An Update and What We Learned at Cincinnati Children's Hospital Thursday

Thursday, we met with a pediatric oncologist, radiation oncologist, and pediatric surgeon at Cincinnati Children's Hospital. We decided to consult with their team regarding how best to proceed regarding Brody's treatment. We chose Cincinnati Children's due to the larger number of clinical trial options available for recurrent rhabdomyosarcoma. They certainly seem to have a greater number of options for us than anywhere else right now. I have been very impressed indeed by the care and attention we received from Cincinnati Children's. It's a great hospital with an absolutely exceptional pediatric hematology/oncology team.

The tumor board at Cincinnati Children's Hospital reviewed Brody's case this week. The meetings we had Thursday were to discuss the group's findings and conclusions with myself, Bill, and Brody. My mom and dad traveled with us to the hospital Thursday and did a great job keeping Brody entertained and happy when the doctors were discussing items that may not be the best news for little Brody to hear at this point. I am quite glad my parents were able to do this for us. Some of the discussions we had to have were definitely not ones I wanted Brody to hear.

The oncologist at Cincinnati Children's Hospital told us several things we really did not want to hear. We learned that Brody's tumor has now infiltrated into the spinal column and there is a suspicious spot on his lung that may be tumor but they aren't sure yet. We were informed that the tumor board at Cincinnati Children's Hospital considers Brody's cancer to be incurable and that it is extremely unlikely that Brody will beat cancer. (This is not the first time we've been told this but it still hurts to hear it again). We were told that we had pretty much done every standard treatment for recurrent rhabdomyosarcoma and that his tumor has been exposed to a tremendous arsenal of chemotherapy agents but yet his tumor still continues to progress. He reassured us that Brody's treatment regimens have been absolutely appropriately chosen. He let us know that we have basically three options as far as chemotherapy at this point: 1) Phase 1 trials, 2) No further Chemotherapy (and possibly no further treatment other than comfort care, 3) Treatment not within a clinical trial. He assured us that any of these options would be appropriate for Brody and it's a very tough decision to make as to how to proceed at this point. He let us know that surgery and radiation treatments may still be an option for Brody too. But the important question is whether or not we should put Brody through another surgery and radiation treaments again. Will it provide him with any significant improvement in quality of life? It's hard to say this is something worth pursuing knowing that the tumor cannot be completely removed surgically and that it will certainly continue to grow and recur. It's more reasonable to consider if a chemotherapy option is found that significantly slows or stabilizes the disease and that we could expect a significant increase in the amount of time and quality of life for and with Brody. It was also discussed that radiation treatments could be done to the spinal column area to decrease the size of the tumor in that area to help improve Brody's symptoms. Fortunately, although Brody's tumor has entered the spinal column, it is not yet touching the spinal cord. Radiation treatments would not be possible around the spinal cord. We were surprised to learn that the radiation oncologist at Cincinnati Children's Hosptial still felt Brody could benefit from radiation treatments. When Brody's tumor recurred, it came back growing right in the pins that were used to mark where exactly to deliver his previous radiation treatments. The tumor was concentrated in an area that was known to have been hit very hard with radiation already. But we were told that sometimes, radiation treatments may still work anyway in cases like this. I guess we won't know until we try it. (Brody's radiation oncologist in Toledo did not feel that Brody's recurrent tumor would respond to further radiation treatments). We were also informed that if we decided surgical resection or debulking of as much as possible of Brody's tumor, that the radiation oncologist would have the surgeon place a "sleeve" to pull the bowel away from the area where the tumor is removed. He would want to do this so that radiation treatments could follow after Brody has healed from surgery to the area the tumor had been before surgery. The bowel cannot withstand very large doses of radiation and so if they can pull the bowel away from this area then they could provide higher amounts of radiation treatments.

The oncologist at Cincinnati Children's Hospital discussed each of the Phase 1 trials he felt would be most appropriate for us to consider for Brody. Two of them would be offered at Cincinnati Children's and one of them is offered in Columbus, Ohio at Nationwide Children's Hospital.

