OCEANS study: Bevacizumab (Avastin) Halves Progression Risk in Recurrent Ovarian Cancer

lindaprocopio
lindaprocopio Member Posts: 1,980
Bevacizumab Halves Progression Risk in Recurrent Ovarian Cancer
Elsevier Global Medical News. 2011 Jun 5, S London


CHICAGO (EGMN) - Adding the antiangiogenic agent bevacizumab to platinum-based chemotherapy halves the risk of progression in women with recurrent ovarian, peritoneal, or fallopian tube cancer, new data show.

In OCEANS, a randomized phase III trial, patients given bevacizumab (Avastin) during and after chemotherapy were 52% less likely to have progression of their disease than were patients given placebo.

The absolute difference in median progression-free survival was 4 months, according to results reported at the annual meeting of the American Society of Clinical Oncology. Interim overall survival results also favored the drug.

"The OCEANS study is a positive study," lead investigator Dr. Carol Aghajanian said in a press briefing. The combination therapy "provides a clinically meaningful benefit in recurrent ovarian cancer."

"This regimen should be considered a new option for women with recurrent platinum-sensitive ovarian cancer, recommended Dr. Aghajanian, chief of the gynecologic medical oncology service at Memorial Sloan-Kettering Cancer Center in New York.

Patients with advanced ovarian cancer often receive multiple lines of chemotherapy, noted Dr. Andrew Seidman, who moderated the press briefing. "There are many chapters in the story, so to speak, and I think the ability to prolong each and every chapter in this disease will, in my estimation, make the story longer - that is, ultimately improve survival. These trial results are certainly an important step in this direction."

Maintenance therapy with a biologic agent also allows patients to avoid the harsh adverse effects of chemotherapy, added Dr. Seidman, an attending physician for breast cancer medicine at Memorial Sloan-Kettering and professor of medicine at Weill Cornell Medical College, New York.

"With the ... prolongation in the time to progression, patients can live with more time to lead full and active lives, in the absence of chemotherapy," he said. "It's also comforting to see that there were no new safety signals in this trial, and in particular, [no] bowel perforations."

The 484 women enrolled in the trial had platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; had not received any chemotherapy for their recurrence; and had measurable disease.

They were assigned in equal numbers to receive 6-10 cycles of standard chemotherapy (carboplatin and gemcitabine) plus either bevacizumab, a monoclonal antibody to vascular endothelial growth factor given at a dose of 15 mg/kg every 3 weeks, or a placebo concurrently, followed by single-agent bevacizumab or placebo, respectively.

The bevacizumab dose was based on that showing activity in single-arm phase II trials of the drug leading up to the OCEANS trial, according to Dr. Aghajanian. This dose has not been directly compared with lower doses in ovarian cancer.

Treatment continued until the time of progression, the trial's primary end point, assessed using RECIST (Response Evaluation Criteria in Solid Tumors).

Trial results showed that the median number of cycles of chemotherapy received was six in each group. The median number of cycles of bevacizumab and placebo was 12 and 10, respectively.

After a median follow-up of 24 months, patients in the bevacizumab group had a slightly more than one-half reduction in the risk of progression relative to their counterparts in the placebo group as assessed by the investigators (hazard ratio, 0.48; P less than .0001).

Median progression-free survival was 12.4 months with bevacizumab, compared with 8.4 months with placebo. "The curves separate at 2 months and remain separated throughout," Dr. Aghajanian noted. The findings were similar when progression was instead ascertained by an independent review committee.

In addition, bevacizumab was associated with better progression-free survival across subgroups of patients stratified by factors such as the platinum-free interval before recurrence, age, and receipt of cytoreductive surgery for recurrence.

Results also showed that patients in the bevacizumab group had a comparatively higher objective response rate (78.5% vs. 57.4%, P less than .0001) and longer duration of response (10.4 vs. 7.4 months, P less than .0001).

Overall survival results are not yet mature, she cautioned. But an interim analysis also showed a trend favoring bevacizumab, with median overall survival of 35.5 months with the drug, compared with 29.9 months with placebo (hazard ratio, 0.75; P = .094).

"The safety data were reassuring and consistent with the known bevacizumab side effect profile," reported Dr. Aghajanian.

