News on 5-ARI for newly diagnosed Low Risk Prostate Cancer

VascodaGama

Here are good news from the European Urology published online 25 January 2011. This is from the world’s leading publisher of science and health information, Elsevier, based in Amsterdam, probably the most recognized reliable source of medical information in the world.

The news relate to a study named “The Use of 5α-Reductase Inhibitors (5-ARI) for the Prevention and Treatment of Prostate Cancer”.It was done in 389 patients on Active Surveillance (Watchful Waiting), on a long period of 15 years (1995 to 2010). The patients were initially diagnosed with low-risk prostate cancer, meaning that they belong to the wider population of cases in recent years.
They have found that patients taking a 5-ARI experienced lower rates of progression (18.6% vs 36.7%).
The traditional (Finasteride and Dutasteride) drugs are inexpensive, do not interact with other medication and have low (or zero) side effects.
You can read the article here;

http://www.europeanurology.com/article/S0302-2838(11)00049-2/fulltext

In the full text from European Association of Urology, they comment that since the PSA testing “revolution”, it is estimated that 1 in 6 men will develop prostate cancer, but it is believed that only1in34 will die from the cancer.

Because of that,
“…There has been debate about the best management strategy for localized prostate cancer, and given that surgery and radiation have an adverse impact on quality of life, active surveillance has emerged as a popular strategy. Low-risk prostate cancer, defined as a PSA level < 10 ng/ml, stageT1c–T2a, and Gleason score <6, accounts for approximately 50% of newly diagnosed prostate cancers…..”

“….The National Comprehensive Cancer Network and the National Institute for Health and Clinical Excellence both suggest that active surveillance be considered a first-line treatment strategy in low-risk disease…”

In commenting about the 5-ARI study, the EAU says;
“…Despite slight differences in study design, both 5-ARIs (finasteride and dutasteride) were associated with an approximately 25% relative reduction in prostate cancer diagnoses compared with placebo. Given the benefits of the 5-ARIs, it has been hypothesized that they may delay or prevent progression of low-risk prostate cancer….”

Here is the full text;
http://www.europeanurology.com/article/S0302-2838(10)01196-6/pdf/Impact+of+5-Reductase+Inhibitors+on+Men+Followed+by+Active+Surveillance+for+Prostate+Cancer

Indolent cancers will be gone forever.
Wishing all the best
VGama

Kongo

Interesting Study
Vasco,

Thanks for posting this interesting study. A couple of things I think ought to be noted in the context of this report.

First the study authors were paid consultants of Glaxo Smith Kline, a large drug manufacturer.

The study does not highlight any side effects or adverse reactions to taking the 5-ARI drugs and I had difficulty finding the dosage used in the study in the long report and the end state of the cohort was judged to be a validated cancer progression. Evidently, from the first link the dosage was 10mg per day.

I questioned the statement: "The traditional (Finasteride and Dutasteride) drugs are inexpensive, do not interact with other medication and have low (or zero) side effects."

The FDA has indicated that the most common side effects of these drugs include trouble getting or keeping an erection (impotence), decrease in sex drive, decreased volume of ejaculate, ejaculation disorders, enlarged or painful breast. Other allergic reactions, including rash, itching, hives, and swelling of the lips and face have been reported. In rare cases male breast cancer has been reported.

It should also be noted that women, particularly women of child bearing age, should avoid all contact with these drugs (even touching them) as it has potential to damage a male fetus.

For a 5 mg/day dosage, the common side effects of dutasteride, one of the 5-ARI drugs used in the study had the following side effects:

Erectile dysfunction (ED) or impotence -- in up to 18.5 percent of people
Decreased libido (sex drive) -- up to 10 percent
Abnormal ejaculation, including decreased ejaculate amount -- up to 7.2 percent
Breast enlargement -- up to 2.2 percent.

Since apparently, the dosage administered in the study was 10 mg/day I could only assume that the side effects would be more intense and affect a larger population, but this was not addressed in the results and I wonder if the consultants to Glaxo were motivated to report only the positive results -- the reduction in PCa progression in some patients -- rather than dwell on any adverse impact of the drug use.

Don't get me wrong, I think these studies are important and add to the body of knowledge we have about the complexities of prostate cancer. To me, at least, it seems that one of the reasons men choose AS to deal with their cancer is it's absence of side effects and men on AS who might be tempted to try such a treatment need to go into it with their eyes wide open and fully understand the potential for adversde side effects which are inherent in any medicines used to treat cancerous conditions.

