clinical trials impracticable. Consequently, we must use the best surrogates of long-term survival to analyze a new drug.
Novel agents not demonstrating overall survival benefit have to be attributed to the time limitations involved in the studies. For instance, UAMS TT2 demonstrated an overall survival of 12 years. In TT3, UAMS added Velcade to their trial. The TT3 trial is only a few years old. But, at 5 years, overall survival in TT3 was 82% as compared to 69% at 5 years in TT2. To verify a survival benefit, we would have to wait until the median survival of TT2 (12 years) to analyze the overall survival benefit of Velcade. However, if overall survival is the primary end-point, the goal of speeding progress toward the cure is impossible. Additionally, to say "no overall survival benefit has been demonstrated" is not to say "there is no survival benefit." It simply means the time limitations preclude an absolute answer.
Because of the limitation of a prospective overall survival analysis, depth of response must be the primary end-point. I say this because the significance of the impact on overall survival of complete response in multiple myeloma is well-documented. A Blood article published in April of this year studied multiple myeloma patients diagnosed between 1989 and 1998. At 12 years after diagnosis, the survival numbers correlated to depth of response: CR 35%, nCR 22%, VGPR 16%, and PR 16%. In addition, recent studies have suggested sCR, a deeper response than CR, predicting an even better outcome.
The fact that myeloma patients are living so long makes overall survival as a primary endpoint of clinical trials impracticable. Consequently, we must use the best surrogates of long-term survival to analyze a new drug.
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Perseverance - When were you/they diagnosed?: 2010
Re: Are CR and PFS suboptimal surrogate endpoints?
Thanks for the response.
It seems that the trials which are showing overall survival are the most toxic and high-dose intensive chemotherapy with tandem stem cell transplant, correct? That is what TT2 and TT3 in Arkansas are, no?
Clinical evidence undemonstrated means that we are back to weighing risk vs benefit when it comes to overall survival which was NOT a primary endpoint while treatment induction is based on progression-free survival and complete response.
I think Rajkumar lays out the significance of that issue exceptionally well in this article, where he discusses the 'myth of CR'.
Rajkumar, SV, et al, "Approach to the treatment of multiple myeloma: a clash of philosophies," Blood, 2011 (full text of article)
While I certainly understand the focus on overall survival as a benefit, the deeper question is at what cost and how much toxicity by the patient that diminishes quality of life when we know that progression-free survival is more of an interval between relapses based on the level of sensitivity of the tests. In other words, undetectable does not mean PF.
It is somewhat like believing that because we mowed off the top of the dandelions that our lawn is free of them, but the truth is that the roots are alive and will sprout above earth and become visible (detectable) once again. So, given that we know this, how toxic should the regimen be that destroys the above ground sprout? And that is not even considering the magnitude of the cost of therapy itself. Just the human toll.
I do appreciate your response regarding the time limitations involved with data for overall survival, and that was what I found so disturbing about the European regulatory report. Safety surveillance in the USA is wholly voluntarily and warnings are typically the tip of the iceberg as adverse event (AE) reports are not mandatory and require time to complete the paperwork. A warning is somewhat like the Titanic, in that only the tip of the iceberg is being seen as there are hundreds of thousands of AE's going unreported. So warnings based on increased frequency are highly significant.
It is good news that patients are living longer with multiple myeloma. I am just wondering if the additional toxicities have not resulted in overall survival if newly diagnosed patients should use less toxic regimens, monitor labs, use bisphosphonates and other therapeutic interventions to prevent end organ damage without the extreme toxicities? And opt for stem cell transplant when necessary vs. ongoing toxic regimens.
Again thank you for your response and, lastly, would you be able to provide the citation for the April Blood issue?
I appreciate the discussion.
It seems that the trials which are showing overall survival are the most toxic and high-dose intensive chemotherapy with tandem stem cell transplant, correct? That is what TT2 and TT3 in Arkansas are, no?
Clinical evidence undemonstrated means that we are back to weighing risk vs benefit when it comes to overall survival which was NOT a primary endpoint while treatment induction is based on progression-free survival and complete response.
I think Rajkumar lays out the significance of that issue exceptionally well in this article, where he discusses the 'myth of CR'.
