Painkillers

I've been meaning to write about this topic for a while. My experience with them over the past year has given me a perspective that I've really wanted to share. I was reminded this morning by some pain around one of my ribs on the left side of my chest, likely a tumor pushing on something as I'd mentioned yesterday.

When I was at my worst last year, I had to deal with pain. Right before my pleurodesis, as I was in pre-op, I felt a sharp pain in both sides of my chest. It wasn't fully correlated with my tumors; while I had a lot of them in me, mainly on the left side of my chest, I think some of it was the stress of the moment. I called for the nurse, and she gave me an IV push of dilaudid. Almost immediately, I felt a warm feeling starting from the center of my chest pushing outward and pushing all the pain out of my body. I also felt sedated and calm. It creeped me out a bit -- did I just get high?

I have to say, though, that dilaudid was very helpful in getting through those days. First, the ones in the hospital for pleurodesis, and then right before I started chemo again, thanks to pain from a spine tumor that oxycodone barely made a dent in. Yes, I've gotten quite familiar with the opioid family of medicines. With most chemo regimens, aspirin and ibuprofen aren't allowed because of their blood-thinning effects. So if Tylenol doesn't work, the only choice left is to go with a narcotic.

I'm glad my pain went away quickly after I started chemo, minimizing my need for painkillers. Once I experienced the effects of the dilaudid push, I felt that I saw in a way that I hadn't seen before the tempting nature and addictive potential of these drugs. Looking back on that experience, where I was able to get a very strong painkiller (here's an interesting chart showing the relative strengths of different opioid medicines -- dilaudid is four times as strong as heroin, which is actually a legally available prescription drug in some countries) on demand, I remembered how downright miserable I felt. My tumors were causing me pain, fatigue, lack of appetite, coughing, and on-and-off fevers, and I was only getting sicker. The narcotic high was about the only thing that could wipe that all away, at least temporarily. So even with all the negative connotations around the term "getting high," it is in fact medically necessary to do so sometimes. I was fortunate to recover from that condition so that it was no longer necessary, but for many other cancer patients with advanced disease, it is a way to ease their last moments of life.

For all the good that these medicines have done, though, they also are major contributors to the societal problem of drug addiction. Sometimes it is a result of having to take opioid medicines for a long time due to severe chronic pain. But in other cases, otherwise healthy individuals are using them for the "feel good" effects. I wanted these medicines when I was feeling utterly miserable. The question in my mind is, what is the source of sadness, unhappiness, emptiness, or frustration in the lives of otherwise healthy people that makes them feel like they need to turn to drugs that are this powerful for an escape? Based on this, I feel that the mental health aspects associated with this, or any other illness for that matter, should never be neglected.

No pain, no gain?

Sure feels like it. The regorafenib didn't work. I got the news on Wednesday. The pleural tumors grew; the largest is now 2.6cm. Three enlarged lymph nodes near the heart, and some tiny lung spots too. And I'd had my life (mostly) back. I was going to work full-time again and getting stuff done. Thankfully I got one project I was working on to a stage where I could submit a paper. Fingers crossed...

So now, I've had two treatments which are low on side effects compared to my others (regorafenib and Keytruda), and neither worked. The "classic" chemo treatments that did work were, on the other hand, harsh. Does that mean that a treatment has to be tough in order to work? I sure hope not! But I wouldn't mind that holding true now. I'm considering a few options, that I expect to be harder on me than regorafenib:

1. TK-216 clinical trial: this is one of the first drugs specifically targeted to Ewing's sarcoma. It's supposed to act on a protein produced by the EWS/FLI-1 gene fusion present in most cases of Ewing's. The downside is that it's a Phase I trial. In Phase I trials, the goal is to establish the right dose to give to human patients. So patients start at a low dose, likely to be subtherapeutic. Subsequent patients (they are organized into cohorts) get higher doses; this escalation continues until unacceptable side effects (formally referred to as dose-limiting toxicities) result. Some Phase I trials allow for dose escalation within cohorts, and some don't. I meet with the closest participating institution (UCLA) on Monday to find out all the details.