Specifically, patients in the bevacizumab group were comparatively more likely to experience grade 3 or higher hypertension (17% vs. less than 1%) and proteinuria (9% vs. 1%). And 1% of patients in that group experienced reversible posterior leukoencephalopathy syndrome, but it resolved in all cases after drug discontinuation.

Of particular note, none of the bevacizumab-treated patients experienced gastrointestinal perforation during treatment, she pointed out. And none experienced previously undescribed adverse effects.

Dr. Aghajanian reported being a consultant to and receiving research funding from Genentech, manufacturer of bevacizumab, and the trial was sponsored by Genentech. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

Comments

  • tjpt16
    tjpt16 Member Posts: 27
    Avastin Study
    Thanks so much for posting this article, Linda.
  • eward
    eward Member Posts: 210
    Thanks
    My mom is starting gemzar, cisplatin, and avastin next week.

    How are you feeling?
    Eileen
  • LaundryQueen
    LaundryQueen Member Posts: 676
    eward said:

    Thanks
    My mom is starting gemzar, cisplatin, and avastin next week.

    How are you feeling?
    Eileen

    It's hard to get real
    It's hard to get real excited about this research when the benefit of using Avastin is to provide only 4 months longer in remission. Newer anti-angiogenic agents are being sought after. The low-dose weekly Taxol is thought to also provide an anti-angiogenic benefit.

    Thanks for posting.

    LQ
  • antcat
    antcat Member Posts: 270

    It's hard to get real
    It's hard to get real excited about this research when the benefit of using Avastin is to provide only 4 months longer in remission. Newer anti-angiogenic agents are being sought after. The low-dose weekly Taxol is thought to also provide an anti-angiogenic benefit.

    Thanks for posting.

    LQ

    I agree
    I agree with LQ. It is very hard to get excited with the Avastin research. I've read also that it provides 4 months longer in remission and honestly I was disappointed to read that. 4 months is not a long time, some of us, get that with regular chemotherapy. I had been on Avastin for 6 months and I don't know, maybe it was the chemo combination I had with the other drug, but it didn't do anything for me, so we stopped it. Right now I'm on low dose Taxotere, which is similar to Taxol.
  • lindaprocopio
    lindaprocopio Member Posts: 1,980
    antcat said:

    I agree
    I agree with LQ. It is very hard to get excited with the Avastin research. I've read also that it provides 4 months longer in remission and honestly I was disappointed to read that. 4 months is not a long time, some of us, get that with regular chemotherapy. I had been on Avastin for 6 months and I don't know, maybe it was the chemo combination I had with the other drug, but it didn't do anything for me, so we stopped it. Right now I'm on low dose Taxotere, which is similar to Taxol.

    It's a matter of perspective, I guess.
    My longest remission was 5 1/2 months; and my only other remission was 4 1/2 months. So an extension of 4 more months of remission sounds SOOOOO promising to me. It's a matter of perspective, I suppose.

    That being said, I had disease progression after 4 months on Avastin/Cytoxan, so for the unlucky chemo refractory (chemo resistant) like me, Avastin may not be the 'magic' bullet that buys any extra time. I felt it was worth a shot since it works so differently than the other chemo drugs I've tried that allowed diseased progression (i.e., dense dose taxol, doxil, & carboplatin).

    I am convinced that the secret to long survival is LONG remissions that allow you to re-visit first line chemo drugs; and GOOD response to treatment that shoots you back into another long remission. Unfortunately not the path my cancer took, but if you can achieve those long remissions, you can live a decent life span even with OVC.
  • Cafewoman53
    Cafewoman53 Member Posts: 735 Member

    It's a matter of perspective, I guess.
    My longest remission was 5 1/2 months; and my only other remission was 4 1/2 months. So an extension of 4 more months of remission sounds SOOOOO promising to me. It's a matter of perspective, I suppose.

    That being said, I had disease progression after 4 months on Avastin/Cytoxan, so for the unlucky chemo refractory (chemo resistant) like me, Avastin may not be the 'magic' bullet that buys any extra time. I felt it was worth a shot since it works so differently than the other chemo drugs I've tried that allowed diseased progression (i.e., dense dose taxol, doxil, & carboplatin).