Rajkumar, SV, et al, "Approach to the treatment of multiple myeloma: a clash of philosophies," Blood, 2011 (full text of article)
While I certainly understand the focus on overall survival as a benefit, the deeper question is at what cost and how much toxicity by the patient that diminishes quality of life when we know that progression-free survival is more of an interval between relapses based on the level of sensitivity of the tests. In other words, undetectable does not mean PF.
It is somewhat like believing that because we mowed off the top of the dandelions that our lawn is free of them, but the truth is that the roots are alive and will sprout above earth and become visible (detectable) once again. So, given that we know this, how toxic should the regimen be that destroys the above ground sprout? And that is not even considering the magnitude of the cost of therapy itself. Just the human toll.
I do appreciate your response regarding the time limitations involved with data for overall survival, and that was what I found so disturbing about the European regulatory report. Safety surveillance in the USA is wholly voluntarily and warnings are typically the tip of the iceberg as adverse event (AE) reports are not mandatory and require time to complete the paperwork. A warning is somewhat like the Titanic, in that only the tip of the iceberg is being seen as there are hundreds of thousands of AE's going unreported. So warnings based on increased frequency are highly significant.
It is good news that patients are living longer with multiple myeloma. I am just wondering if the additional toxicities have not resulted in overall survival if newly diagnosed patients should use less toxic regimens, monitor labs, use bisphosphonates and other therapeutic interventions to prevent end organ damage without the extreme toxicities? And opt for stem cell transplant when necessary vs. ongoing toxic regimens.
Again thank you for your response and, lastly, would you be able to provide the citation for the April Blood issue?
I appreciate the discussion.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Are CR and PFS suboptimal surrogate endpoints?
Suzierose,
Here is the link to the Blood article on the significance of depth of response:
Martinez-Lopez, J., et al, "Long-term prognostic significance of response in multiple myeloma after stem cell transplantation," Blood, 2011 (full text of article)
Abstract
For establishing the true effect of different response categories in patients with multiple myeloma treated with autologous stem cell transplantation, we evaluated, after a median follow-up of 153 months, 344 patients with multiple myeloma who received a transplant between 1989 and 1998. Overall survival (OS) at 12 years was 35% in complete response (CR) patients, 22% in near complete response (nCR), 16% in very good partial response (VGPR), and 16% in partial response (PR) groups. Significant differences in OS and progression-free survival were found between CR and nCR groups (P = .01 and P = .002, respectively), between CR and VGPR groups (P = .0001 and P = .003), or between CR and PR groups (P = .003 and P = < 10−5); no differences were observed between the nCR and VGPR groups (P = .2 and P = .9) or between these groups and the PR group (P = .1 and P = .8). A landmark study found a plateau phase in OS after 11 years; 35% patients in the CR group and 11% in the nCR + VGPR + PR group are alive at 17 years; 2 cases had relapsed in the nCR + VGPR + PR group. In conclusion, multiple myeloma achieving CR after autologous stem cell transplantation is a central prognostic factor. The relapse rate is low in patients with > 11 years of follow-up, possibly signifying a cure for patients in CR.
Here is the link to the Blood article on the significance of depth of response:
Martinez-Lopez, J., et al, "Long-term prognostic significance of response in multiple myeloma after stem cell transplantation," Blood, 2011 (full text of article)
Abstract
For establishing the true effect of different response categories in patients with multiple myeloma treated with autologous stem cell transplantation, we evaluated, after a median follow-up of 153 months, 344 patients with multiple myeloma who received a transplant between 1989 and 1998. Overall survival (OS) at 12 years was 35% in complete response (CR) patients, 22% in near complete response (nCR), 16% in very good partial response (VGPR), and 16% in partial response (PR) groups. Significant differences in OS and progression-free survival were found between CR and nCR groups (P = .01 and P = .002, respectively), between CR and VGPR groups (P = .0001 and P = .003), or between CR and PR groups (P = .003 and P = < 10−5); no differences were observed between the nCR and VGPR groups (P = .2 and P = .9) or between these groups and the PR group (P = .1 and P = .8). A landmark study found a plateau phase in OS after 11 years; 35% patients in the CR group and 11% in the nCR + VGPR + PR group are alive at 17 years; 2 cases had relapsed in the nCR + VGPR + PR group. In conclusion, multiple myeloma achieving CR after autologous stem cell transplantation is a central prognostic factor. The relapse rate is low in patients with > 11 years of follow-up, possibly signifying a cure for patients in CR.
