Dear ASPS Community Friends,
A 21 year old ASPS patient who was diagnosed two years ago seems to be having a successful response to her Sutent treatment which she has been receiving for the past six months. Her most recent scan results which she received on Tuesday encouragingly showed no new tumors, no increased growth in the size of her lung mets, and shrinkage in some of them. If you would like to follow her journey or contact her you can visit her blog at http://LCMA.blogspot.com .
With special caring thoughts and continued Hope,
Bonni
Sutent
-
Bonni Hess
- Senior Member
- Posts: 1677
- Joined: Mon Aug 14, 2006 11:32 pm
- Location: Sammamish, WA USA
Note of caution re. Sutent/new publications
There is a new article at the Cancer Cell, Volume 15, Issue 3, 232-239, 3 March 2009
http://www.cell.com/cancer-cell/abstrac ... 09)00029-4
Summary
Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible metastatic conditioning in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.
The article is written by the senior scientist Dr. S. Kerbel from the Sunnybrook Health Sciences Centre, Toronto, Canada. Dr. Kerbel is wide known as a a co-pioneer of metronomic chemotherapy and for his groundbreaking work in tumour angiogenesis done with the J. Folkman, Dr. Kerbel is a current Canada Research Chair in Tumour Biology, Angiogenesis and Antiangiogenic Therapy, Tier 1. This is the link to his profile: http://www.sunnybrook.ca/team/member.as ... e=185&m=96
It is hard to say if this mechanism of accelerating of the metastatic tumor growth and decrease overall survival will be the same in human as it is found to be in mice, also if the trend will be the same across different cancers and different stages of disease. As I understand the situation, there are published results of the clinical trials that sunitinib prolongs progression free survival in some cancers (RCC, GIST) and there is an evidence of it prolonging the overall survival in some cancers (CRC). There are some documented cases of the response to it in ASPS (shrinkage and stable disease) and it seems that it prolongs PFS (progression free survival) although there was no registered trial done. There is no information if it will also prolong an OS (overall survival) or its positive effect will be eliminated by the negative effect of a type that was described by the Dr.Kerbel in this new article. Currently Sutent is being used in ASPS patients on a compassionate basis off label with the hope that its beneficial effect as found in the renal cell carcinoma will be realized in an ASPS as well but RCC is a faster growing and overall different disease.
There are a few related supporting articles in the same issue of Cancer Cell:
http://www.cell.com/cancer-cell/abstrac ... 09)00040-3
Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited
Clinical practice reveals that therapy with angiogenesis inhibitors often does not prolong survival of cancer patients for more than months, because tumors elicit evasive resistance. In this issue of Cancer Cell, two papers report that VEGF inhibitors reduce primary tumor growth but promote tumor invasiveness and metastasis. These perplexing findings help to explain resistance to these drugs but raise pertinent questions of how to best treat cancer patients with antiangiogenic medicine in the future. We discuss here how VEGF inhibitors can induce such divergent effects on primary tumor growth and metastasis.
and
http://www.cell.com/cancer-cell/abstrac ... 09)00034-8
Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis
Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.
all of these articles represent a real warning that until there are phase 3 studies that are done to confirm that the treatment with some of the targeted therapy drug is really able to increase the OS (overall survival), it is unreasonable to assume that it will do so only based on a fact that it increases the PFS (progression free survival).
http://www.cell.com/cancer-cell/abstrac ... 09)00029-4
Summary
Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible metastatic conditioning in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.
The article is written by the senior scientist Dr. S. Kerbel from the Sunnybrook Health Sciences Centre, Toronto, Canada. Dr. Kerbel is wide known as a a co-pioneer of metronomic chemotherapy and for his groundbreaking work in tumour angiogenesis done with the J. Folkman, Dr. Kerbel is a current Canada Research Chair in Tumour Biology, Angiogenesis and Antiangiogenic Therapy, Tier 1. This is the link to his profile: http://www.sunnybrook.ca/team/member.as ... e=185&m=96
It is hard to say if this mechanism of accelerating of the metastatic tumor growth and decrease overall survival will be the same in human as it is found to be in mice, also if the trend will be the same across different cancers and different stages of disease. As I understand the situation, there are published results of the clinical trials that sunitinib prolongs progression free survival in some cancers (RCC, GIST) and there is an evidence of it prolonging the overall survival in some cancers (CRC). There are some documented cases of the response to it in ASPS (shrinkage and stable disease) and it seems that it prolongs PFS (progression free survival) although there was no registered trial done. There is no information if it will also prolong an OS (overall survival) or its positive effect will be eliminated by the negative effect of a type that was described by the Dr.Kerbel in this new article. Currently Sutent is being used in ASPS patients on a compassionate basis off label with the hope that its beneficial effect as found in the renal cell carcinoma will be realized in an ASPS as well but RCC is a faster growing and overall different disease.
There are a few related supporting articles in the same issue of Cancer Cell:
http://www.cell.com/cancer-cell/abstrac ... 09)00040-3
Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited
Clinical practice reveals that therapy with angiogenesis inhibitors often does not prolong survival of cancer patients for more than months, because tumors elicit evasive resistance. In this issue of Cancer Cell, two papers report that VEGF inhibitors reduce primary tumor growth but promote tumor invasiveness and metastasis. These perplexing findings help to explain resistance to these drugs but raise pertinent questions of how to best treat cancer patients with antiangiogenic medicine in the future. We discuss here how VEGF inhibitors can induce such divergent effects on primary tumor growth and metastasis.
and
http://www.cell.com/cancer-cell/abstrac ... 09)00034-8
Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis
Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.
all of these articles represent a real warning that until there are phase 3 studies that are done to confirm that the treatment with some of the targeted therapy drug is really able to increase the OS (overall survival), it is unreasonable to assume that it will do so only based on a fact that it increases the PFS (progression free survival).
Olga
-
Fictional
Re: Sutent
As mentioned in the other published studies, these new studies should urge caution, but there is fairly extensive evidence for anti-angiogenesis agents being net beneficial for cancer patients with vascular tumors, and these new publications appear to be mouse and dish studies, not ones in humans. There are many studies in which something happens to mice, but not to humans.
It would be wise for clinical research trials with anti-angiogenesis agents to make sure they are still collecting data from patients after they have left studies, but also it is possible to overreact to these two new non-human studies too - especially as it seems as if there are many patients with long lasting benefits and no anecdotal human reports of worsening disease from these agents. It is possible that the benefits still outweigh the risks. Perhaps a hard search will be made to look for possible subpopulation of patients who do better or worse with these new classes of drugs.
Avoidance of any therapies besides surgery could also increase the risk of microscopic spread / metastases. That is the terrible dilemma that ASPS patients are in - better to do no systemic therapy if possible harm could result, or to try one that has a reasonably safety profile? Ultimately the uncertainty factor for doing something or doing nothing is significant both ways.
It would be wise for clinical research trials with anti-angiogenesis agents to make sure they are still collecting data from patients after they have left studies, but also it is possible to overreact to these two new non-human studies too - especially as it seems as if there are many patients with long lasting benefits and no anecdotal human reports of worsening disease from these agents. It is possible that the benefits still outweigh the risks. Perhaps a hard search will be made to look for possible subpopulation of patients who do better or worse with these new classes of drugs.
Avoidance of any therapies besides surgery could also increase the risk of microscopic spread / metastases. That is the terrible dilemma that ASPS patients are in - better to do no systemic therapy if possible harm could result, or to try one that has a reasonably safety profile? Ultimately the uncertainty factor for doing something or doing nothing is significant both ways.