2. Vigil clinical trial: this is a Phase II trial of a vaccine made from a patient's individual tumor. The idea is to train the immune system to recognize tumors as foreign entities and kill them. Phase II means the dose has been established; the goal now is to study efficacy. In this trial, there's also a comparison arm with a chemotherapy regimen (gemcitabine/docetaxel) used to treat a number of sarcomas. Assignment to arms is at random, so there's only a 50% chance of getting the vaccine. The other issue is that surgery is required to obtain the tumor sample used for vaccine production (unless I get "lucky" and have at least 500 mL of pleural effusion handy), and surgery has had a history of causing any tumors in the vicinity of the operation to blow up and grow even more quickly (the one exception was my amputation, where the cut was made in a disease-free area and all of the tumors were removed). On top of that, I'm not sure how much local control of remaining tumors if any I'll be allowed to pursue while I'm recovering from surgery/the vaccine is being produced. The closest participating location for this trial is a sarcoma clinic in Santa Monica, which I'll also be visiting to get more details.

3. More chemo: there are a couple of drug combinations I can still try, which I can get these close to home. One in particular has shown promise in early published data; I'll be more specific if that's the route I end up pursuing.

On top of deciding between these options for systemic treatment, I'll also be looking at using radiation to kill the tumors I currently have. I think I can feel one of my pleural tumors starting to push on something, which has resulted in a feeling of heaviness/tightness on the left side of my chest near where I had my thorascopic surgeries last year. I can still breathe fine for the moment, but that won't last forever if I don't do something. Hopefully I'll have a decision in a few days.

Second cycle of regorafenib

I'm now a little over a week into my second cycle of regorafenib. I ended up making it through the first cycle without a dose reduction. My side effects were all fairly mild too. I did get a couple of mouth sores, but otherwise, there was no progression from the dry mouth I had earlier on. More significantly, I did get some red irritated spots on my hands and one on my right ring toe. They were sensitive, and I could feel the burning sensation of irritated skin rubbing against something when they touched something. This particular side effect is known as hand-foot syndrome. It can get nasty in some patients. Thankfully, it only popped up for me towards the end of the third week of the first cycle, and there weren't too many spots. The irritated skin has since dried and flaked off, or is in the process of doing so. To keep on top of this in the future, I have some prescription strength (10%) urea cream to keep my hands moist.

My scan is on May 2nd, and I get the results from the doctor on May 4th. I have a feeling I'll know when I either see new pills being brought in for me or not. I still feel great overall, and even went swimming again last Thursday for the first time in over a year. So here's hoping that also means my tumors are in check!

One Week of Regorafenib in the Books

I've been taking regorafenib for a little over a week now, having started the date of my previous post. Four pills (40mg each), taken with a low fat meal. I've been doing it at breakfast, as I'm a big fan of cereal, which fits the bill. So far, so good as far as side effects. Things I've been told to watch out for are high blood pressure, mucositis, mouth sores, and a rash on my hands and feet. I did have dry nasal passages briefly for a couple of days after I started. No mouth sores yet, but I've had dry mouth since last Monday.  Thankfully, regular use of biotene mouthwash keeps that in check. I'm supposed to check my blood pressure twice a day, as it's possible for it to climb dangerously high. Thankfully, I have some wiggle room there. I normally run low (100s/60s), and so far I've only had a bump of 10 above my baseline numbers, which is still low. The trial doctor told me that side effects often force a dose reduction, and most patients end up taking two pills, with the second week of treatment being the toughest. With that facing me now, I guess I'll soon know how I'll fare.

Scans to see if it's working are in the 8th week. And that's the big question I'll have to face as I continue up to that point. With the chemo, since I was so symptomatic, it was easy to tell that it was working by tracking my symptoms and the tumor sticking out of my back. Here, I'll have to rely on not developing any symptoms, but lung tumors can get pretty big before they result in symptoms. So far, I can breathe in pretty deep, perhaps even a little deeper than before I started the trial, so here's hoping that's a good sign.

Still fighting it...

It's been a long time since I last posted an update. A lot has happened between the day I started the immunotherapy trial and now. There are far too many details to publish in one post; I will be addressing those in separate posts. Here, I'll just give a long overview.

The immunotherapy trial did nothing to stop the cancer. In fact, it only grew even faster. By mid-June, I had 2 liters of fluid build up around my left lung, owing to tumors in the lining blocking any path for the fluid to leave the pleural cavity. The pleural cavity is the area between the lung and its lining that normally has some fluid, but various diseases can lead to fluid buildup by blocking the normal cycling of fluid through it. After getting the fluid drained, I underwent a procedure called pleurodesis, fusing my left lung to its lining to prevent further buildup. It was at that point that I officially went off the trial -- the surgeon noted that the pleural cavity was full of tumors. This was after only two doses of Keytruda. Perhaps the most frustrating part of it all was that was that the signs that the drug was working mimicked the symptoms of disease progression. Coughing, shortness of breath, anemia, and random fevers, all of which I dealt with, were side effects of the drug I was told to watch out for.