    I am convinced that the secret to long survival is LONG remissions that allow you to re-visit first line chemo drugs; and GOOD response to treatment that shoots you back into another long remission. Unfortunately not the path my cancer took, but if you can achieve those long remissions, you can live a decent life span even with OVC.

    It is exciting
    Even if Avastin is not the cure all at least it is making a difference for some it might be a big difference because isn't four months the average ? Anyway it may be a starting point for the researchers, They have to keep on trying we need better outcomes for us and our sisters who will follow us.
    I think you are right Linda on long remissions keeping us strong enough to fight this cancer and live with it.
  • carolenk
    carolenk Member Posts: 907 Member

    It is exciting
    Even if Avastin is not the cure all at least it is making a difference for some it might be a big difference because isn't four months the average ? Anyway it may be a starting point for the researchers, They have to keep on trying we need better outcomes for us and our sisters who will follow us.
    I think you are right Linda on long remissions keeping us strong enough to fight this cancer and live with it.

    Here's to long remissions
    I can see where Linda is coming from...I think the long remissions are needed to keep us alive long enough until something offering a cure can be found.

    I read about the EC145 (folate + low-dose Doxil) therapy that is currently in clinical trials and think it sounds promising. There is SO MUCH folate added to our food supply via white flour, it makes sense to stay off the bread just to keep folate levels low.

    I don't know how new this information is on folate but I wish someone had clued me in about it as I was eating lots of green leafy veggies (basically a healthy diet) pre-diagnosis and I think the cancer was loving all the folate that I was feeding it!

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707764/

    Carolen
  • carolenk
    carolenk Member Posts: 907 Member
    carolenk said:

    Here's to long remissions
    I can see where Linda is coming from...I think the long remissions are needed to keep us alive long enough until something offering a cure can be found.

    I read about the EC145 (folate + low-dose Doxil) therapy that is currently in clinical trials and think it sounds promising. There is SO MUCH folate added to our food supply via white flour, it makes sense to stay off the bread just to keep folate levels low.

    I don't know how new this information is on folate but I wish someone had clued me in about it as I was eating lots of green leafy veggies (basically a healthy diet) pre-diagnosis and I think the cancer was loving all the folate that I was feeding it!

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707764/

    Carolen

    Abstract on folate receptor research
    There's more info when you go to the link above but here's the abstract on the research:

    Folate receptor alpha as a tumor target in epithelial ovarian cancer

    Kimberly R. Kalli,a* Ann L. Oberg,b Gary L. Keeney,c Teresa J.H. Christianson,b Philip S. Low,d Keith L. Knutson,e and Lynn C. Hartmanna

    a Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA
    b Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
    c Department of Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
    d Purdue University and Purdue Cancer Center, Department of Chemistry, West Lafayette, IN, USA
    e Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA
    * Corresponding author. Women's Cancer Program, Charlton 6-118; Mayo Clinic College of Medicine; 200 First Street SW, Rochester, MN 55905, USA. Fax: +1 507 266 2478

    Folate receptor α (FRα) is a folate-binding protein overexpressed on ovarian and several other epithelial malignancies that can be used as a target for imaging and therapeutic strategies. The goal of this study is to improve historical data that lack specific information about FRα expression in rare histological subtypes, primary disease versus metastatic foci, and recurrent disease.

    Methods
    FRα expression was analyzed by immunohistochemistry on 186 primary and 27 recurrent ovarian tumors, including 24 pairs of samples obtained from the same individuals at diagnosis and at secondary debulking surgery. For 20 of the 186 primaries, simultaneous metastatic foci were also analyzed. FRα staining was analyzed in light of disease morphology, stage, grade, debulking status, and time from diagnosis to recurrence and death.

    Results
    FRα expression was apparent in 134 of 186 (72%) primary and 22 of 27 (81.5%) recurrent ovarian tumors. In 21 of 24 (87.5%) matched specimens, recurrent tumors reflected the FRα status detected at diagnosis. Metastatic foci were similar to primary tumors in FRα staining. FRα status was not associated with time to recurrence or overall survival in either univariate or multivariable analyses.