Another thing about these studies, particularly those that are looking at only a single variable (such as the use of 5-ARI drugs) is that they do not address the underlying causes of the cancer but instead look at symptoms or rate of progression.

Best,

K

hopeful and optimistic

Jury still out
I've read, and personally asked about 10 docs about this drug......aout 1/3 of them prescribe the drug, while the other 2/3 do not.....I gave a lot of thought about taking this drug......anyway, I'm still investigating, and beleive that it is prudent to wait a while to see if any unbiased studies emerge that targets those who have been diagnosed with low grade cancer.....to my knowledge there are no ongoing studies among this population in the United States.

VascodaGama

Kongo said:

Interesting Study
Vasco,

Thanks for posting this interesting study. A couple of things I think ought to be noted in the context of this report.

First the study authors were paid consultants of Glaxo Smith Kline, a large drug manufacturer.

The study does not highlight any side effects or adverse reactions to taking the 5-ARI drugs and I had difficulty finding the dosage used in the study in the long report and the end state of the cohort was judged to be a validated cancer progression. Evidently, from the first link the dosage was 10mg per day.

I questioned the statement: "The traditional (Finasteride and Dutasteride) drugs are inexpensive, do not interact with other medication and have low (or zero) side effects."

The FDA has indicated that the most common side effects of these drugs include trouble getting or keeping an erection (impotence), decrease in sex drive, decreased volume of ejaculate, ejaculation disorders, enlarged or painful breast. Other allergic reactions, including rash, itching, hives, and swelling of the lips and face have been reported. In rare cases male breast cancer has been reported.

It should also be noted that women, particularly women of child bearing age, should avoid all contact with these drugs (even touching them) as it has potential to damage a male fetus.

For a 5 mg/day dosage, the common side effects of dutasteride, one of the 5-ARI drugs used in the study had the following side effects:

Erectile dysfunction (ED) or impotence -- in up to 18.5 percent of people
Decreased libido (sex drive) -- up to 10 percent
Abnormal ejaculation, including decreased ejaculate amount -- up to 7.2 percent
Breast enlargement -- up to 2.2 percent.

Since apparently, the dosage administered in the study was 10 mg/day I could only assume that the side effects would be more intense and affect a larger population, but this was not addressed in the results and I wonder if the consultants to Glaxo were motivated to report only the positive results -- the reduction in PCa progression in some patients -- rather than dwell on any adverse impact of the drug use.

Don't get me wrong, I think these studies are important and add to the body of knowledge we have about the complexities of prostate cancer. To me, at least, it seems that one of the reasons men choose AS to deal with their cancer is it's absence of side effects and men on AS who might be tempted to try such a treatment need to go into it with their eyes wide open and fully understand the potential for adversde side effects which are inherent in any medicines used to treat cancerous conditions.

Another thing about these studies, particularly those that are looking at only a single variable (such as the use of 5-ARI drugs) is that they do not address the underlying causes of the cancer but instead look at symptoms or rate of progression.

Best,

K

You are correct about drugs side effects
Kongo,
You are correct about drugs side effects. I was too optimist in my statement as I intended to signal a comparison with the side effects from treatments such as surgery or radiation therapy in terms of QoL. The 5-ARI drugs, finasteride and dutasteride, are quite mild in the vast majority of cases in doses of 5mg and 0.5mg, but you “dug to the lowest platforms”. Guys in AS would stop taking drugs as well as stop the whole AS period if symptoms or progression were verified. As Dr. Mark Scholz rationale goes “It can’t hurt, and it might help.”

The study included consultants from Glaxo Smith Kline but I do not think that the drug manufacturers would influence the outcome because these are drugs in use for many years and got their names in the medical world from long time usages and successful experiences. The drugs are now sold as generics too, therefore cheaper (on the 80%) and with less influence from the big names as Proscar and Avodart.
The underlying causes are in pair with active surveillance in regards to the rate of progression; causes are not taken into consideration. If patients demonstrate suspicious developments then they move to a radical treatment. Nevertheless, this will reasonably answer the debate about the best management strategy for localized prostate cancer. Many including myself would find in it an option away from the thoughts on “get rid of it”.
The silver bullet was not yet found.