The first trial the oncologist told us about combines the novel drug, Crizotinib with conventional chemotherapy. The trial number is ADVL1212. He felt this trial may be of particular interest for us to consider because the conventional chemotherapy used in it is a combination Brody has not yet tried. The "conventional chemotherapy" in this trial is the combination of Topotecan and Cyclophosphamide. Brody has, however, taken Irrinotecan which is very similar to Topotecan. And, Brody has taken A LOT of Cyclophosphamide. Brody was not taking cyclophosphamide though while he was on irrinotecan. He was taking Vincristine and irrinotecan together. The tumor grew very quickly when he was on this combination. So, initially I was not very enthusiastic about this trial even though it did add a novel drug with some exciting potential for treating rhabdomyosarcoma into the mix of agents that Brody has been exposed to before or exposed to a very similar drug. Crizotinib is a medication that is one I have been certainly wanting to have Brody try but I was hesitant about the idea of the combination of Topetecan and Cyclophosphamide due to Brody's lack of response in the past to irrinotecan and that he has been taking cyclophosphamide for a long time and yet the tumor is growing. (I do think it would be growing a lot faster without the cyclophosphamide though). After giving it some more thought though, I do think this trial is one that is worthy of consideration for Brody. There have been cases of tumors responding to Topotecan that did not respond to Irrinotecan. In fact, there are trials that combine both of these drugs into the same regimen even though they are very similar medications since if a tumor is resistant to one it may not still be resistant to the other. So maybe Topotecan is worth a try. Crizotinib is a tyrosine kinase inhibitor, which inhibits anaplasitc lymphoma kinase (ALK), Hepatocyte Growth Factor Receptor (HGFR, C-MET), and Recepteur d'Origine Nantais (RON). ALK gene abnormalities due to mutations or translocations may result in expression of oncogenic fusion proteins (eg, ALK fusion protein) which alter signaling and expression and result in cellular proliferation and survival in tumors which express these proteins. ALK expression is found in 15-32% of embryonal rhabdomyosarcomas and 45-81% of alveolar rhabdomyosarcomas. (Brody has embryonal rhabdomyosarcoma). Because ALK is normally only expressed in embryos and neonatal brain tissue, any expression after birth in any tissue other than brain tissue is abnormal. The N-methyl-N-nitroso-guandine human ostesarcoma transforming gene (MET) receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are over-expressed in a variety of cancers and involved in cell growth, invasion, metastasis and angiogenesis. This is more of a potential target in aveolar rhabdomyosarcoma than in embryonal rhabdomyosarcoma. Over-expression of MET/HGF is more common with aveolar rhabdomyosarcoma. Interestingly, though in other cancers (glioblastoma, for example) patients that have been exposed to bevacizumab (which Brody has taken this for over a year), the MET/HGF pathway plays a critical role in invasion (metastasis) when vascular endothelial growth factor (VEGF) has been inhibited. Bevacizumab is a VEGF inhibitor. Blocking VEGF is a mechanism to block angiogenesis (formation of new blood vessels....tumors can't continue to grow if they can't form new blood vessels to supply them). HGF is a protein that controls the growth and movement of cells. VEGF can decrease HGF signaling. So if VEGF is inhibited by Bevacizumab, there is increased HGF signaling through its receptor MET. For patients with glioblastoma it was found that combining VEGF inhibition and MET inhibition allowed patients the benefits from bevacizumab without developing more invasive tumors. Because, VEGF and HGF/MET signaling pathways are active in a variety of tumors, this combined treatment strategy may also apply to other types of cancer. Since Brody's tumor has been exposed to a VEGF inhibitor (bevacizumab) for quite some time, maybe now the HGF signaling through MET is amplified in his tumor? This, as explained, can lead to increased potential for metastases. A means to block MET/HGF signaling may be very important in treating Brody's tumor. Recepteur d'origine nantais (RON) is a receptor tyrosine kinase closely related to MET. Both receptors are involved in cell proliferation, migration, and invasion, and there is evidence that both are deregulated in cancer. A small-molecule dual inhibitor of RON/c-Met has the potential to inhibit tumor growth and could therefore be useful for the treatment of patients with cancers where RON and/or c-Met are activated. So, anyhow, I am interested in possibly pursuing this trial for Brody. However, the trial is currently closed. The oncologist at Cincinnati Children's said if we decide we should want to participate in this trial, to let him know and our name can be added to the waiting list for it. He explained that this trial will open back-up again but he could not give us a timeline for when this would happen.

