Sree from India (now USA) - Dx 2008 - RIP 03/05/2012

[Fictional]

Hi Arch, I'm sorry to hear this.

'K' had some pop-up mets that did this after surgery and then stopped growing and I hope that for Sree.
You are in India, is that right? What drugs might you have available? We have heard lots of good things about Cediranib, but it may not be available where you are and it might be effective more for the larger ones (greater than 1.5 cm). By profile I think Pazopanib is similar to Cediranib (both get VEGFR 1,2,3 - I think) - pazopanib anecdotally has benefited at least 1 person with ASPS (that is why they specifically included ASPS in their solid tumor trials). Duration of benefit for pazopanib may be longer than sutent and the side effect profile looks better (some people really love that drug).

Difficult to know what inhibits new metastases. We got the feeling that ARQ197 inhibited new metastases in 'K', but it did not prevent growth of existing lung mets. 'K''s last definitely new lung met was one year or so ago. I don't know whether I would recommend in Sree's case though. Probably ARQ197 needs to be combined with another drug to get the small ones and the big ones.

R1507 seems to have halted the growth we saw during our metronomic trial, but only slight shrinkage in a few and not all. Some of the ones that appear smaller on R1507 are very small (2-3 mm) though, so that might bode for inhibiting new metastases. The mechanism (blocking IGF-like growth factor) is different from the anti-angiogenesis agents that might be effective mainly after the tumors get larger and have blood vessels grow in.

Another candidate drug is something like RAD001 or Afinitor / Everolimus. That has also generally been well tolerated, but rarely a reversible pneumonitis can occur (requires steroids), there are some mouth side effects, and there is risk of rebound growth if the medication is discontinued and nothing replaces it.

Another drug which is interesting and may also have a similar profile to Cediranib but be less toxic is ABT869. I don't know if that might be where you are. It is a Genentech drug. There are lots of trials in Japan I think and it looks promising. We can't get it here in the US yet.

'F'

[Arch]

Thanks 'F' for your reply. I did a google search on ABT 869 and can see some encouraging results on solid tumors. I will go and look for more information on that. Regarding Cediranib, it does appear that bigger tumors showed more dramatic shrinkage, but is there any evidence that it does not work on smaller tumors ? Maybe Bonni or Brian will reply to this post, but I thought they saw no new tumors and some small lung mets also disappear while on cediranib.
With all this optimism about cediranib, we too are inclined to trying it, irrespective of the additional logistical challenges that we face since we live in India.
I will let all of you know how things go for us. In the meantime, please do let us know if you have any inputs for us, we need to have alternative plans ready.

We have also sent the CT scan to Dr.Rolle and are waiting for his comments.

[Olga]

Arch - you might want to try to get Sunitinib as it is approved for other indications, there is a girl in NY on it that is stable for quite awhile, so it works for some ASPS patients. Also try to figure out if there are only a few faster growing mets - it happens with ASPS when some of them are stable and some start to grow - it is unknown why is it, either because of the location, or starting from certain size or may be they just happen to develop some specific mutation that speeds the grows, but anyways there are some mets that grow faster and they might need to be addressed specifically and then you get a time to try some systemic treatment. In some cases they can be ablated if they happened to be located in the favorable place for that, I have no idea if there is cryo or RFA ablation avail. in India but it is fairly available treatment in US and Canada now (even we have it in Vancouver now).
I was too suspecting that cediranib would not work on the smaller ASPS mets because there was an idea that their growth is VEGF independent as they are not vascular until more then 3-4 mm but I spoke to someone who was studying the very small mets and said that even tiny they grow tiny blood vessels and that they get vascular from the very small size.