Thanks for the comments.
VGama

kddh

The EAU Should Cut its Marketing Dept!
Hi All:

This is an interesting topic. When I followed the link that you provided to look at the article, I couldn't believe that the European Association of Urology boasts a slogan like "a Cut Above the Rest!"

Are you sure they're so reputable? They sure have bad taste in marketing!

sbj

Kongo said:

Interesting Study
Vasco,

Thanks for posting this interesting study. A couple of things I think ought to be noted in the context of this report.

First the study authors were paid consultants of Glaxo Smith Kline, a large drug manufacturer.

The study does not highlight any side effects or adverse reactions to taking the 5-ARI drugs and I had difficulty finding the dosage used in the study in the long report and the end state of the cohort was judged to be a validated cancer progression. Evidently, from the first link the dosage was 10mg per day.

I questioned the statement: "The traditional (Finasteride and Dutasteride) drugs are inexpensive, do not interact with other medication and have low (or zero) side effects."

The FDA has indicated that the most common side effects of these drugs include trouble getting or keeping an erection (impotence), decrease in sex drive, decreased volume of ejaculate, ejaculation disorders, enlarged or painful breast. Other allergic reactions, including rash, itching, hives, and swelling of the lips and face have been reported. In rare cases male breast cancer has been reported.

It should also be noted that women, particularly women of child bearing age, should avoid all contact with these drugs (even touching them) as it has potential to damage a male fetus.

For a 5 mg/day dosage, the common side effects of dutasteride, one of the 5-ARI drugs used in the study had the following side effects:

Erectile dysfunction (ED) or impotence -- in up to 18.5 percent of people
Decreased libido (sex drive) -- up to 10 percent
Abnormal ejaculation, including decreased ejaculate amount -- up to 7.2 percent
Breast enlargement -- up to 2.2 percent.

Since apparently, the dosage administered in the study was 10 mg/day I could only assume that the side effects would be more intense and affect a larger population, but this was not addressed in the results and I wonder if the consultants to Glaxo were motivated to report only the positive results -- the reduction in PCa progression in some patients -- rather than dwell on any adverse impact of the drug use.

Don't get me wrong, I think these studies are important and add to the body of knowledge we have about the complexities of prostate cancer. To me, at least, it seems that one of the reasons men choose AS to deal with their cancer is it's absence of side effects and men on AS who might be tempted to try such a treatment need to go into it with their eyes wide open and fully understand the potential for adversde side effects which are inherent in any medicines used to treat cancerous conditions.

Another thing about these studies, particularly those that are looking at only a single variable (such as the use of 5-ARI drugs) is that they do not address the underlying causes of the cancer but instead look at symptoms or rate of progression.

Best,

K

Avodart study results
Kongo,

I read a news report today (Feb 15) that reviewed the outcome of a new study that tested Avodart, not to prevent cancer, but to prevent the progression of it. Dr. Maha Hussain, a University of Michigan cancer specialist chaired a cancer conference in Florida where the study will be presented later this week. Is this the same drug and study you are referring to?

About 300 men in the United States and Canada with low-risk cancer that was confirmed by biopsy enrolled in the study. They were given daily Avodart or dummy pills and had biopsies 1 1/2 and three years later. Prostate cancer got worse in 38 percent of men taking Avodart and 49 percent of those on dummy pills. Final biopsies showed no signs of cancer in 36 percent of men on Avodart versus 23 percent of those on dummy pills.

Most amazingly, a third of those on the pill and a quarter on placebo showed no sign of cancer after previously being diagnosed only 3 years earlier! Moreover, from the numbers, it would it appear that 28%, (100-49)-23, of placebo takers' cancers remained stable. Significantly too, half of placebo takers' (watcher and waiters?) cancers got worse. One wonders by how much.

One immediately wonders also, what the cancer free %age would have been (after 3 years) if radiation had been incorporated into the study. And if you're like me, one wonders yet again what the effect of the drug would be on slowing/stopping PSA rise following RP.

sbj

Kongo

sbj said:

Avodart study results
Kongo,

I read a news report today (Feb 15) that reviewed the outcome of a new study that tested Avodart, not to prevent cancer, but to prevent the progression of it. Dr. Maha Hussain, a University of Michigan cancer specialist chaired a cancer conference in Florida where the study will be presented later this week. Is this the same drug and study you are referring to?