The pleurodesis provided some relief, but the tumors continued their march in the 10 days between then and when I started chemo. (I couldn't start immediately because the fusion takes time to hold, and giving chemo before that happens ends up undoing it.) I started feeling signs of disease in the lining of my right lung the day before I was discharged from the hospital, in the form of a crackling feeling on that side when breathing in. By the end of the week, walking more than a very short distance was too much for me, and I needed to be pushed in a wheelchair. My appetite was gone, I lost a bunch of weight, and I felt downright miserable, with fevers as high as 103. Then over the weekend, some intense back pain developed that I would many months later find out was due to a tumor in my spine. There was also a tumor sticking out of my back, under one of my surgical scars, that had grown to the size of a small egg. A CT scan of my chest showed that tumors had taken over almost all of my left lung. With all of those many symptoms indicating advanced disease, I began my chemo treatments at Sloan so I could be near the experts.

The drugs I received were cyclophosphamide and topotecan. The dosing was spread out in small intervals over 5 days, so that I didn't need the constant hydration that I'd previously needed when getting cyclophoshamide or its relative, ifosfamide. I was told that I could expect a response, if there was one (the response rate is around 30% in relapsed patients), in a week. Miraculously, it happened instantly. On day 1, I had to be wheeled to the clinic. On day 2, I was able to walk there on my own power, but had to be wheeled back, and was not in pain anymore. On day 3, I was walking on my own power again. The fevers and coughing disappeared almost instantly. The tumor on my back was shrinking. After a second cycle and confirmation of a response by scans, I came back home to continue treatment at a nearby clinic. By the end of October, confirmable live tumors were gone from my scans.

This routine went on until the beginning of this month. Four new spots popped up in my left pleura, the largest 1.2cm in size. So after 12 rounds of cyclo/topo, it was time to try something else. The good news is that, unlike last year, there are some drugs specifically targeted to Ewing's sarcoma that are supposed to be entering trials this year. There are also a couple of other chemo options. I weighed those versus current clinical trials. What I ended up choosing is a trial of a drug called regorafenib at Stanford. It's a chemo taken in pill form in 4 week cycles, 3 weeks on and 1 week off. It targets growth factors that tumors take advantage of to grow and spread. A related drug, pazopanib (Votrient), is used by a number of relapsed sarcoma patients. The trial doctor said that the majority of her Ewing's patients had at least a few months of disease stabilization. It doesn't sound like a lot, but that's my goal right now. I do not have a high tumor burden, so I want to keep it stable until the promising targeted therapies are ready. I also have a couple of other chemo combinations and/or radiation treatments to turn to if this does not work. Plus, the side effects are not as severe, so I will be getting a lot of my life back, versus the pattern of chemo week, low counts week, and good week that I once again dealt with on cyclo/topo. I really hope this works out for me, because I could very much use some time to recover from the IV chemo, both mentally and physically.

New Treatment

When I last checked in, I'd just gone back home from New York. I put treatment on hold while my doctors, my family, and I investigated treatment options. There is no standard second-line therapy for Ewing's sarcoma. Rather, different doctors and hospitals have their own protocols. Sloan-Kettering used to use irinotecan and temozolomide as a second-line treatment. Now that they use these drugs as part of first-line therapy, they've switched to cyclophosphamide and topotecan. Some places, though Sloan is not one of them, if second line chemotherapy produces a response, proceed to high-dose chemotherapy. High dose chemo involves giving a dose large enough to wipe out a patient's bone marrow. To counteract this, stem cells are first harvested from the patient, that are then given back after the chemo has had its effect. High dose chemo is often a first line treatment for metastatic Ewing's in Europe.

This goes to show that there's no consensus on what to do in metastatic and recurrent Ewing's, which is difficult to treat. In my case, with the multiple lung spots and my having already had irinotecan, Dr. Meyers was concerned that combining the related drug topotecan with cyclophosphamide, another drug I've already had, wouldn't produce a satisfactory response. So we started exploring clinical trials, where a particular treatment that has not been used before is tested for safety and effectiveness. During this time, I couldn't get any treatment. Clinical trials have strict eligibility criteria that treatments can easily violate. Blood tests have to fall within certain parameters. There needs to be a gap of at least the cycle length between a chemo administration and starting treatment. Major surgery also requires a recovery period before treatment can begin.