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Perseverance - When were you/they diagnosed?: 2010
Re: Are CR and PFS suboptimal surrogate endpoints?
Suzierose, Perseverance,
I think there is a problem whenever you try to use averages with any single statistic (CR, PFS, etc) and try to draw a definitive conclusion from it. In myeloma, patients who achieve CR (or sCR) and maintain it for a longer time period have the best outcomes. Patients that achieve CR and lose it quickly tend to have poorer outcomes than those patients that remain stable at something less than CR . That can greatly influence the averages.
Here is a link in which Dr. Barlogie says that achieving CR in Total Therapy 1-3 does not correlate to a better OS in TT patients:
Carlson, RH, "Myeloma: Quest for CR May Be Misplaced," Oncology Times, Feb 25, 2008 (full text of article)
http://journals.lww.com/oncology-times/pages/articleviewer.aspx?year=2008&issue=02250&article=00013&type=fulltext
Here are 2 sentences from the article:
"In his presentation, The Pursuit of Cure in Multiple Myeloma, Dr. Barlogie compared the outcomes of the Total Therapy trials TT1, TT2, and TT3 to show that improvement in the CR rate does not translate into longer overall survival."
"In fact, patients with multiple myeloma who show no response to chemotherapy and stem cell transplant have longer overall survival than patients who achieve a complete response that is not sustained, he said in a presentation here at the Lymphoma & Myeloma meeting"
Mark
I think there is a problem whenever you try to use averages with any single statistic (CR, PFS, etc) and try to draw a definitive conclusion from it. In myeloma, patients who achieve CR (or sCR) and maintain it for a longer time period have the best outcomes. Patients that achieve CR and lose it quickly tend to have poorer outcomes than those patients that remain stable at something less than CR . That can greatly influence the averages.
Here is a link in which Dr. Barlogie says that achieving CR in Total Therapy 1-3 does not correlate to a better OS in TT patients:
Carlson, RH, "Myeloma: Quest for CR May Be Misplaced," Oncology Times, Feb 25, 2008 (full text of article)
http://journals.lww.com/oncology-times/pages/articleviewer.aspx?year=2008&issue=02250&article=00013&type=fulltext
Here are 2 sentences from the article:
"In his presentation, The Pursuit of Cure in Multiple Myeloma, Dr. Barlogie compared the outcomes of the Total Therapy trials TT1, TT2, and TT3 to show that improvement in the CR rate does not translate into longer overall survival."
"In fact, patients with multiple myeloma who show no response to chemotherapy and stem cell transplant have longer overall survival than patients who achieve a complete response that is not sustained, he said in a presentation here at the Lymphoma & Myeloma meeting"
Mark
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Mark
Re: Are CR and PFS suboptimal surrogate endpoints?
This is a great discussion.
I do want to note, though, that you have to be very careful about how you interpret statements about "depth and length of CR" being associated with longer survival.
In particular, should we be surprised at that? Does it really tell us anything about what sort of treatments will give people the longest survival?
It's almost like just another way of saying that "the people who respond best to a treatment live the longest".
Ah, yeah. But I think we already knew that.
The question, which I think isn't definitely answered yet, is whether throwing everything at a myeloma patient to "deepen and lengthen" the length of treatment actually extends survival once you adjust somehow for the reduced quality of life that usually is associated with "throwing the kitchen sink" at the patient.
As I said, this is a great discussion. It makes me appreciate the Beacon even more than I already did.
I do want to note, though, that you have to be very careful about how you interpret statements about "depth and length of CR" being associated with longer survival.
In particular, should we be surprised at that? Does it really tell us anything about what sort of treatments will give people the longest survival?
It's almost like just another way of saying that "the people who respond best to a treatment live the longest".
Ah, yeah. But I think we already knew that.
The question, which I think isn't definitely answered yet, is whether throwing everything at a myeloma patient to "deepen and lengthen" the length of treatment actually extends survival once you adjust somehow for the reduced quality of life that usually is associated with "throwing the kitchen sink" at the patient.
As I said, this is a great discussion. It makes me appreciate the Beacon even more than I already did.
Re: Are CR and PFS suboptimal surrogate endpoints?
