› Forums › General Melanoma Community › Ipilimumab without dacarbazine?
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buffcody.
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- June 25, 2011 at 3:11 pm
Hi all. First time poster here, although I've been following the forum occasionally for some time. Perhaps my question is a bit dumb but please bear with me and help me clear up some things. My 70 year old father is a stage IV melanoma victim, with mets in his lungs, liver and lymph nodes. He was first diagnosed in 2009 as stage III and had had subsequently removed his primary tumor and some lymph nodes in his neck.
Hi all. First time poster here, although I've been following the forum occasionally for some time. Perhaps my question is a bit dumb but please bear with me and help me clear up some things. My 70 year old father is a stage IV melanoma victim, with mets in his lungs, liver and lymph nodes. He was first diagnosed in 2009 as stage III and had had subsequently removed his primary tumor and some lymph nodes in his neck.
He was now given a choice of treatment that would consist first of dacarbazine and then of ipilimumab (if necessary, I guess). The thing is, my father is extremely negative towards any chemotherapy and doesn't even want to hear about it. He insists he will beat the disease on his own terms. It's really his body, his illness and ultimately his decision, and I think it ought to be respected, but on the other hand I also try to explain to him that ipi really doesn't work like classical chemo, and that there are many people out there who benefited wonderfully from this drug. He might take my word for it when I present him with some success stories from this website. However, his doctor maintains that the only possible way of treatment is to administer dacarbazine first, and only later ipi.
Is this true? I've read on the Internet that this combination is a standard procedure "one-two" punch, but can't a patient demand to undertake ipi treatment alone if such his desire happens to be? I also find it a bit counterintuitive to administer a cytotoxic drug first, with all its detrimental effects on the immune system, and only afterwards apply ipilimumab, which is then supposed to work through this compromised immune response. Wouldn't a more logical sequence be ipi first, dacarbazine second?
Again, I apologize for my ignorance of the subject. Any clarifications will be greatly appreciated.
I also wish best of luck to all of you battling this disease. Stay strong! Whenever I read a success report, I want to just high-five that person. 🙂
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- June 25, 2011 at 4:14 pm
Where is he being seen? Is it a melanoma center?
You may wish to ask the doctor why they feel the need in doing this combination. They may be getting their reasoning from a article such as this:
http://www.empr.com/addition-of-ipilimumab-to-dacarbazine-improves-survival-in-metastatic-melanoma/article/204537/
Addition of Ipilimumab to Dacarbazine Improves Survival in Metastatic Melanoma
June 5, 2011:
Ipilimumab in combination with dacarbazine (DTIC) significantly improved overall survival (OS) in metastatic melanoma compared with dacarabazine alone, according to data presented at the American Society of Clinical Oncology's 2011 Annual Meeting.
Here is another page you may wish to read: It is from ASCO. The American Society of Clinical Oncology.
You will see that the three year survival with dacarbazine is higher than without.
http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34536
Long-term survival of patients (pts) with advanced melanoma treated with ipilimumab with or without dacarbazine.
Also be aware that ipilimumab, which is also known as MDX-010 or MDX-101, was approved by the FDA on March 25, 2011 and is now being marketed as Yervoy by Bristol-Myers Squibb..
Be aware that yervoy (and dacarbazine also called DTIC) are not easy treatments, especially for the elderly. In the end, what he decides to do is his decision to make.
Good Luck,
Michael
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- June 25, 2011 at 4:14 pm
Where is he being seen? Is it a melanoma center?
You may wish to ask the doctor why they feel the need in doing this combination. They may be getting their reasoning from a article such as this:
http://www.empr.com/addition-of-ipilimumab-to-dacarbazine-improves-survival-in-metastatic-melanoma/article/204537/
Addition of Ipilimumab to Dacarbazine Improves Survival in Metastatic Melanoma
June 5, 2011:
Ipilimumab in combination with dacarbazine (DTIC) significantly improved overall survival (OS) in metastatic melanoma compared with dacarabazine alone, according to data presented at the American Society of Clinical Oncology's 2011 Annual Meeting.
Here is another page you may wish to read: It is from ASCO. The American Society of Clinical Oncology.
You will see that the three year survival with dacarbazine is higher than without.
http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34536
Long-term survival of patients (pts) with advanced melanoma treated with ipilimumab with or without dacarbazine.