The second trial the Cincinnati oncologist told us about is a Phase 1 trial study of TEM-1 antibody, MORb-004 (IND# 103821) now known as Onutuxizumab, in children with relapsed or refractory tumors. The study number is ADVL1213. The oncologist explained that Onutuxizumab is a monoclonal antibody directed against endosialin, a cell surface glycoprotein, which is expressed on cells involved in tumor vasculature. Studies have found endosailin to play a key role in tumor growth and new blood vessel formation in numerous cancer types. He also cautioned that unfortunately only about 60% of rhabdomyosarcoma cells express endosailin. He stated, "it would be more encouraging if it were more ubiquitous in rhabdomyosarcoma." But he also stated, "60% is also not insignificant." This trial is also not open at this time but we can be added to a waiting list for when it opens should we decide to pursue this option.

The third Phase 1 trial explained to us is no longer offered at Cincinnati Children's Hospital but is still offered at Nationwide Children's Hospital in Columbus, Ohio. This trial uses the oncolytic virus HSV-1716 which is a mutated version of the herpes simplex virus which has been demonstrated to selectively infect cancer cells rather than normal cells. Here is a link with information on this trial.

http://clinicaltrials.gov/show/NCT00931931

The Cincinnati oncologist explained that unfortunately so far the human clinical trials have not been nearly as exciting as the pre-clinical and animal studies. It has not yet cured any of the children that have participated in this trial. And, so far there has only been one child with rhabdomyosarcoma that has participated in this trial. This was a 13 year old who received this treatment back in 2010. A phase 1 trial is a dose-finding trial though. Maybe the correct dose has not yet been given? Phase 1 trials start with low doses and then work upwards. The trial enrolls three children at a time and tests the effects of one dose on each child. If that dose is tolerable then the next set of 3 kids receive a higher dose. It could be more effective as dosages increase. At least I really hope so, anyway. That would be seriously awesome if it worked one day.

We also discussed a little more about the pros and cons of molecular profiling and gene sequencing of cancer cells. I posted in a previous blog post about the opinions concerning this topic of the Cincinnati oncologist. He is not overly impressed so far with the information gained from doing this. Nonetheless he did send a previous biopsy sample of Brody's to have some focused molecular profiling done. He expects the results on this within 2 months and hopes it will provide some useful information to guide decisions later on down the road for us. We did talk to him about having GeneKey do the complete genome on a new biopsy sample. He did not feel that this would provide us with usable information. Basically he felt it would be too much information and that the likelihood is small of drugs being available to act on the pathways that may be shown to be involved in Brody's tumor. I do understand that there is a huge chance that we will not be able to get actionable information from proceeding with GeneKey. But, I can't not try. So I will likely move forward with this analysis anyway.

The news yesterday that Brody's tumor has now infiltrated the spinal column was startling, scary, and certainly surprised us. Apparently each of his CT scans since September show the tumor now within the spinal column. And, unfortunately each scan since September shows it getting a little bigger in this space with each scan. The radiologist at Cincinnati Children's Hospital made this discovery when reviewing the CT scans sent from Toledo Children's Hospital. Nobody from Toledo Children's Hospital had told us that Brody's tumor had infiltrated the spinal column. The Cincinnati team did tell us that it was an "easy miss" not to see it and at first their team did not see it either. In the most recent CT scan it appears there is significant pressure on the nerves within the spinal column. Brody has been having symptoms consistent with these nerves being under pressure. These include: inability to fully empty his bladder, intense shooting pains in his left leg, muscle spasms, and incontinence. He has been having trouble emptying his bladder fully for the past 3 weeks. We have to tell Brody to try to go pee every 30 minutes during the day and then we are now up to letting him go about every 4 hours overnight (compared to every 1 to 2 hours overnight, this is a blessing). If Brody doesn't keep up with this frequency he becomes fluid overloaded and unfortunately the excess fluid tends to accumulate in his groin area. This has caused him very significant discomfort. Three weeks ago Brody was having issues with bowel incontinence. This fortunately has improved and has not been a problem for the past 2 weeks. His muscles spasms seemed more frequent three weeks ago compared to the past 2 weeks too. Of special importance to noticing this, is that Brody received high dose IV cyclophosphamide in addition to temsirolimus and vinrelabine that he normally receives weekly. The cyclophosphamide may have made a difference if we go by symptoms. Also, his bladder emptying started to improve about 5 to 6 days after the cyclophosphamide dose. Then it was stable for awhile and then started becoming more problematic recently (and by recently, I mean just before being due for his next round of IV high dose cyclophosphamide). This makes me think maybe we don't have full resistance to cyclophosphamide and that is still somewhat effective.