[Bonni Hess]

Dear Arch,
I am so very sorry about Sree's most recent scan results which show some new lung mets as well as increased growth of at least one existing lung met. I know that this must be very discouraging for both Sree and you, but I am grateful that you are moving forward so quickly with exploring possible treatment options to try to stabilize the disease progression. 'F' and Olga have both offered some excellent treatment suggestions and input. The ABT869 certainly sounds promising, but I am personally unfamiliar with it. Regarding Brittany's Cediranib related tumor shrinkage and necrosis, her most recent scans showed dramatic shrinkage/necrosis of all of the targeted mets including a right middle lobe nodule which was previously 2.0 x 1.4 cm and is now 0.7 x 0.4 cm, a right middle lobe nodule which was previously 1.7 cm x 1.6 cm is now 0.4 x 0.4 cm, a right lower lobe nodule which was 1.7 cm x 1.5 cm is no longer visible!, the previously 3.8 cm x 3.8 cm pancreatic head solid mass is now 2.2 cm x 1.3 cm and cystic, and the previously 1.5 cm x 1.4 cm lateral fascia nodule is now nearly totally resolved. As you can see all of these nodules were previously between 1+ to 3+ cms, so perhaps 'F''s observation that Cediranib might be more effective for larger mets is correct, but I don't personally have any information to confirm or disprove this theory. We are certainly very excited and encouraged by Brittany's seemingly extremely positive response to the medication, but as both Olga and 'F' have reminded and cautioned us, the long term efficacy of the drug is still not known as it is still very new and still in Clinical Trial. Please let me know If there are any other questions that I can try to answer for you regarding Brittany's Cediranib experience and results thus far. Take care dear Arch and know that my special thoughts and best wishes are with Sree and your family. Please keep in touch as you are able and keep us updated on the results of Dr. Rolle's review of Sree's recent scans as well as your treatment decision.
Reaching out to share special caring thoughts and continued Hope,
Bonni

[Fictional]

In 'K''s situation, the fact that small lung mets grew (and new ones appeared) early in her diagnosis despite being on Sutent (stopped the primary from growing) suggested that the Sutent and similar drugs would be most effective on the larger ones, and when we molecularly profiled various lung mets (different sizes), the smallest ones were VEGF-negative, which suggested that they wouldn't respond to VEGF receptor blockers like Sutent or Cediranib.

What is nice to hear from Brittany's situation is that some mets dissolved on Cediranib until they were no longer visible. If a met is partially killed and gets below 1 cm, it may still be able to be killed off completely although it is small - either because the whole nodule changed once it became vascularized (positive VEGFR) or maybe the dying tumor released other toxic substances that helped kill the whole met.

BTW I was checking into Pazopanib, the specialty pharmacy that works through Blue Cross / Walmart pharmacies said they thought Pazopanib would be available in their pharmacy as early as the middle of next week.

[Arch]

Dear Bonni, Olga and 'F', Thanks,I really appreciate your inputs, gives me so much to think about. Maybe we should tackle the bigger, faster growing mets by Cryo or RFA and then consider a systemic treatment. When we spoke to the nurse at NCI, she told me that they see encouraging results so far with cediranib, they probably have 7 ASPS patients on the trial now, she could not comment on the size of the tumor vs effectiveness of the drug, which is our concern now, she however told us that Dr.Shivanni Kumar who is the principal investigator of this trial could answer those questions for us, but she would first want to see the latest CT scan. We'll try every possible route...I'll keep all of you updated.

[Fictional]

Just to give you a full background of information about cryo and RFA... there is a possibility that cryo and RFA can increase the chance of dissemination. It seems at least for ASPS that cryo and RFA can kill the tumor that is treated and the experience of the process is relatively simple, but I did read in the literature that at least in one study cryo had a slightly higher rate of presumed secondary metastatic complications compared to RFA (not ASPS). Cryo and RFA are different from metastatsectomy because in cryo and RFA the tumor is left in the body, but burned - for the surgery, the tumor is completely resected out and removed with a margin. With cryo / rfa is always a possibility that small tumor cells break off from the procedure and are carried to the liver or other parts of the body.