Also be aware that ipilimumab, which is also known as MDX-010 or MDX-101, was approved by the FDA on March 25, 2011 and is now being marketed as Yervoy by Bristol-Myers Squibb..
Be aware that yervoy (and dacarbazine also called DTIC) are not easy treatments, especially for the elderly. In the end, what he decides to do is his decision to make.
Good Luck,
Michael
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- June 25, 2011 at 5:11 pm
Thanks for pointing that out. The first link was at 10 mg/kg, and the second (ASCO) one was at 3 mg/kg.
http://www.empr.com/addition-of-ipilimumab-to-dacarbazine-improves-survival-in-metastatic-melanoma/article/204537/
http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34536
Michael
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- June 25, 2011 at 5:11 pm
Thanks for pointing that out. The first link was at 10 mg/kg, and the second (ASCO) one was at 3 mg/kg.
http://www.empr.com/addition-of-ipilimumab-to-dacarbazine-improves-survival-in-metastatic-melanoma/article/204537/
http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34536
Michael
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- June 25, 2011 at 5:56 pm
Since you posted as annon. we cannot see a profile. My question is where are you from? If Canada then that is the only way to get Yervoy/Ippi. First the person has to have tried traditional chemo such as DTIC and then they can get into a compassionate care trial. if in the US then your Dr is doing this on his own. As other posters have said there have been trials with the two combined.
Ultimately as you said it is your dad's choice. My concern would be to make sure he realizes that he can't just beat this without doing anything. Once it is systemic and in several places surgery is no longer an option.
While Ippi has worked for some on this board there are also many who have had some severe side effects. I wish there was an easy option. Been doing a lot of thinking myself. I have a friend who was on this board about a year ago. She did the ipi first in a trial and when it didn't work she did the DTIC. It controlled growth for about 5 months for Lynn. Some say by doing the DTIC first it quickly shrinks the tumor growth (not known for lasting results) and then ippi since ippi takes longer to work and often swells tumors first.
Go with your dad to his appointments and make sure that he understands his options, but it's his decision.
Please keep us up to date, I'm sorry you've had to join us.
Linda
Stage IV since 06 Ned 3 Weeks, radiation starts on Monday
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- June 25, 2011 at 5:56 pm
Since you posted as annon. we cannot see a profile. My question is where are you from? If Canada then that is the only way to get Yervoy/Ippi. First the person has to have tried traditional chemo such as DTIC and then they can get into a compassionate care trial. if in the US then your Dr is doing this on his own. As other posters have said there have been trials with the two combined.
Ultimately as you said it is your dad's choice. My concern would be to make sure he realizes that he can't just beat this without doing anything. Once it is systemic and in several places surgery is no longer an option.
While Ippi has worked for some on this board there are also many who have had some severe side effects. I wish there was an easy option. Been doing a lot of thinking myself. I have a friend who was on this board about a year ago. She did the ipi first in a trial and when it didn't work she did the DTIC. It controlled growth for about 5 months for Lynn. Some say by doing the DTIC first it quickly shrinks the tumor growth (not known for lasting results) and then ippi since ippi takes longer to work and often swells tumors first.
Go with your dad to his appointments and make sure that he understands his options, but it's his decision.
Please keep us up to date, I'm sorry you've had to join us.
Linda
Stage IV since 06 Ned 3 Weeks, radiation starts on Monday
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- June 25, 2011 at 7:57 pm
Hi all. OP here. Thanks for all your explanations. They clarified things up quite a bit. I guess I should clarify some matters, too.
My father was diagnosed and treated at the general Oncologic Institute in Slovenia (Europe). (This should also explain possible quaint use of English and weird grammar on my behalf.) We do not have a specialized melanoma center here. Our location (outside US) also suggests why doctors are only willing to administer Yervoy along with dacarbazine, just as Linda pointed out for Canada. I guess they are under some kind of obligation, although I feel patients should have the right to choose treatments themselves, even if their results are less than optimal.
Thanks to Michael for the trial links. I see now that DTIC-ipilimumab combo offers better results that ippi alone (especially at the 3-year mark), though only in standard dose. Since my father refuses to be treated with anything that would adversely affect his immune system, DTIC is for now out of the question. Ipilimumab/Yervoy might be an option because it works by actually enhancing the immune system (with possible severe side effects, I know), but if it only comes in bundle with DTIC than we have to scratch that one, too. For the time being, at least. As I've said, it's his decision.
