IT TURNS OUT not all hi dose chemo/stem cell transplants were in vain-Stanfordresults

[Lani]

will try to look up how many of these patients were her2+

Survival of stage-4 breast cancer patients improves with stem cell treatment, study finds
BY KRISTA CONGER



A new long-term study of women with stage-4 breast cancer at the Stanford University School of Medicine is likely to revive a decade-old debate about high-dose chemotherapy as a treatment option. Specifically, researchers found that a greater proportion of patients who received the aggressive treatment 12 to 14 years ago, followed by a rescue with their own, specially purified blood stem cells that had been purged of cancer, survived compared with those who were rescued with unmanipulated blood grafts.

The study, although small, is the first to analyze the long-term outcomes of women who received their own (autologous) stem cells that had undergone this purification process. While high-dose chemotherapy followed by autologous blood stem cell transplantation was largely discarded at the end of the 1990s — interim analyses of several then-ongoing phase-3 clinical trials suggested it produced no better outcomes than other forms of treatment — women in this report received blood stem cells that had been prepared very differently.

“Most people in the oncology community feel that this issue is a done deal, that high-dose chemotherapy does not work for patients with breast cancer,” said associate professor of medicine, Judith Shizuru, MD, PhD. “But our study suggests that the high-dose therapy strategy can be modified to include the use of cancer-free purified blood stem cells to yield better overall outcomes in women with advanced breast cancer.”

Shizuru is the senior author of the research, which was published online last week in Biology of Blood and Marrow Transplantation. She and the study’s first author, Antonia Mueller, MD, along with hematologist Robert Negrin, MD, chief of Stanford’s Blood and Bone Marrow Transplant Program, followed the outcome of a number of women with metastatic breast cancer who enrolled in the mid- to late 1990s in a small phase 1-2 study to assess the effectiveness and feasibility of using highly purified stem cells from circulating blood, instead of an unmanipulated blood graft, for transplantation. The women in the study were treated at either Stanford Hospital & Clinics or the Barbara Ann Karmanos Cancer Institute in Detroit.


At present, women with metastatic breast cancer have few options. “For over 10 years, women with metastatic breast cancer have not been offered high-dose chemotherapy treatments,” said Shizuru, who is also a member of the Stanford Cancer Institute. “In contrast, other cancer patient groups benefit from aggressive approaches that include high-dose chemotherapy with autologous blood stem cell transplantation as a treatment platform in combination with novel agents. Such strategies have continued to improve their outcomes. But in the meantime most women with metastatic breast cancer are primarily offered palliative treatment.”

High-dose chemotherapy is considered to be an aggressive treatment because, in addition to killing cancer cells, it also destroys a patient’s blood forming system. Therefore, such patients need to be rescued with stem cells that can restore blood production, which includes red blood cells, platelets and infection-fighting white blood cells. To increase the proportion of blood-forming stem cells in the bloodstream patients routinely receive drugs that “mobilize” the stem cells out of the bone marrow into the blood. Unfortunately, studies by many groups have shown that cancer cells often stowaway in the blood as well and may cause an eventual relapse.

As a result, in the mid-1990s Stanford researchers headed by professors of medicine Karl Blume, MD, Robert Negrin, MD, and professor of pathology Irving Weissman, MD, wondered if there was a way to overcome this problem. They opted to use antibodies that recognized newly identified markers on the surface of the blood stem cells to purify the stem cells away from regular blood and any roving cancer cells. They then used this purified population of stem cells in 22 women with metastatic breast cancer who enrolled in the trial from December 1996 to February 1998. Then they waited as the years passed.

Last year, Mueller and the research team began to compare the progression-free and overall survival of their experimental group to those of a group of 74 women who received identical chemotherapy treatments between February 1995 and June 1999 but who received unmanipulated, mobilized peripheral blood.

Although the overall numbers are small, the difference in survival 12 to 14 years after therapy is stark: Five of the 22 women (23 percent) who received the purified stem cells are still alive, four of whom have no sign of disease. Their median overall survival was 60 months. In contrast, just seven of the 74 women (9 percent) who received the untreated cells are living, five of whom have no sign of disease. Their median overall survival was 28 months.

“Even with this small sample size, this paper demonstrates much-better overall and progression-free survival in those patients who received cancer-free stem cells,” said Weissman, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research at the medical school and co-author of the paper. “It is important to use these findings as a basis for future trials not only for breast cancer, but also other cancers in which autologous transplants are used to enable high-dose chemotherapy.”

“Hopefully the message comes across clearly in this paper,” said Mueller. “We need to revisit this issue and give these patients the option to pursue aggressive treatment.” The Stanford Blood and Marrow Transplant group are currently planning a larger clinical trial of the treatment, although the details are still being finalized.