I don't know if Brittany's trouble with unusual locations of her metastases were due to the fact that she did not have lung metastasectomy / laser or otherwise - but had cryo / rfa instead. A woman who we met in Germany (with Rolle) had leimyosarcoma - also told us that she RFA to a lung met and the procedure was 'easy', but I subsequently learned she had a liver met within 6 months of the RFA procedure.Don't know if that is a coincidence or not. Because of the relatively slow pace of ASPS, I think it might be especially important with our cancer not to do a therapy that can contribute to spread to new organs.

The earliest cases on record with repeated lung metastasectomy in ASPS seemed like it could halt the spread of ASPS beyond the lung (at least suggested by UK's Judson data) at least for many years. They did not do cryo or RFA and had relatively disease stability. Again, I do not know that there is a bad effect of cryo or RFA, but it is something to consider. If you could keep ASPS from spreading beyond the lung, that is ideal.

Also I think initially Ivan had a very heavy tumor burden to the lungs, but has had no spread beyond the lungs and only repeated metastasectomies. Is there anyone on the list who has had cryo or RFA and not had a new site of a met in the following 6 months to a year or so?

Rolle suggested to us that 'K' have RFA to the two nodules she has > 1 cm, but we told him of our concerns about secondary dissemination.

[Olga]

I think that we did not have any people on the board that ever done cryo/RFA to a smaller met but only the lung mets that were in the critically big sizes when probably secondary dissemination has already happened as these mets were bigger then 30 mm and were very vascular by then and long sitting there. I think that the concern about cryo/RFA has something to do with the immune suppression from having the large necrotic mass in the body that is left after the ablation, not with the secondary dissemination during the procedure (and I read some article giving the advantage to RFA versus cryo in the liver from that point of view). RFA is widely used for colorectal lung mets and since these patients are a big group there is even some statistics done and they show the same survival advantage for RFA versus surgery dealing with the lung mets.
On the other hand, Arch, I support what Fernetter said about the dynamics - after the surgery the growth may speed up a little but wait to see the next scan, it can stabilize again and then Sree can get into the cediranib trial.

[Bonni Hess]

Dear 'F' and Olga,
You both make some very good points regarding Cryo and RFA, and 'F' you certainly raise some concerning questions regarding the safety of Cryo or RFA in regard to the possibility of the prodedures causing further dissemination of the disease. However, in Brittany's situation, she intially experienced metastasis to the liver and to the brain PRIOR to having undergone her first lung Cryo procedure in November 2004. After she underwent her lung RFA procedure in February 2008, she was diagnosed with new mets to her brain and lungs in May, and then mets to her pancreas, spleen, small bowel, and duodenum several months later, but we really feel that was the result of her large undiagnosed spinal tumor, which we subsequently learned was actually present PRIOR to her lung RFA, and which we think may have acted like a primary tumor spreading tumor cells into the bloodstream and throughout her body. You make a good observation 'F' regarding those who have had repeated lung metastasectomies without any further metastasis beyond the lungs, versus those who have undergone lung Cryo or RFA who did experience new mets in other parts of their bodies including Brittany and at least three other patients who I am aware of (tragically three of the patients have now succumbed to their disease). It is very difficult, as you say 'F', to try to determine if this is just coincidence, or if the dissemination to other parts of the body would have occurred anyway as a natural progression of the disease, but I certainly think that it is an issue which warrants further study and consideration before proceeding with Cryo or RFA. One note that should be made is that laser resection of the lung mets does not seem to prevent further growth of lung mets as, if I am correct in my observations, many (all?) of the patients who have undergone this procedure have had new lung mets appear within the first several months following the procedure. Unfortunately there does not yet seem to be any perfect or definitive answer as to the best approach for localized treatment of lung mets.
With special caring thoughts and continued Hope,
Bonni

[Fictional]

Thanks for the clarification, Bonnie.