Brody has also been having more frequent episodes of random and intense pain in his abdomen. He says these are not his usual pains but different and worse than his "normal" belly pains. He frequently has problems with gas pains, constipation, diarrhea, and nausea. These are fairly normal belly pains for Brody. But lately, he has had a lot more episodes of belly pains that are very intense pain located at the top of his abdomen in the center just below his heart. This morning was a heart wrenching drive into the hospitial as Brody's belly was hurting very bad and he was screaming and crying all the way, "Mommy, please help me!!! Mommy, Mommy, Mommy, It HURTS!! My Belly!!." He was in obvious tremendous pain and I could not do anything to make it stop. Then he started vomited too. It was awful! The vomiting was on top of the pain. The pain was not because he had to vomit. He was still in a lot of pain even after vomiting. Somehow, the pain just finally stopped. Thank Goodness!! This episode lasted for about 45 mins this morning but believe me it felt more like 5 hours to me. I can't imagine how long it must have felt for Brody. I was then physically ill from the stress of the whole event. After Brody finally was better, I was so sick from the stress of it all that I ended up vomiting three times myself before I finally calmed down. I was in utter panic inside. Brody regularly has multiple belly pains each day. But for him, he considers it part of his normal daily life and he is able to cope with them and bare it expecting it to soon go away. He is tremendously strong and a brave young boy with regards to this. Today was different. He was in a panic too and so scared. It was obviously not like anything he normally deals with each day. (He doesn't make a big deal of vomiting either and he didn't today when it was happening on top of all the pain he was experiencing either). He has had some shorter (couple of minutes) episodes of worse than normal pains the past couple of weeks. These were scary too but not like today. I was especially panicked after hearing all the news yesterday at Cincinnati Children's. My mind was going places I did not want it to go. I was thinking, "This is it! It's over! We are going to lose him and watch him suffer terribly first and not be able to do a thing about it!" I fear the suffering far more than his death. Seeing your child go through so much pain is so incredibly awful! I don't have the words.

Yesterday, I talked with our oncologist at Toledo Children's Hospital. He was surprised too to learn that Brody's tumor has infiltrated the spinal column. It was not in the radiologist reports and is not entirely obvious. This knowledge especially helps explain why Brody has had such trouble lately with emptying his bladder. Without knowing this, we were getting very suspicious that it was the temsirolimus he had recently started that was causing the problems. Looks like this is likely not the culprit now.

Temsirolimus is a promising biological in the "war" against rhabdomyosarcoma. Temsirolimus inhibits mTOR signaling, halting the cell cycle at the G1 phase in tumor cells. Cells that are stuck in G1, cannot divide. mTOR inhibition also exhibits anti-angiogenesis activity by reducing levels of HIF-1 and HIF-2 alpha (hypoxia inducible factors) and vascular endothelial growth factor (VEGF). The mTOR pathway has been demonstrated to be aberrantly activated in rhabdomyosarcoma. Temsirolimus also inhibits the Hedgehog pathway. Activation of the hedgehog pathway has been implicated in the development of a variety of cancers. Abnormal activation of the pathway probably leads to development of disease through transformation of adult stem cells into cancer stem cells that give rise to the tumor. A recent study showed that approximately 30% of embryonal rhabdomyosarcomas contain an altered Hedgehog pathway signature consistent with activation of the pathway. (In contrast, the hedgehog pathway is not known to play a significant role in aveolar rhabdomyosarcoma). Since temsirolimus may be targeting some attractive targets in Brody's tumor, I do not want to stop giving Brody this medication as long as he is tolerating it okay and we suspect it may be helping.