    Conclusion
    FRα expression occurs frequently, especially in the common high-grade, high-stage serous tumors that are most likely to recur. New findings from this study show that FRα expression is maintained on metastatic foci and recurrent tumors, suggesting that novel folate-targeted therapies may hold promise for the majority of women with either newly diagnosed or recurrent ovarian cancer.
  • wingsoftheheart
    wingsoftheheart Member Posts: 1
    best maintenance of remission after ovarian cancer recurrence?
    Hello fellow survivors,
    This is my first post. I am recently cancer-free after a first recurrence of stage three ovarian cancer. I was in remission for three years, after surgery and six cycles of Taxol/Carbo. After the recurrence diagnosis in 2010, I had "aborted" surgery, in which my tumor was left in when the surgeon opened me up. Then I went to Germany for heated intraperitoneal chemo, but the doctors found that my vaginal bleeding from a fistula was too much to do that chemo. However, I had some other therapies, and took low-dose chemo pills, before returning home and starting regular chemo. I have read quite a bit about low-dose in pills and IV forms, and it seems that though the drugs vary, low-dose is on the same principle as Avastin, which I have also been researching. I like the sound and feel of anti-angiogenic drugs, the minimum effective dose, versus the maximum tolerated dose. I am very sensitive to everything, and don't need or do well with the overkill of standard chemo.
    My doctor suggests six months of full-dose Taxol as maintenance. I don't like the thought of more of that awful nausea and weakness, plus the problem of neuropathy, cited by the studies as cause for many dropping out. And all of those problems often increase with added doses. So I'm thinking about combining Avastin with taxene and/or some other drug at low-dose, as maintenance, maybe for 18--24 months, with "drug holiday" breaks from the taxene but not the Avastin. Maybe dropping back to just Avastin for the second year. I have not passed this by my oncologist yet, but will in a few weeks. Your report on Avastin is encouraging because of course the bleeding problems mentioned are scary.
    Please let me now anything any of you know about anyone combining Avastin with low-dose taxene or other common chemo agent, as maintenance, especially for ovarian.
    Thank you all so much! I want to live to be at least 75, and I'm 56 now. I've seen the statistics--I am determined anyway.

    Blessings,
    "wingedheart"
    Sarasota, FL
  • Hissy_Fitz
    Hissy_Fitz Member Posts: 1,834

    best maintenance of remission after ovarian cancer recurrence?
    Hello fellow survivors,
    This is my first post. I am recently cancer-free after a first recurrence of stage three ovarian cancer. I was in remission for three years, after surgery and six cycles of Taxol/Carbo. After the recurrence diagnosis in 2010, I had "aborted" surgery, in which my tumor was left in when the surgeon opened me up. Then I went to Germany for heated intraperitoneal chemo, but the doctors found that my vaginal bleeding from a fistula was too much to do that chemo. However, I had some other therapies, and took low-dose chemo pills, before returning home and starting regular chemo. I have read quite a bit about low-dose in pills and IV forms, and it seems that though the drugs vary, low-dose is on the same principle as Avastin, which I have also been researching. I like the sound and feel of anti-angiogenic drugs, the minimum effective dose, versus the maximum tolerated dose. I am very sensitive to everything, and don't need or do well with the overkill of standard chemo.
    My doctor suggests six months of full-dose Taxol as maintenance. I don't like the thought of more of that awful nausea and weakness, plus the problem of neuropathy, cited by the studies as cause for many dropping out. And all of those problems often increase with added doses. So I'm thinking about combining Avastin with taxene and/or some other drug at low-dose, as maintenance, maybe for 18--24 months, with "drug holiday" breaks from the taxene but not the Avastin. Maybe dropping back to just Avastin for the second year. I have not passed this by my oncologist yet, but will in a few weeks. Your report on Avastin is encouraging because of course the bleeding problems mentioned are scary.
    Please let me now anything any of you know about anyone combining Avastin with low-dose taxene or other common chemo agent, as maintenance, especially for ovarian.
    Thank you all so much! I want to live to be at least 75, and I'm 56 now. I've seen the statistics--I am determined anyway.