Re: Rolle's laser work, I can only really tell you our impression because we personally looked at and mapped all of hers heading into surgery and after. Radiology reports are unreliable to go on...too vague.

Rolle removed more than we counted on spiral CT - a pretty good feat all-in-all, but after each surgery we noticed that he missed 1 nodule (fairly large one, too - but in a similar locations and deep - so that we think it may be a common place for them to be missed by his surgery..I think the blood vessels get in the way of feeling them). We did see some tiny ones grow after surgery..but when we went back to earlier scans, they were there, but just a speck and not distinguishable from normal tiny blood vessels.

The dilemma re: timing on metastasectomy, is that because the surgery seems to have a favorable course on the growth of disease (it slows growth down), do you do it early ...which would slow things down quicker, or do you wait because there may be small mets that are not detectable yet that will only become visible (and removable) by later surgery? I don't know if there is an ideal single answer to this question, but we chose to do the surgery as early as possible - and we know that she can have a 're-do' (at least that's what Rolle has said) if she needs to in the future. In the meantime, we have done clinical trials like ARQ197 and the R1507 that we hope would reduce microscopic tumor disease, new mets etc.

We definitely saw the growth of mets on the same side slow down after lung surgery (and probably to a lesser extent the opposite side), but at least in our daughter's case the growth did not completely stop, though it was pretty slow. There is data that repeated lung metastasectomy has a beneficial effect on the survival of sarcomas though - so the surgery can be seen as reducing tumor burden regardless if the resection is 'complete', and in some cases progressing to long term remission or clearance of disease with repeated surgery.

We never saw rebound increased growth (quick growth) after lung surgery. We only saw rebound increased growth after her large pelvic primary was removed. It might be that rebound effects could occur after surgery if a lung met was especially large. That may have happened to Lucio as I think the lung met that was removed was 4 cm. The kind of growth we saw in residual mets - was usually pretty slow (1 mm or so every few months) - but when Rolle missed an 8 mm or so one, that continued to grow - and now those are the ones (over 1 cm) that allowed her to get into her current R1507 trial. Her Rolle lung surgeries are now 9 months ago and 1 year and 2 months ago. Neither of those mets are in 'dangerous positions', but we don't want to let them get too big if we can help it. We are glad she only has one of those on either side and not 20.

Re: what you see on scans after Rolle surgery - we could see e.g. a met in the preop scans, and then post op, it was gone, and then a line of laser scar could be tracked to the outside of the lung. Over months these small scar lines tended to disappear, but on some of the really deep mets that were removed, 'K' still has a significant residual line or stellate scarring. It is usually easy to distinguish scar from round or oval mets, but occasionally it is a little confusing.

Olga, in case this extra bit of information might be helpful in the lung surgery thread, I will copy the relevant parts of this post there.

[Bonni Hess]

Thank you for all of the very helpful additional information 'F'. It would certainly be very interesting and beneficial if more patients who have undergone either metastasectomies (laser resection, VATS, or thoracostomy), or Cryo or RFA for lung mets would write to share their input and information for better evaluation/comparison of the results and outcomes of the procedures. A couple of additional points which I would like to share. Cryo or RFA can be used to try to destroy mets (usually no larger than 4 cm.) which are located in an unresectable location of the lung ( as was done in Brittany's case) if they are not located too close to an artery or an adjacent organ. Also, these procedures can be done even if there are existing mets in other parts of the body, unlike Dr. Rolle's procedure, for which it is my understanding, he will only accept patients with no other known areas of disease dissemination, which precluded Brittany from being a candidate for his treatment. We did raise the issue regarding our concerns about possible seeding of the tumor cells when the probe is withdrawn from the tumor through the lung tissue following either the Cryoablation (freezing) or the RFA (burning) of the tumor. We were assured that the probe is withdrawn through the same needle tract as it was inserted, and that there is no chance of seeding tumor cells with the probe from the treated tumor since the tumor cells will (theoretically) have been killed by the freezing or burning. A concern that we have with laser or surgical resection of lung mets is that because of the development of scar tissue from the procedures, there is a limit to the number of times that these procedures can be done, whereas, it is our understanding, that Cryo or RFA can be done as many times as necessary for the development of new lung mets. However, Cryo and RFA are limited to treating only a couple of nodules during each procedure, versus laser or surgical resection which can remove multiple nodules, so in the case of patients who have a very large tumor burden in their lungs, Cryo or RFA are not viable options. All of these factors certainly need to be addressed and considered before making the treatment decision.
With special caring thoughts and continued Hope,
Bonni