Other Stanford researchers involved in the study include hematology and oncology fellow Holbrook Kohrt, MD; Steven Cha, MD; associate professors of medicine Ginna Laport, MD, and Laura Johnston, MD; and the former director of medical informatics at Stanford Hospital & Clinics Alice Guardino, MD.

The study received no outside funding.

The antibodies used to purify the stem cells for this study were initially provided by Systemix, which has since been purchased by Novartis. Weissman was a co-founder and director of Systemix. He has no financial interest in Novartis.

[Rich66]

Heh..and Wicha is not too impressed: http://www.medscape.com/viewarticle/747179

[Jackie07]

From Medscape Medical News > Oncology

Controversial Therapy May Benefit Advanced Breast Cancer

Fran Lowry

July 28, 2011 — Better-than-expected survival in patients with stage IV breast cancer who were treated with high-dose chemotherapy (HDCT) and purified blood stem cells more than a decade ago is prompting a new look at the controversial treatment.
An update on the long-term outcomes of women with advanced breast cancer who were treated aggressively with HDCT followed by rescue with their own blood stem cells, which had been purged of cancer, was published online July 18 in Biology of Blood and Marrow Transplantation.
"This is a controversial treatment," senior author Judith A. Shizuru, MD, PhD, from Stanford University in California, told Medscape Medical News.

Dr. Judith Shizuru

[The original article has her picutre inserted here. You can get a free log-in from Medscape to view it - use Rich's link http://www.medscape.com/viewarticle/747179 in his posting .]

"A number of studies in the 1990s suggested that this treatment would be effective for women with advanced breast cancer, but then other randomized trials showed no particular benefit," she said.
There has also been controversy. Werner Bezwoda, MD, from the University of Witwatersrand, Johannesburg, South Africa, reported positive results with HDCT and autologous stem cell rescue at the 1999 annual meeting of the American Society Clinical Oncology, but when it emerged that he had falsified his results, the ensuing uproar helped put the kibosh on further studies of this aggressive and expensive treatment.
"Most people in the oncology community now feel that this is a done deal and that this aggressive treatment does not work," Dr. Shizuru said. "I think we should be taking another look."
In their report, Dr. Shizuru and lead author Antonia M.S. Muller, MD, also from Stanford, looked at the long-term outcome of a pilot study of 22 patients with metastatic breast cancer enrolled from December 1996 to February 1998.
The patients were treated at Stanford or at the Barbara Ann Karmanos Cancer Institute in Detroit, Michigan.
The small phase 1/2 study was undertaken to test the effectiveness and feasibility of using highly purified stem cells from circulating blood, instead of an unmanipulated blood graft, for transplantation.
"We knew that you could have micrometastases in the bone marrow, so it was likely that you could mobilize cancer cells into the blood stream when you gave a blood stem cell transplant," Dr. Shizuru explained. "We purified the stem cells to make sure that there was no cancer contamination."
They found that more than 12 years after the end of the study, 5 of the 22 patients had survived. In addition, 4 of these patients were free from recurrence and had normal hematopoietic function.
The study also showed that the median progressive-free survival of these patients with advanced breast cancer was 16 months, and that median overall survival was 60 months.
In contrast, a retrospective comparison of 74 patients transplanted between 1995 and 1999 with the identical high-dose chemotherapy regimen, but who received unmanipulated blood stem cells, showed that only 7 (9%) of the patients are alive; of these, 7% are without disease.
In this historic cohort, median progressive-free survival was 10 months and median overall survival was 28 months.
"This is quite a difference, even though this is a small sample," Dr. Shizuru said.
"We weren't really planning to open up the whole field again, but I think — from looking at how these surviving women have done — ...[it's] good to know that we can give them back a pure blood stem cell product that's been fairly well processed and they can still make blood cells normally after so many years," Dr. Shizuru noted.
She cautioned that the pilot study is small. "Usually, you would want to have many more patients before you jump to any major conclusions, but we feel that, with this second look, the findings are very striking to us, and we want to rethink and reexamine this treatment," she said. "We are definitely going to try to study this further."
Logistics of Doing So Will Be Formidable
Max Wicha, MD, professor of medicine at the University of Michigan Comprehensive Cancer Center in Ann Arbor, is skeptical that further studies of this therapy will end up being done.
"Is it actually worth doing a large randomized study, which is what it would take to prove one way or another whether this aggressive treatment really works? Such a trial is very expensive and involves a lot of potential toxicity," he said when approached for comment.
"I don't think you could recruit the women, given the state of this field and how most people are so against it. I doubt that you could get women to agree to become part of such a study because there has been so much publicity about how it really doesn't work," he said.
In Dr. Wicha's opinion, the most interesting aspect of this small study is the revelation that using purified blood stem cells does not interfere with a patient's ability to reconstitute normal blood elements in the long term.
However, this does not prove that using stem cells improves survival, he said.
"My belief is quite strong that the reason this treatment regimen doesn't work and that patients relapse is because the actual cancer stem cells are resistant, even to high doses of chemotherapy, so you never really get rid of them once you have metastatic disease. The cancer just comes back. What we really need are cancer stem cell targeted therapies, not just more chemotherapy and bone marrow transplant," he said.
Dr. Shizura and Dr. Wicha have reported no relevant financial relationships.
Biol Blood Marrow Transplant. Published online July 18, 2011. Abstract