About 300 men in the United States and Canada with low-risk cancer that was confirmed by biopsy enrolled in the study. They were given daily Avodart or dummy pills and had biopsies 1 1/2 and three years later. Prostate cancer got worse in 38 percent of men taking Avodart and 49 percent of those on dummy pills. Final biopsies showed no signs of cancer in 36 percent of men on Avodart versus 23 percent of those on dummy pills.

Most amazingly, a third of those on the pill and a quarter on placebo showed no sign of cancer after previously being diagnosed only 3 years earlier! Moreover, from the numbers, it would it appear that 28%, (100-49)-23, of placebo takers' cancers remained stable. Significantly too, half of placebo takers' (watcher and waiters?) cancers got worse. One wonders by how much.

One immediately wonders also, what the cancer free %age would have been (after 3 years) if radiation had been incorporated into the study. And if you're like me, one wonders yet again what the effect of the drug would be on slowing/stopping PSA rise following RP.

sbj

sbj
I too read that news report yesterday. I believe it is a complementary report to the one Vasco highlighted that gave similar results. As I recall, the news story also did not go into potential side effects of using one of the two drugs...perhaps when the paper is actually presented there will be more details forthcoming.

Like the report Vasco referred to, this one does not appear to address any underlying causes of cancer in the first place but it is interesting, as you point out, that fairly high percentages of men who were on the placebo apparently saw their cancer remain steady or even decrease. Although since these results evidently were based on biopsy results, it's certainly possible that follow-on biopsies simply missed an indolent cancer or that in the cases where progression is shown, happened to hit a spot that was overlooked before.

K

hopeful and optimistic

Kongo said:

sbj
I too read that news report yesterday. I believe it is a complementary report to the one Vasco highlighted that gave similar results. As I recall, the news story also did not go into potential side effects of using one of the two drugs...perhaps when the paper is actually presented there will be more details forthcoming.

Like the report Vasco referred to, this one does not appear to address any underlying causes of cancer in the first place but it is interesting, as you point out, that fairly high percentages of men who were on the placebo apparently saw their cancer remain steady or even decrease. Although since these results evidently were based on biopsy results, it's certainly possible that follow-on biopsies simply missed an indolent cancer or that in the cases where progression is shown, happened to hit a spot that was overlooked before.

K

Didn't see the article,
.....can you direct me to the source.

Kongo

hopeful and optimistic said:

Didn't see the article,
.....can you direct me to the source.

Link
http://news.yahoo.com/s/ap/20110216/ap_on_he_me/us_med_prostate_cancer

sbj

hopeful and optimistic said:

Didn't see the article,
.....can you direct me to the source.

hopeful
The article was an AP piece in yesterday's Yahoo News. Here's a full copy of it:


By MARILYNN MARCHIONE, AP Medical Writer – Wed Feb 16, 6:30 am ET
A new study suggests a way to help men with early, low-risk prostate cancer avoid being overtreated for a disease that in most cases will never threaten their lives. It found that a drug can slow the growth of these tumors in men who opt to be monitored instead of having treatment right away.
This is the first time that a drug for treating enlarged prostates also has been shown to help treat prostate cancer in a rigorous study. It may persuade more men to choose active surveillance, or "watchful waiting," instead of rushing to have treatments that can leave them with urinary or sexual problems, doctors say.
However, the results also show that most of these men do very well with no treatment at all.
"We're identifying men who are not likely to need even a pill," said Dr. Maha Hussain, a University of Michigan cancer specialist. But Americans fear cancer so much that they want some kind of treatment and underestimate the financial and medical risks of treating low-risk cases, she added.
She is program chair of a cancer conference in Florida where the study will be presented later this week. Results were released Tuesday in a telephone news conference sponsored by the American Society for Clinical Oncology.
Roughly half of the 218,000 men diagnosed each year in the United States with prostate cancer have low-risk disease — PSA blood levels under 10 and low tumor aggressiveness scores.
"The American view of cancer" is that it's always best to treat, so about 80 percent of these men choose to have that right away, said Dr. Otis Brawley, a prostate cancer expert who is chief medical officer of the American Cancer Society.
In Europe, though, most choose watchful waiting — close monitoring and treatment only if the cancer progresses or causes pain or other problems.
Doctors know that drugs that shrink the prostate — GlaxoSmithKline PLC's Avodart and Merck & Co.'s Proscar — can help prevent prostate cancer. But federal health advisers recently recommended against taking them for this purpose because of potential risks.
The new study tested Avodart "not to prevent cancer, but to prevent the progression" of it in men who already have the disease, which may be a much better use of such drugs, said the study's leader, Dr. Neil Fleshner of University Health Network and Princess Margaret Hospital in Toronto.
"We know the vast majority of these men are not destined to die from that cancer," and wanted to see if Avodart could make "watchful waiting" safer, Fleshner said.
The study enrolled about 300 men in the United States and Canada with low-risk cancer that was confirmed by a biopsy. They were given daily Avodart or dummy pills and new biopsies 1 1/2 and three years later.
Prostate cancer got worse in 38 percent of men taking Avodart and 49 percent of those on dummy pills. Final biopsies showed no signs of cancer in 36 percent of men on Avodart versus 23 percent of those on dummy pills. Doctors say this last result shows how tiny many of these cancers were to start with, that they couldn't even be found when new biopsies were done.
Doctors don't think Avodart can cure cancers, but it seems to suppress it, said Dr. Howard Sandler, a prostate cancer specialist at Cedars-Sinai Medical Center in Los Angeles. He had no role in the study but is involved with the cancer conference.
Researchers gave no details on Avodart's side effects, but said no new ones appeared in the study. Avodart and Proscar are known to cause sexual problems for some men, but many men over 50 have this anyway and only about 5 percent more do when taking these drugs, said Brawley, who helped test Avodart for cancer prevention.
The new study was sponsored by Avodart's maker, GlaxoSmithKline. Avodart and Proscar cost about $4 a pill; generic versions of Proscar are available for about $2. Proscar is similar to Avodart but has not been tested for treating early cancer as this study did.
Sandler said Avodart might relieve some men's anxiety about monitoring their disease and may make them more comfortable not having immediate treatment.
"If it was me, I'd choose active surveillance," he said. Avodart "has the potential to be an important help."

sbj

sbj

Kongo said:

sbj
I too read that news report yesterday. I believe it is a complementary report to the one Vasco highlighted that gave similar results. As I recall, the news story also did not go into potential side effects of using one of the two drugs...perhaps when the paper is actually presented there will be more details forthcoming.

Like the report Vasco referred to, this one does not appear to address any underlying causes of cancer in the first place but it is interesting, as you point out, that fairly high percentages of men who were on the placebo apparently saw their cancer remain steady or even decrease. Although since these results evidently were based on biopsy results, it's certainly possible that follow-on biopsies simply missed an indolent cancer or that in the cases where progression is shown, happened to hit a spot that was overlooked before.

K

Kongo
One would have thought that in such a trial, great care would have been taken to ensure post-study biopsy's were done by the same lab technician(s) using the exact same equipment, in exactly the same location as were the pre-study samples. And I'm sure they were. So whatever tumor growth was there originally that presumably produced rising PSA and showed up in a biopsy must have been extremely microscopic.
As regards side effects, the report did say: "Researchers gave no details on Avodart's side effects, but said no new ones appeared in the study. Avodart and Proscar are known to cause sexual problems for some men, but many men over 50 have this anyway and only about 5 percent more do when taking these drugs, said Brawley, who helped test Avodart for cancer prevention."
The fact that the drug can't cure cancer is disappointing, but the claim that the drug suppressed growth can only be encouraging news to sufferers, especially those with low grade malignancy, but others also, since one would assume that their cancers too would be shrunk or growth slowed.

sbj

hopeful and optimistic

sbj said:

hopeful
The article was an AP piece in yesterday's Yahoo News. Here's a full copy of it:


By MARILYNN MARCHIONE, AP Medical Writer – Wed Feb 16, 6:30 am ET
A new study suggests a way to help men with early, low-risk prostate cancer avoid being overtreated for a disease that in most cases will never threaten their lives. It found that a drug can slow the growth of these tumors in men who opt to be monitored instead of having treatment right away.
This is the first time that a drug for treating enlarged prostates also has been shown to help treat prostate cancer in a rigorous study. It may persuade more men to choose active surveillance, or "watchful waiting," instead of rushing to have treatments that can leave them with urinary or sexual problems, doctors say.
However, the results also show that most of these men do very well with no treatment at all.
"We're identifying men who are not likely to need even a pill," said Dr. Maha Hussain, a University of Michigan cancer specialist. But Americans fear cancer so much that they want some kind of treatment and underestimate the financial and medical risks of treating low-risk cases, she added.
She is program chair of a cancer conference in Florida where the study will be presented later this week. Results were released Tuesday in a telephone news conference sponsored by the American Society for Clinical Oncology.
Roughly half of the 218,000 men diagnosed each year in the United States with prostate cancer have low-risk disease — PSA blood levels under 10 and low tumor aggressiveness scores.
"The American view of cancer" is that it's always best to treat, so about 80 percent of these men choose to have that right away, said Dr. Otis Brawley, a prostate cancer expert who is chief medical officer of the American Cancer Society.
In Europe, though, most choose watchful waiting — close monitoring and treatment only if the cancer progresses or causes pain or other problems.
Doctors know that drugs that shrink the prostate — GlaxoSmithKline PLC's Avodart and Merck & Co.'s Proscar — can help prevent prostate cancer. But federal health advisers recently recommended against taking them for this purpose because of potential risks.
The new study tested Avodart "not to prevent cancer, but to prevent the progression" of it in men who already have the disease, which may be a much better use of such drugs, said the study's leader, Dr. Neil Fleshner of University Health Network and Princess Margaret Hospital in Toronto.
"We know the vast majority of these men are not destined to die from that cancer," and wanted to see if Avodart could make "watchful waiting" safer, Fleshner said.
The study enrolled about 300 men in the United States and Canada with low-risk cancer that was confirmed by a biopsy. They were given daily Avodart or dummy pills and new biopsies 1 1/2 and three years later.
Prostate cancer got worse in 38 percent of men taking Avodart and 49 percent of those on dummy pills. Final biopsies showed no signs of cancer in 36 percent of men on Avodart versus 23 percent of those on dummy pills. Doctors say this last result shows how tiny many of these cancers were to start with, that they couldn't even be found when new biopsies were done.
Doctors don't think Avodart can cure cancers, but it seems to suppress it, said Dr. Howard Sandler, a prostate cancer specialist at Cedars-Sinai Medical Center in Los Angeles. He had no role in the study but is involved with the cancer conference.
Researchers gave no details on Avodart's side effects, but said no new ones appeared in the study. Avodart and Proscar are known to cause sexual problems for some men, but many men over 50 have this anyway and only about 5 percent more do when taking these drugs, said Brawley, who helped test Avodart for cancer prevention.
The new study was sponsored by Avodart's maker, GlaxoSmithKline. Avodart and Proscar cost about $4 a pill; generic versions of Proscar are available for about $2. Proscar is similar to Avodart but has not been tested for treating early cancer as this study did.
Sandler said Avodart might relieve some men's anxiety about monitoring their disease and may make them more comfortable not having immediate treatment.
"If it was me, I'd choose active surveillance," he said. Avodart "has the potential to be an important help."

sbj

SBJ and Kongo
Thanks for the AP news release ........

VascodaGama

kddh said:

The EAU Should Cut its Marketing Dept!
Hi All:

This is an interesting topic. When I followed the link that you provided to look at the article, I couldn't believe that the European Association of Urology boasts a slogan like "a Cut Above the Rest!"

Are you sure they're so reputable? They sure have bad taste in marketing!

Hopeful & kddh; Avodart and Heart Failure
Hopeful & kddh
Sorry for the late reply.
I think you got some of your queries from above posts. Here are some materials you may be interested in reading with regards to Avodart (dutasteride). This is one of the 5-ARI included in the study. This drug has been connected to heart failure but it is not clear yet if the causes found were due to other medical issues. Finasteride does not made part in the study independently for the same purposes.

Effect of Dutasteride on the Risk of Prostate Cancer
http://www.nejm.org/doi/pdf/10.1056/NEJMoa0908127

The “juri” (second opinion) from professor of urology Dr. Patrick Walsh (JH) is in this article (Mar 2010), but this doctor is not a big “fan” of AS.

Avodart May Lower Prostate Cancer Risk
http://www.medicinenet.com/script/main/art.asp?articlekey=114950


Thanks for the comments.
VGama