[Olga]

Getting back to the Sree's situation - as I remember Dr.Rolle was not sure from the very beginning that he might remove all the mets, that he will just make an attempt to remove as many as possible and all parties were expecting his surgery to be the bridge for the other treatments as they became available or to be the bridge for the second round of the surgeries. Of course I was in the same situation and every surgery we hoped that Dr.Rolle will produce the miracle and resect all mets but...Dr.Rolle can miss mets when the lung gets stiff and the lung gets stiff if the surgery goes long, as it often happens with multiple ASPS mets. There are different routes to go with the residual nodules and the plan depends on the rate of growth, what Dr.Rolle says re. repeated surgery - is it possible, when? availability of the skilled RFA/cryo interventional radilogist locally and if these nodules are accessible for the ablation, what are the conditions of the enrollment into cediranib trial - do they require any nodules to be bigger then 10 mm?
Generally, ablations have to be reserved for the unresectable situations as being less reliable that all targeted tumor is gone. But if it might be a tactical advantage, can buy a time until the next surgery for the rest of the lung mets and give the lung the time to recover then it might be justified?

[Arch]

Olga is right, we always knew that its not a complete resection, but somehow we were hoping that we wouldn't see anything big, there are limitations even with the laser technique and we beleive Prof.Rolle did whatever best he could. We are now understanding what our options are and we need to take a well informed decision,thanks for your inputs.

We found out that anything that's commercially available in the US can also be got here in India. So we might get pazopanib right here. For the cediranib trial, you need to have atleast one 10mm nodule, I think Sree already has it, so he may qualify for that also. We are still waiting to hear from Prof. Rolle, if he says he can do a redo, we might still want to try some systemic treatment and then go for the redo. We also happened to talk to an interventional radiologist last week and RFA is widely available here. Having said all that, I feel that our real concern is not those 1or 2 nodules that are big, we probably can take care of that, we need to stop new metastasis from growing, we need to control the small mets. We still don't know what might help in controlling that. As 'F' suggested, maybe ARQ 197 or maybe R1507 ?? From your discussion it appears that VEGF inhibitors may not help here, I'll check that with Dr.Kumar.

[Amanda]

Hi Arch,
I just wanted you to know that i am thinking about you both and i hope that what ever treatment you chose it will work well
I am at a stand still in what i feel about the two things in my left lung and i may ask for another surgery to have then removed then i will be clear *I hope* and stronger to fight what ever comes up next.

How are you two holding up emotionaly thru this and is he still working?

In healing hopes for all with cancer!

Amanda

PS.. Arch, i just did a google search and though this is from 2007 it explaines a lot of stuff in it and then if you like how one works you can google for more up dated info http://www.icr.ac.uk/about_us/annual_re ... t/9718.pdf
again, this is from 2007 but it helped me and i am still so new at this it helped me

[Amanda]

Dear Arch and Sree,
I have had you both in my thoughts the last few days! I hope that all is going ok and would love ot hear how Sree is feeling.
How are you holding up Arch and how is the lil one? Did you all have a nice new years? So many questions i know but i feel as if i have been gone for a year because fr the last five weeks i have been so drugged *sigh* Anyhow, when you have time post please and i just wanted you both to know that you are both in my mind and heart even if i have been so silent...

In healing hopes for all!

Amanda