Cure Alveolar Soft Part Sarcoma International (iCureASPS)

It's been a while that I wanted to post this abstract of a presentation on ASPS at the 2010 German Cancer Congress (http://dkk2010.de/). The authors conclude that Trabectedin, Everolimus and Sorafenib seem to be active in ASPS.

I guess the findings don't make these agents a first choice-treatment, since, at best, stabilization could be reached. But perhaps it could make sense to imagine e.g. a combination of Everolimus with an anti-angiogenic agent!?

New therapeutic options in the treatment of alveolar soft part sarcoma (ASPS)
Bertz J, Pink D, Busemann C, Bitz U, Richter S, Rahm J, Schoeler D, Reichardt P

Background: Alveolar soft part sarcoma (ASPS) is a rare malignant soft tissue tumor
often occurring in young patients. Although it shows an indolent slow-growing clinical
course, its prognosis is usually poor, especially if complete surgical resection is not
possible, with a characteristic late appearance of metastases. Since standard
chemotherapy regimens used for the treatment of other soft tissue sarcomas lack
efficacy in ASPS, new therapeutic options are needed. Recently, responses to
sunitinib were reported in three patients.

Methods: All patients with metastatic ASPS that were treated in the last 4 years in the
Sarcoma Center Berlin-Brandenburg and the University Hospital of Greifswald were
screened for “new treatments” in our sarcoma database of more than 2000 sarcoma
patients. 8 patients with ASPS were treated with either Trabectedin, Everolimus or
the multi kinase inhibitor Sorafenib. Of 6 patients receiving Trabectedin, 3 patients
had been pretreated with conventional chemotherapy, one had been treated with a
monoclonal IGF1-antibody and two patients received Trabectedin as first-line
therapy. Everolimus was given once as first-line therapy and twice after progression
under other chemotherapy. The application of Sorafenib was realised in one patient
as third-line therapy.

Results: One patient treated with trabectedin is too early for evaluation. In all other 5
patients, a disease stabilization (SD according to RECIST) was reached under
treatment with trabectedin. Median progression free survival (mPFS) in these 5
patients was 7 months (3+, 4, 7, 14, 23 months, respectively). All three patients
treated with Everolimus are still alive. One patient progressed after 9 months, and
two are stable on continuous treatment for 18+ months. The application of sorafenib
resulted in disease stabilization lasting 5 months in one patient. All of the above “new
treatments” have been well tolerated with no high-grade toxicity.

Conclusions: The poor prognosis of patients with ASPS is due to the unavailability of
effective systemic treatment options. We report about three new promising
therapeutic options in patients with ASPS: Trabectedin, Everolimus and Sorafenib. All
three agents seem to have antineoplastic activity in ASPS and are able to induce a
stabilisation of the disease. Further studies with larger patient numbers are
necessary to better evaluate the efficacy of these agents.

Thanks for posting this, Johannes. This is great news.

We considered Afinitor in the past and even went so far as having it ordered to the pharmacy, but then our daughter got into the R1507 trial and now we are doing crizotinib.

Afinitor really has an excellent side effect profile. It makes me wonder if it might be more effective than Sutent? Or similar?

Because Afinitor is FDA-approved, it is another option besides Sutent, and something that could be consider in the rotation if Cediranib stops working, etc.

p.s. Afinitor or Everolimus (used to be known as RAD001) IS an antiangiogenesis agent. Theoretically, it could still cause the rebound problems when it is discontinued - but I don't think it's quite the problem as in the old days when no antiangiogenesis agents were commercially available - so if you came off a study, you weren't on any drug, and so the rebound could be particularly marked. If you came off Afinitor, you could switch to Sutent for instance.

Afinitor is an early generation mTOR, and at least theoretically some of the later generation drugs may be more effective because they can inhibit TORC1 and TORC2.

It is nice to hear but I do not know how it is going to be implemented in practice - it looks like after being on the one of the trials until the progression you could switch between sunitinib (Sutent), Everolimus (Afinitor ), Sorafenib at last but how to get insurance to pay for it and the oncologist to prescribe it - as our oncologist say, there is no proof that some stability will translate into prolonged survival. I have seen a study in RCC for everolimus where previous sunitinib was the risk factor for decreased survival time.

Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors.
http://www.ncbi.nlm.nih.gov/pubmed/20549832
"Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01)."
It is hard to figure out what to make off it - either previous sunitinib decreases the efficacy of everolimus, or the people that progress on sunitinib are more likely to progress on everolimus...It might be also important which one goes first etc.

In the US, doctors can (usually) order any off-label drugs and have them covered by insurance - but I realize insurance companies are getting more aggressive about what they authorize.

For a rare cancer, having a published abstract or email from an established expert or investigator can help the drug be paid for by insurance.

Publications support the use of Cediranib, Sutent, Afinitor, and Trabectin now for alveolar soft part sarcoma. They also support repeated metastasectomy and cryoablation.

The questions you raise about survival are good ones.

To answer that you have to think about what can kill you. I'm sorry to be blunt other readers, but this is what we have to consider when making all these tough decisions. And the main goal is to know what can kill you so you can avoid it.

Olga I know you know all this, but will recap here for other readers. Based on my understanding (which is definitely limited) - ASPS can kill you with new metastases into vital organs - so that could be a met to the brain, a met to a vital organ that can't be resected, or overwhelming metastases throughout the body. The primary seems to be the worst for spreading new metastases, so that's why if you can removing the primary is a priority. Most of the metastases after the primary has been removed seem to be in the first 2 years, but in the literature, mets have occurred years or decades after the primary has been removed.

In the lungs, mets are usually deadly with overwhelming seeding, but more commonly if the tumor presses on vital (usually central structures) - like growing into the heart or pulmonary vessels, collapses the main bronchus etc. There is an idea that having a solitary or a few really large tumors is not a good idea because it may be immunosuppressive - and make it more likely for other tumors to grow, but it is not known whether this is a common reason for people to die from disease. There are 15 year + ASPS survivors with large tumors that seemed to have stop growing. I think Clare's after Cediranib was 4 cm (had been 6 cm I think), and Andreas said his inoperable lung met was the size of a quarter. So it is possible to have lung mets that aren't growing much that won't kill you. Some mets are more important than others - those that can press on major structures.

Also in the lungs, blood vessels are end arterioles, so at least one oncologist told me mets in the lungs won't seed to the rest of the body. The one exception case may be if RFA to the lungs may cause seeding. We've talked about this before - based on Brittany's experience.

So when the question is whether medications can extend survival - I don't know whether comparing the results in other cancers is completely applicable. If it keeps a large tumor from pressing on something vital, I would think it is beneficial. But if most of the mets are peripheral, it may not make a difference especially if the tumors are very slow growing. In the case that disease has already spread to an important organ like the pancreas, I would have to think that inhibiting growth or shrinking tumors has to be a good thing. It is not as clear if a person only has mets confined to the lungs and none are in dangerous places.

For ASPS there is data supporting long term survival with repeated surgeries only as well as a mixture of clinical trials drugs.

Re: Overall survival - there are reports that antiangiogenesis agents increase overall survival for other tumors. I haven't don't an exhaustive search, but here's one link - http://cancerology.blogspot.com/2010/07 ... eatic.html
Sutent improved progression-free survival as well as overall survival for pancreatic neuroendocrine tumors something like 90% survival vs. 70% survival. In the data you mention, Olga, the lower overall survival might also include people who progressed on Sutent - and so it could have included more aggressive or disseminated cancers.

I was not at all talking about the whether this 3 medications can extend survival but that we should not assume that even if each of them can extend survival given separately, the sequence of them will work the same way.
Generally, we can not apply the statistics data from other cancers to ASPS, because if the survival time is really short overall, like in some of the aggressive cancers, only a few months, stopping a growth for a few month to a year will increase the overall survival. If the survival time is long overall, it is less obvious what the result will be as the period of no growth might be followed by the period of the speedy growth when the resistance develops.
We hope that the consequently taken some other drug (without delay), that was found to be able to stop the growth for awhile, will be able to add its time and so on - every time buying add.time as long as there is a choice of the drugs.

But the article I quoted seems to contradict to the idea as people being previously on sutent fared worse on Everolimus, I was not at all talking about sutent being able to increase the overall survival but about this particular sequence being noted to decrease the overall survival. We should not assume that 1+1=2 esp. in ASPS. And I thought that RCC is the closest cancer that can be used for a reference.