He does not plan to just sit on his behind, though. He is already pursuing various alternative treatments. I've also read so much recently, while trying to wade through often murky waters of alternative medicine, that I feel my head is about to burst. I always say that information is the most potent weapon of all but it can get overwhelming sometimes. I'm not sure what the attitude of this board toward alternative cancer treatments is. It seems that most of the posts deal with the traditional approach. But if anyone can contribute something valuable from the nontraditional options I'd be more than glad to listen.
Thank you all for helpful answers. Good luck, take care.
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- June 25, 2011 at 7:57 pm
Hi all. OP here. Thanks for all your explanations. They clarified things up quite a bit. I guess I should clarify some matters, too.
My father was diagnosed and treated at the general Oncologic Institute in Slovenia (Europe). (This should also explain possible quaint use of English and weird grammar on my behalf.) We do not have a specialized melanoma center here. Our location (outside US) also suggests why doctors are only willing to administer Yervoy along with dacarbazine, just as Linda pointed out for Canada. I guess they are under some kind of obligation, although I feel patients should have the right to choose treatments themselves, even if their results are less than optimal.
Thanks to Michael for the trial links. I see now that DTIC-ipilimumab combo offers better results that ippi alone (especially at the 3-year mark), though only in standard dose. Since my father refuses to be treated with anything that would adversely affect his immune system, DTIC is for now out of the question. Ipilimumab/Yervoy might be an option because it works by actually enhancing the immune system (with possible severe side effects, I know), but if it only comes in bundle with DTIC than we have to scratch that one, too. For the time being, at least. As I've said, it's his decision.
He does not plan to just sit on his behind, though. He is already pursuing various alternative treatments. I've also read so much recently, while trying to wade through often murky waters of alternative medicine, that I feel my head is about to burst. I always say that information is the most potent weapon of all but it can get overwhelming sometimes. I'm not sure what the attitude of this board toward alternative cancer treatments is. It seems that most of the posts deal with the traditional approach. But if anyone can contribute something valuable from the nontraditional options I'd be more than glad to listen.
Thank you all for helpful answers. Good luck, take care.
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- June 25, 2011 at 8:36 pm
OP,
Your location does explain a lot. Ipi/Yervoy is only FDA approved at this point in the US (at least that's my understanding) so your dad's Dr cannot get his hands on it unless in a trial.
Another thought is to have one of his removed tumors tested for the b-raf mutation. There are braf trials in many countries. That is a targeted therapy and different than chemo. There have been good responses with it, however it is not long lasting results at this point. They have started combining this drug with others. He must be b-raf positive to be eligible for these trials. The tumor would be tested through the companies offering the trials.
As far as attitude towards alternative care, this board varies. None of us know the answer. There is someone, Carole, who posts everyonce and awhile who did go the alternative route with success. I'm linking a post of hers that you can read plus it gives her e-mail.
Linda
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- June 25, 2011 at 8:36 pm
OP,
Your location does explain a lot. Ipi/Yervoy is only FDA approved at this point in the US (at least that's my understanding) so your dad's Dr cannot get his hands on it unless in a trial.
Another thought is to have one of his removed tumors tested for the b-raf mutation. There are braf trials in many countries. That is a targeted therapy and different than chemo. There have been good responses with it, however it is not long lasting results at this point. They have started combining this drug with others. He must be b-raf positive to be eligible for these trials. The tumor would be tested through the companies offering the trials.
As far as attitude towards alternative care, this board varies. None of us know the answer. There is someone, Carole, who posts everyonce and awhile who did go the alternative route with success. I'm linking a post of hers that you can read plus it gives her e-mail.
Linda
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- June 25, 2011 at 9:05 pm
Just wondering if your father has been tested for the BRAF mutation? Because I know at Hoffman-La Roche has several trials running in Europe that include the BRAF mutation drugs.
They do not harm the immune system the way that chemotherapy would and have been shown to be quite successful in a relatively short period of time. It might, at least, open up other options for your father if the tumor burden could be lightened.