TerryH,
I think an essential argument in favor of the kitchen sink approach, or at least a multi-drug cocktail including some novel agents, is the recognition that, often times, standard-risk myeloma can evolve to high-risk at relapse. The prolongation of TTP allows us time to develop better treatments for high-risk disease and add them to the treatment arsenal for when, and if, patients relapse. It should be noted that Dr. Barlogie has a significant number of patients with sustained CR at 4 years who have never relapsed well after a decade.
Further. the quality of life concern seems to be addressed when using PFS as an end-point. Indeed, a patient who is able to go longer intervals without symptoms and/or treatment is living a better quality of life.
The cure v. control debate is a legitimate one. It's also tremendously exciting that, in a disease that was uniformly fatal 30 years ago, we are talking about whether we should control it as a chronic disorder or attempt to eradicate it completely. I am deeply thankful to all the researchers, clinicians, doctors, patients, and caretakers who have battled this disease to bring us to this point.
I think an essential argument in favor of the kitchen sink approach, or at least a multi-drug cocktail including some novel agents, is the recognition that, often times, standard-risk myeloma can evolve to high-risk at relapse. The prolongation of TTP allows us time to develop better treatments for high-risk disease and add them to the treatment arsenal for when, and if, patients relapse. It should be noted that Dr. Barlogie has a significant number of patients with sustained CR at 4 years who have never relapsed well after a decade.
Further. the quality of life concern seems to be addressed when using PFS as an end-point. Indeed, a patient who is able to go longer intervals without symptoms and/or treatment is living a better quality of life.
The cure v. control debate is a legitimate one. It's also tremendously exciting that, in a disease that was uniformly fatal 30 years ago, we are talking about whether we should control it as a chronic disorder or attempt to eradicate it completely. I am deeply thankful to all the researchers, clinicians, doctors, patients, and caretakers who have battled this disease to bring us to this point.
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Perseverance - When were you/they diagnosed?: 2010
Re: Are CR and PFS suboptimal surrogate endpoints?
Hi Mark,
I think Dr Barlogie, is saying what I am.
To use the dandelion analogy again, which is that the length of time between how long the dandelion shows above ground again, does nothing to eradicate the root (which is the true issue) and thus there is no overall increase in survival. I agree that that length between seeing new responses is simply indicative of that particular dandelion being sensitive to the regimen, even though the root remains alive.
So we are in agreement about averages when it comes to looking at what is the average of dandelion regrowth for multiple lawns, we can't say, since the disease multiple myeloma is so heterogeneous and involves so many subsets of unique cellular components. I suppose that would be analogous to the type of dandelion that grows best in the numerous types of grasses available.
And also means while Bermuda and fescue might thrive and never reach CR a bluegrass would could likely have a CR on TT2 or TT3.
Thanks for the discussion.
I think Dr Barlogie, is saying what I am.
To use the dandelion analogy again, which is that the length of time between how long the dandelion shows above ground again, does nothing to eradicate the root (which is the true issue) and thus there is no overall increase in survival. I agree that that length between seeing new responses is simply indicative of that particular dandelion being sensitive to the regimen, even though the root remains alive.
So we are in agreement about averages when it comes to looking at what is the average of dandelion regrowth for multiple lawns, we can't say, since the disease multiple myeloma is so heterogeneous and involves so many subsets of unique cellular components. I suppose that would be analogous to the type of dandelion that grows best in the numerous types of grasses available.
And also means while Bermuda and fescue might thrive and never reach CR a bluegrass would could likely have a CR on TT2 or TT3.
Thanks for the discussion.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Are CR and PFS suboptimal surrogate endpoints?
Hi Terry,
I concur with you about the toxicities reducing quality of life while the benefit of the regimen does not increase overall survival being a major concern for patients, thus the kitchen sink conundrum.
I spent my day yesterday at Mayo getting a second opinion and this was a part of the discussion.
As we know different physicians have different philosophies about how to treat with Barlogie in Arkansas having the most radical approach. Mayo has a different therapeutic strategy.
One is that they agree quality of life is and should be a great consideration as there is no cure.
Second they treat based on risk stratification which means the 'kitichen sink' is reserved for high risk patients.
Third, they engage the patient actively in the decision-making process.