    Blessings,
    "wingedheart"
    Sarasota, FL

    Dear Wings....I did a year
    Dear Wings....I did a year of Taxol maintenance (monthly infusions) and have been NED since early 2010. I tolerated it very well, and in fact, I begged my doctor to let me do another year of it, or even six months. He wouldn't go for that idea, but I really credit the Taxol with a year + of good health. I would do it again in a heartbeat.

    I agree with Linda....the longer the remissions, the better chance you have of long-term survival. There was a woman in my real life support group who survived 13 years with Stage IIIc, even though her longest remission was 12 months and subsequent ones only 6-9 months. She reused many of the same drugs - first line drugs - over and over.

    Not everyone is willing to go the same route I did, and that's perfectly understandable. I would be remiss, though, if I didn't share my story.

    Carlene
  • antcat
    antcat Member Posts: 270

    best maintenance of remission after ovarian cancer recurrence?
    Hello fellow survivors,
    This is my first post. I am recently cancer-free after a first recurrence of stage three ovarian cancer. I was in remission for three years, after surgery and six cycles of Taxol/Carbo. After the recurrence diagnosis in 2010, I had "aborted" surgery, in which my tumor was left in when the surgeon opened me up. Then I went to Germany for heated intraperitoneal chemo, but the doctors found that my vaginal bleeding from a fistula was too much to do that chemo. However, I had some other therapies, and took low-dose chemo pills, before returning home and starting regular chemo. I have read quite a bit about low-dose in pills and IV forms, and it seems that though the drugs vary, low-dose is on the same principle as Avastin, which I have also been researching. I like the sound and feel of anti-angiogenic drugs, the minimum effective dose, versus the maximum tolerated dose. I am very sensitive to everything, and don't need or do well with the overkill of standard chemo.
    My doctor suggests six months of full-dose Taxol as maintenance. I don't like the thought of more of that awful nausea and weakness, plus the problem of neuropathy, cited by the studies as cause for many dropping out. And all of those problems often increase with added doses. So I'm thinking about combining Avastin with taxene and/or some other drug at low-dose, as maintenance, maybe for 18--24 months, with "drug holiday" breaks from the taxene but not the Avastin. Maybe dropping back to just Avastin for the second year. I have not passed this by my oncologist yet, but will in a few weeks. Your report on Avastin is encouraging because of course the bleeding problems mentioned are scary.
    Please let me now anything any of you know about anyone combining Avastin with low-dose taxene or other common chemo agent, as maintenance, especially for ovarian.
    Thank you all so much! I want to live to be at least 75, and I'm 56 now. I've seen the statistics--I am determined anyway.

    Blessings,
    "wingedheart"
    Sarasota, FL

    Dear Wings
    I am currently on a low dose of Taxotere, which is the similar to Taxol (as my oncologist informed me). I have this treatment once a week for 3 weeks in a row, then have a week of rest. The reason he suggested the Taxotere was that people didn't get the bad side effects like neuropathy with Taxotere. This is the 3rd time I'm on Taxotere (had it the first 2 times with my original diagnosis) and I never had any real bad side effects. The only thing I am now is a little tired because I've been on so many different chemos since last year. I also tried Avastin, for 6 months along with other chemo drugs. It didn't help me, the tumors still progressed a little. And, i was very concerned about the bleeding that could occur with Avastin. Anyway, I wish you the best.
  • Tethys41
    Tethys41 Member Posts: 1,376 Member
    antcat said:

    Dear Wings
    I am currently on a low dose of Taxotere, which is the similar to Taxol (as my oncologist informed me). I have this treatment once a week for 3 weeks in a row, then have a week of rest. The reason he suggested the Taxotere was that people didn't get the bad side effects like neuropathy with Taxotere. This is the 3rd time I'm on Taxotere (had it the first 2 times with my original diagnosis) and I never had any real bad side effects. The only thing I am now is a little tired because I've been on so many different chemos since last year. I also tried Avastin, for 6 months along with other chemo drugs. It didn't help me, the tumors still progressed a little. And, i was very concerned about the bleeding that could occur with Avastin. Anyway, I wish you the best.