One more comment about the chemo. I certainly respect that your father has certain beliefs when it comes to the chemo, but my husband is proof that chemo can work. He just started his second round of chemo (not with dacarbazine, a combo of 2 other drugs) and has had a fantastic response.
I don't know much about alternative medicines, unfortunately. My husband's melanoma spread so quickly initally that it just wasn't an option for us.
I wish you the very best of luck with your father's treatment.
Michelle, wife of Don
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- June 25, 2011 at 9:05 pm
Just wondering if your father has been tested for the BRAF mutation? Because I know at Hoffman-La Roche has several trials running in Europe that include the BRAF mutation drugs.
They do not harm the immune system the way that chemotherapy would and have been shown to be quite successful in a relatively short period of time. It might, at least, open up other options for your father if the tumor burden could be lightened.
One more comment about the chemo. I certainly respect that your father has certain beliefs when it comes to the chemo, but my husband is proof that chemo can work. He just started his second round of chemo (not with dacarbazine, a combo of 2 other drugs) and has had a fantastic response.
I don't know much about alternative medicines, unfortunately. My husband's melanoma spread so quickly initally that it just wasn't an option for us.
I wish you the very best of luck with your father's treatment.
Michelle, wife of Don
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- June 25, 2011 at 10:45 pm
I just found this…hope it helps-
2011 Jun;29(3):489-98. Epub 2010 Jan 16.
A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma.
Hersh EM, O'Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer LD, Samlowski WE, Nichol GM, Yellin MJ, Weber JS.Source
Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA. [email protected]
Abstract
OBJECTIVE:
Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma.
METHODS:
Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m(2)/day. The primary efficacy endpoint was objective response rate.
RESULTS:
Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively.
CONCLUSION:
Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.
http://www.ncbi.nlm.nih.gov/sites/entrez?db=PubMed&cmd=Retrieve&list_uids=20082117&dopt=Citation
Lynn
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- June 25, 2011 at 10:45 pm
I just found this…hope it helps-
2011 Jun;29(3):489-98. Epub 2010 Jan 16.
A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma.
Hersh EM, O'Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer LD, Samlowski WE, Nichol GM, Yellin MJ, Weber JS.Source
Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA. [email protected]
Abstract
OBJECTIVE:
Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma.
METHODS:
Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m(2)/day. The primary efficacy endpoint was objective response rate.
RESULTS:
Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively.
CONCLUSION:
Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.
http://www.ncbi.nlm.nih.gov/sites/entrez?db=PubMed&cmd=Retrieve&list_uids=20082117&dopt=Citation
Lynn
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- June 26, 2011 at 9:43 pm
OP here. Thanks again for everyone's answers and useful links. Michelle, I just don't know if my father was tested for BRAF. I wasn't with him at the clinic at the time (in fact, my parents were hiding the news of recurrence from me for a couple of weeks…) and I somehow doubt they explained the details of the disease to him anyway. He didn't even know what kind of drug they wanted to use on him. I specifically told him to ask the onc if it was ippi, since the regimen was supposed to be once every three weeks with four repetitions. It turned out I was right but DTIC was planned to be used first. And I do know that chemo can and does work but a person's expectations are of extreme importance, too. If one has such aversion to chemo like my father has at the moment, then perhaps it's wisest not to take that road because negative feelings can surely contribute to the possible lack of success. I'm glad your husband is doing well and wish him all the best.
Thanks to Lynn, too. The results you've posted are consisted with the ones posted previously by Michael. By the way, I've googled that the Committee of EMA (European Medicines Agency) has just recently recommended the use of Yervoy (5 mg/ml) in the EU, although the final decision is still pending. Link: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002213/smops/Positive/human_smop_000227.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d127
And best of luck to Linda with her radiation tomorrow. I will keep my fingers crossed! 🙂
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- June 26, 2011 at 9:43 pm
OP here. Thanks again for everyone's answers and useful links. Michelle, I just don't know if my father was tested for BRAF. I wasn't with him at the clinic at the time (in fact, my parents were hiding the news of recurrence from me for a couple of weeks…) and I somehow doubt they explained the details of the disease to him anyway. He didn't even know what kind of drug they wanted to use on him. I specifically told him to ask the onc if it was ippi, since the regimen was supposed to be once every three weeks with four repetitions. It turned out I was right but DTIC was planned to be used first. And I do know that chemo can and does work but a person's expectations are of extreme importance, too. If one has such aversion to chemo like my father has at the moment, then perhaps it's wisest not to take that road because negative feelings can surely contribute to the possible lack of success. I'm glad your husband is doing well and wish him all the best.