The combination of temsirolimus, topotecan, and cyclophosphamide have been used together tolerably. Since Brody has not tried using topotecan and cyclophoshpamide both together and he has been tolerating temsirolimus fine, we have decided to try switching Brody over to using these three medications in combination rather than the vinorelabine, temsirolimus, and cyclophosphamide he is using now. I spent some time researching yesterday various doses and schedules of this combination that have been used especially with respect to the topotecan and cyclophosphamide together. Numerous doses and schedules have been shown to be ineffective in rhabdomyosarcoma when using topotecan and cyclophosphamide together. However, I did find a study that had very encouraging results when using a set dose of cyclophosphamide and topotecan on days 1 thorugh 5 of a 21 day cycle. We will be sure to follow the dosing and schedule of this study for Brody's regimen. (There is a Phase 1 trial in San Francisco for recurrent rhabdomyosarcoma that combines Sirolimus (the active metabolite in temsirolimus), topotecan, and cyclophosphamide. After reviewing what doses and schedules have been used and studied for topotecan plus cyclophosphamide, I would definitely not want to enter this trial. It will be using doses and a schedule of topotecan plus cyclophosphamide that will likely not be effective. The trial will use all lower doses than what has been seen to be effective and do it orally at home every day rather than larger doses for 5 days every 21 days). So our plan is to switch over to this chemo regimen I have just described. We are hoping this will at least help stop the tumor from continuing to get larger (stabilize the disease again). (If this regimen does not work....I do have other chemo regimen ideas that I certainly think are worth trying. And, I know our oncologist here in Toledo is certainly brainstorming some "outside of the box" ideas too).

If we can find a chemo regimen that will stabilize the disease again, then we will proceed with surgery to debulk or remove as much of the tumor again as possible followed by radiation treatments. Then, we would continue with the chemo regimen that was found to stabilize the disease in hopes that it keeps the disease in check/prevents it from progressing for awhile. It is highly likely that even if we find a regimen again that stabilizes the disease again that this stabilization will most likely be only temporary. We are hoping we can at least find another way to gain more time with Brody. (However, I will always continue to keep clinging to that little sliver of hope that Brody will somehow beat this despite the odds. Miracles do happen. You just never know).

In the meantime we are also attempting to move forward with GeneKey. Finding a surgeon to do the biopsy and timing the biopsy without having to delay giving chemo is problematic right now though. Also, the lack of insurance coverage is an issue too. The procedure to obtain the fresh biopsy is not covered by insurance. We will have to pay for this and for the analysis by GeneKey. Our oncologist is actually consulting with neurosurgery at Toledo Hospital regarding the difficulty of obtaining a tissue sample from the tumor that is actively growing in the spinal column. He was thinking that maybe if we could go ahead and remove tumor from at least this area that it would help Brody feel better and we would have a fresh tissue sample to send to GeneKey at the same time. And, maybe we would then have the procedure covered by the insurance company too. I don't know about this option yet. This really depends on the risks involved. Our oncologist was attempting to get us scheduled this weekend for an MRI to evaluate better the tumor involvement in the spinal column to better make a decision regarding this option. Getting scheduled for this weekend did not happen though. We will have to wait and see what becomes of this on Monday. Currently we are just scheduled to start the new chemo regimen on Monday. But maybe we may end up doing an MRI, consult with neurosurgeon and then deciding whether to have surgery to remove the tumor from the spinal column at least. Obviously, this is a pretty big decision too if they say it's reasonably safe to attempt it.

Despite all the craziness of everything going on lately, Brody continues to remain in good spirits through it all. He knows that his tumor is getting bigger and that we are trying to find another way to stop it from getting bigger. We do not tell Brody that his doctors say it's not curable. We figure his chances of beating cancer are much better if he believes he will beat it. Right now that is what he believes. He talks about things he wants to do when he grows up.

It is so hard to hear him talking about things so far in the future. I want him to get to live his life and enjoy the things he wants to do. I don't want to think about going on with life without Brody here with us. I am so ANGRY!! Cancer is so unfair and cruel! I try to tell myself to just calm down and be thankful for all the wonderful times you have got to spend with Brody and be thankful that he is with you right now. Enjoy these moments! Stop worrying and crying over things you cannot control! It's hard though. So very, very hard! People ask me how I am doing all the time and how I am so strong and how I cope? I cope with it because I have no choice but to just do so. I keep functioning and going on because somehow I have to. I tell myself multiple times a day, "take a long deep breath in and slow deep breath out." "Focus on this moment and take things one step and one day at a time." "Deal with tomorrow, tomorrow." So, I am hanging in there but I just so wish cancer would just GO AWAY!