We talked about the philosophy at Arkansas, as well as the paradigm shift Matsui presented at IMW in Paris.
One thing that was affirmed during the discussion is that once you have a relapse, the cells that have returned are the most resistant. Sorta like how mosquitos are now highly resistant to DDT and their progeny are not impacted by it. As they were the survivors.
In multiple myeloma, only the resistant cells remain to proliferate, which is why they then use triple drug regimens in an attempt to trick the cells as they are being attacked on multiple fronts. Sorta like if it was war, attacking the flank, as well as the front line along with the must likely route of retreat.
And it is those resistant cells that lurk in stem cell transplant reinfusion.
Sooo, I suppose all this comes down to deciding when you want to eat your peas!
If you have good cytogenetics (I don't) early stage disease (I don't), then you have far more options. The doctor marveled at how unsymptomatic I am based on having some of the most aggressive cytogenetics they know of.
However, one thing I know is that statistics never tell about an individual, just like multiple myeloma, that individual while they belong to the population can always have variables that make them an outlier. Such that they do response, they do have longer PFS, and can be around for the newer agents.
The doctors even told the story of a patient they are presently seeing who is in their 40s, low risk based on CRAB and cytogenetics, yet not responding to any therapy.
So much for the stats!
We just have to give it up to God and know that he made each of us DNA unique and thus we can confound and prevail against all of man's science!!
Thanks for taking part in the discussion.
I concur with you about the toxicities reducing quality of life while the benefit of the regimen does not increase overall survival being a major concern for patients, thus the kitchen sink conundrum.
I spent my day yesterday at Mayo getting a second opinion and this was a part of the discussion.
As we know different physicians have different philosophies about how to treat with Barlogie in Arkansas having the most radical approach. Mayo has a different therapeutic strategy.
One is that they agree quality of life is and should be a great consideration as there is no cure.
Second they treat based on risk stratification which means the 'kitichen sink' is reserved for high risk patients.
Third, they engage the patient actively in the decision-making process.
We talked about the philosophy at Arkansas, as well as the paradigm shift Matsui presented at IMW in Paris.
One thing that was affirmed during the discussion is that once you have a relapse, the cells that have returned are the most resistant. Sorta like how mosquitos are now highly resistant to DDT and their progeny are not impacted by it. As they were the survivors.
In multiple myeloma, only the resistant cells remain to proliferate, which is why they then use triple drug regimens in an attempt to trick the cells as they are being attacked on multiple fronts. Sorta like if it was war, attacking the flank, as well as the front line along with the must likely route of retreat.
And it is those resistant cells that lurk in stem cell transplant reinfusion.
Sooo, I suppose all this comes down to deciding when you want to eat your peas!
If you have good cytogenetics (I don't) early stage disease (I don't), then you have far more options. The doctor marveled at how unsymptomatic I am based on having some of the most aggressive cytogenetics they know of.
However, one thing I know is that statistics never tell about an individual, just like multiple myeloma, that individual while they belong to the population can always have variables that make them an outlier. Such that they do response, they do have longer PFS, and can be around for the newer agents.
The doctors even told the story of a patient they are presently seeing who is in their 40s, low risk based on CRAB and cytogenetics, yet not responding to any therapy.
So much for the stats!
We just have to give it up to God and know that he made each of us DNA unique and thus we can confound and prevail against all of man's science!!
Thanks for taking part in the discussion.
-
suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Are CR and PFS suboptimal surrogate endpoints?
OH one last thing I learned with regard to Revlimid and secondary malignancies.
One is that it is that it appears Revlimid has enhanced toxicity with alkylators. Which is a major issue since basically every regimen for stem cell transplant uses an alkylating agent (melphalan or cyclophosphamide), so the combo sequential is unavoidable.
However, the risk of dying from multiple myeloma is higher than the risk of dying from the secondary malignancy.
So there you have it again ... eat your peas!!
Enjoy the day.
One is that it is that it appears Revlimid has enhanced toxicity with alkylators. Which is a major issue since basically every regimen for stem cell transplant uses an alkylating agent (melphalan or cyclophosphamide), so the combo sequential is unavoidable.
However, the risk of dying from multiple myeloma is higher than the risk of dying from the secondary malignancy.
So there you have it again ... eat your peas!!
Enjoy the day.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
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