Thanks to Lynn, too. The results you've posted are consisted with the ones posted previously by Michael. By the way, I've googled that the Committee of EMA (European Medicines Agency) has just recently recommended the use of Yervoy (5 mg/ml) in the EU, although the final decision is still pending. Link: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002213/smops/Positive/human_smop_000227.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d127
And best of luck to Linda with her radiation tomorrow. I will keep my fingers crossed! 🙂
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- June 26, 2011 at 11:32 pm
I'm from Canada, and as Linda mentioned, in order to qualify for the compassionate ipi trial, I had to take chemotherapy first. I was offered a choice of dicarbazine or temodar/temodal if I paid $4,000 for 5 pills. Fortunately, my husband's health plan covered 90% of the cost of temodar so I went with that.
Temodar is an oral chemo and I had 5 days with a mild case of constipation, that's it..it could be a choice for your father. Of course, after reading Michael's et al input…I wish I had taken dicarbazine. Ipilimumab worked excellent on my cutaneous mels but alas, one lymph node growth and sub-qs have resulted in getting kicked off the second round of 4 treatments. Ipilimumab definitely prolonged my life but now I am searching for another trial. Val, stage IV
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- June 26, 2011 at 11:32 pm
I'm from Canada, and as Linda mentioned, in order to qualify for the compassionate ipi trial, I had to take chemotherapy first. I was offered a choice of dicarbazine or temodar/temodal if I paid $4,000 for 5 pills. Fortunately, my husband's health plan covered 90% of the cost of temodar so I went with that.
Temodar is an oral chemo and I had 5 days with a mild case of constipation, that's it..it could be a choice for your father. Of course, after reading Michael's et al input…I wish I had taken dicarbazine. Ipilimumab worked excellent on my cutaneous mels but alas, one lymph node growth and sub-qs have resulted in getting kicked off the second round of 4 treatments. Ipilimumab definitely prolonged my life but now I am searching for another trial. Val, stage IV
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- July 8, 2013 at 7:53 am
After reading anonymous's posts. I just have to say that she has no business talking about "quaint English." You write better English than 95% of us on this Forum. As a 72 year old who has done the IPI with success so far and with few side effects, I hope your father is able somehow to be persuaded to give it a try. In terms of alternative treatments, I am a strong believer in the positive effects of intense aerobic exercise and have recently read a scholarly meta-analysis that, though not centered on melanoma, finds good evidence for my beliefs in the literature.We seem to be talking about "intense" advisedly here, though.6 hours or more a week of running, swimming, etc. at 85% effort. Not for your usual Sunday driver. Reduced mortality rates are stunning.
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- July 8, 2013 at 7:53 am
After reading anonymous's posts. I just have to say that she has no business talking about "quaint English." You write better English than 95% of us on this Forum. As a 72 year old who has done the IPI with success so far and with few side effects, I hope your father is able somehow to be persuaded to give it a try. In terms of alternative treatments, I am a strong believer in the positive effects of intense aerobic exercise and have recently read a scholarly meta-analysis that, though not centered on melanoma, finds good evidence for my beliefs in the literature.We seem to be talking about "intense" advisedly here, though.6 hours or more a week of running, swimming, etc. at 85% effort. Not for your usual Sunday driver. Reduced mortality rates are stunning.
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- July 8, 2013 at 7:53 am
After reading anonymous's posts. I just have to say that she has no business talking about "quaint English." You write better English than 95% of us on this Forum. As a 72 year old who has done the IPI with success so far and with few side effects, I hope your father is able somehow to be persuaded to give it a try. In terms of alternative treatments, I am a strong believer in the positive effects of intense aerobic exercise and have recently read a scholarly meta-analysis that, though not centered on melanoma, finds good evidence for my beliefs in the literature.We seem to be talking about "intense" advisedly here, though.6 hours or more a week of running, swimming, etc. at 85% effort. Not for your usual Sunday driver. Reduced mortality rates are stunning.
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