    Long Term Survival
    I revisited a book last night that I started reading near the beginning of my treatment, Cancer: 50 Essential Things To Do. When the author was diagnosed with stage IV lung cancer, and given 30 days to live, he sought out people who had received similar diagnoses, but who had become long term survivors. What I found interesting is that many of the commonalities among these patients, I also discovered during my journey. It isn't for everyone, because the conclusion of the book is that the approach needs to be wholistic and empowering, and that Western medicine is not the complete answer.
  • carolenk
    carolenk Member Posts: 907 Member
    Tethys41 said:

    Long Term Survival
    I revisited a book last night that I started reading near the beginning of my treatment, Cancer: 50 Essential Things To Do. When the author was diagnosed with stage IV lung cancer, and given 30 days to live, he sought out people who had received similar diagnoses, but who had become long term survivors. What I found interesting is that many of the commonalities among these patients, I also discovered during my journey. It isn't for everyone, because the conclusion of the book is that the approach needs to be wholistic and empowering, and that Western medicine is not the complete answer.

    Chemo maintenance
    Unfortunately, a "chemo maintenance" drug for ovarian cancer (OVCA) has not come forward yet.

    From what I can figure out, the best approach is to hit cancer in as many different ways as you can. With Western medicine (drugs, surgery, radiation), chemo therapy usually involves more than a single agent.

    I noticed that the new clinical trials for OVCA are using the standard of care chemo drugs (a platinum-based drug plus a taxol drug) along with a "non-chemo agent" (such as Avastin or a PARP inhibitor). Some research shows that Avastin only blocks one pathway for angiogenesis (growth of new blood vessels to feed cancer) and there can be a rebound effect where other pathways still activate the growth of new blood vessels even when that one pathway for angiogenesis is blocked by Avastin. That's one of the problems with Avastin.

    The other problem with Avastin is the side effects of hyptertension, possible stroke and blood clots. The "bleeding" problems referred to in the original posting were only found in those who had cancer implants on their intestines. When the cancer necrosed, holes showed up on the intestines and some people had intestinal perforations with bleeding.

    Research on the PARP-inhibitor is detailed extensively somewhere on this discussion board so search for it to learn more about that. PARP-inhibitors seem to only work for the BRACA (+) OVCAs and I don't know much about that.

    Taking a low-dose taxol-type chemo is suspected to have the same anti-angiogenesis effect as Avastin. The problem is a person just can't live on taxol chemo or any other chemo for too long as the bone marrow or kidneys suffer and death will certainly follow from the immunosuppression (sepsis or pneumonia) or kidney failure. I really don't know how long is "too long" but a year seems to be a long time to stay on any chemo if you ask me.

    Another consideration in this discussion is that there are more than 10 different kinds of OVCA--we are talking about a disparity of diseases here all basically being treated the same. Some people are fortunate enough to have their tumor sensitivity tested to see which chemo it is sensitive to before they are put on board "the chemo train."

    So, when you are looking for individualized treatment, be sure you know exactly WHAT kind of OVCA you have been diagnosed with in the first place. The clear cell OVCA has been shown to respond to a chemo called Torisel which is typically used for kidney clear cell cancer.

    I agree with what Tethys41 said: Western medicine alone usually doesn't have the answer for everyone with cancer. However, some lucky people DO remain cancer free after doing nothing more than surgery or surgery and chemo. Those people are in the minority and usually staged early in the disease, too.

    So, unfortunately, there is no good answer for you at this time. If there was a "magic pill" we'd all be taking it; I can assure you that. I read that there are different theories on the ways that cancer activates--one of the theories is that cancer kicks in from stem cells that have been floating around in us since birth. The only way to survive is through stem cell therapy or possibly through a cancer vaccine. I tend to believe this theory and am looking at the vaccine research as being the most hopeful for us to survive.

    The problem with the vaccine is that it is VERY expensive to make a vaccine one-at-a-time for each individual--the drug companies are trying to find a cancer vaccine that can be mass produced economically.

    So, there you have some of my thoughts on the subject--I have a lot more thoughts but they encompass the realm of "alternative medicine therapies" which are often evidence-based but certainly not accepted by oncologists. Look to a book called "Defeat Cancer" if you want to be overwhelmed with more information on how the non-traditional doctors treat cancer.

    Whatever you decide, Wings, I think it must be something that you BELIEVE in--never underestimate the power of the placebo effect. LOL! : )

    Best wishes to you,

    Carolen