[Lani]

. It may turn out that it was something else about this treatment that made this small group of patients do better than others receiving similar but different treatment.

I personally am a big fan of Dr Wicha and his work-- I think there are more mysteries to be discovered in the bone marrow niche and wish researchers and oncologists were testing bone marrows more often

When asked why they don't oncologists usually say patients don't like it--but many patients say that the test is really rather easy to go through and I even had an ex-neighbor, a lady in her late 70s early 80s who volunteered for a bone marrow (she didn't tell me the amount she was paid) and said she was just slightly sore for a day or two.

Some oncologists tell me their colleagues are the ones who just don't want to do it (since oncologists trained recently are no longer hematologists as well, they weren't necessarily trained doing a lot of bone marrow tests and may not be so good at doing them, they say.) If that indeed is the case, why don't they refer the patients for the testing, as they refer patients to radiologists for fine needle aspirations, core biopsies, or to orthopaedic surgeons for bone biopsies?

My comment:

patients don't necessarily like chemotherapy but that doesn't keep oncologists from giving it and if, as Dr. Wicha believes, disseminated tumor cells in the bone marrow are cancer stem cells and lay dormant avoiding chemo and radiation, it will only be by testing the marrow, that one determines whether the chemo or other agent has been effective. If that is true, I doubt a couple days of being a bit sore will be deemed "too terrible" to determine if treatment received has done its job or if different treatment is still needed/and to tell what treatments are the most effective in which patients.

Until more patients get their bone marrow tested we will not know.

CTC testing sounds nicer, but so far CTCs have been inferior to bone marrow DTCs in predicting prognosis and we have yet to determine the best technology for isolating and testing ctcs.

Off my soapbox for now.

[Jackie07]

Thanks, Lani. Please get on the soapbox anytime you feel like it. We love to listen to you.

According to Kim in CA's signature,

http://her2support.org/vbulletin/sho...sisters&page=4

she has had High Dose Chemo with Stem cell rescue when she's first diagnosed in 1997. She's been NED for almost 6 years.

[Ellie F]

Lani- firstly it's often only when ppl continue to get on their soapbox and shout loud that real change occurs so keep on going!

Secondly I am really interested in this bone marrow issue but not sure what sense to make of it. Is it thought that if you test bone marrow aspirate and it is clear of cancer cells then the treatment (whatever that may have been) has eradicated them so the chance of recurrence is low?
If this is the case does that mean that any metastatic cells that have 'lodged' in other areas of the body don't get the stimulus to grow?

Thanks Ellie

[Rich66]

"oncologists trained recently are no longer hematologists as well"

Hmmm. Is that a good thing?


Also..perhaps there was a selection bias in terms of when the experimental therapy was considered. unclear to me whether that was randomized.

[Jackie07]

According to The Medical Specialties Matching Program (MSMP) listed on the National Resident Matching Program website, both 'Hematology' and 'Medical Oncology' requires one year less training (2 years instead of 3 years) than Hematology/Oncology. Though each school can have its own standard (see 'ps.')
My oncologist even spent one extra year getting a degree in pharmacology:

http://www.nrmp.org/fellow/match_name/msmp/about.html

ps.

[From Standford University website: http://oncology.stanford.edu/fellowship/]

"Requirements:

The three-year hematology or oncology program is an intensive training period in clinical care and research. Combined training in hematology/oncology requires 18 months of clinical training and additional time for intensive research training. Applicants to the program will be expected to have completed an internal medicine residency program. Previous investigative experience is helpful. You must have a California medical license prior to the starting date of your fellowship (July 1).
Due to NIH funding restrictions, ALL hematology and oncology applicants must be either United States citizens or have permanent resident status in the United States by the beginning date of their fellowship training. There are no exceptions.
All fellows must be funded through the Divisions of Hematology and Oncology. The School of Medicine does not allow self-funded fellows."

[hutchibk]

From a trusted source in my world (specialist in oncology & hematology): "I think it's 'hypothesis generating' and is a treatment that should only be done as part of a clinical trial."