Immunotherapy, in which the immune system is stimulated to attack tumors, was the theme. The immune system normally plays a big role in attacking cancer cells and keeping them from turning into active disease, but as these cells mutate rapidly, they can find ways to evade the immune system and establish themselves. One popular immunotherapy approach involves using vaccines to train the immune system to recognize tumors as foreign. Another involves counteracting defenses cancer cells evolve to escape destruction by the immune system. The trial we ended up focusing on uses the second method. The specific approach is called checkpoint inhibition. Cancer cells can put the brakes on the immune system by displaying what are called immune checkpoints that tell the immune system not to attack. Immune checkpoints are used by the body to prevent autoimmunity, where the immune system attacks the body itself, but cancer cells can make use of these to evade destruction.

Checkpoint inhibition is already used to treat advanced melanoma, with the FDA having approved multiple drugs that block immune checkpoints. Melanoma is not very responsive to chemotherapy or radiation, so checkpoint inhibition represented a major advance in treatment, and some patients have seen dramatic responses. Clinical trials are now underway to evaluate the effectiveness of checkpoint inhibition in many other cancers. The one I'm in uses a drug called pembrolizumab (trade name: Keytruda). It is open at multiple locations across the country. The closest to me is at the University of Southern California in Los Angeles, a 5-6 hour drive. The treatment is once every three weeks, 30 minutes by IV. There are side effects, but much less than chemo. Common ones are fatigue, diarrhea, and cough. Obviously, I'd prefer to be closer to home, but trips to LA once every three weeks is minimally disruptive compared to how things could have been if I were to get chemo or this same treatment farther away where the only option would have been air travel. I also have family there, so I won't be alone when I come in.

The preliminaries began with an initial consultation on May 5th. Then there was a CT scan of my chest, abdomen, and pelvis to establish a baseline. Thankfully, the tumors have not spread to any other organs, but I've gotten new ones since my last scan, and the existing ones have gotten quite a bit bigger, so I couldn't have waited much longer. This week, there was a needle biopsy on Wednesday to obtain a tumor sample. Another sample will be taken at week 8 to evaluate response to treatment. Then, there was more blood work. Finally, on Friday, I received my first treatment. I will be getting two more for sure. At week 8, there will be another CT scan to evaluate response. Tumor growth greater than 20% or new tumors will be counted as disease progression, at which point I'll be off the trial and will have to find another treatment option. Subsequent scans are taken every 12 weeks.

The first IV bag being hung.

I really hope this treatment works. So far, the only side effect I've felt was some fatigue yesterday. I expect to be able to live a normal life, unlike when I was getting chemo. This makes me very happy, but even so, I am quite nervous. The thing about chemo, as brutal as it is, was that I knew it was doing something to me. How couldn't I with all those nasty side effects? To be fair, that is no guarantee that the chemo is doing anything to the cancer cells, but there is something to be said for perception. With Keytruda, without those side effects, how can I tell that it's doing something? I guess the proof will be in the pudding. If I become symptomatic or start feeling extreme pain somewhere, then I know it's not working, but if I stay asymptomatic, I have reason to be encouraged. A real-life example of the saying, "No news is good news." So, outside of side effects, here's hoping I stay free of symptoms!

Well it's back...

It was all such a whirlwind. The morning after the scans, I go in for the results, and the first question I get from Dr. Meyers was, "Did you have an infection recently?" He then pointed to an enlarged lymph node in my left lung that lit up on the PET scan. There were also a few other tiny lung spots that showed up there and on my chest CT. An infection was his and my hope, given the alternative. The only thing that came to mind was a cold I'd had in late December/early January. At that time, I was given two options: wait and re-scan in 6 weeks to see if anything changed, or do a biopsy and find out now. Not in the mood to wait, I went for option 2.

The procedure was straightforward -- the general surgeon with the pediatric oncology group at Sloan, Dr. La Quaglia, took a piece of the lymph node and a small piece of my left lung as well. He was able to use a scope, which enabled a quick recovery. The alternative, if using a scope didn't work, was working through an incision, in which case I might still be in the hospital recovering instead of writing this post!

The pathology report isn't back yet, but I got the preliminary news right after I woke up. Dr. La Quaglia told me that there were small round blue cells in the biopsy sample. Given that Ewing's sarcoma is one of the small round blue cell tumors, that meant we were almost certainly looking at a recurrence. I say almost certainly, because there is some super small (something like 0.000001%) chance that this is actually another kind of small round blue cell tumor such as a lymphoma. Small enough not to be worth mentioning except that I had such small odds of having cancer back in 2012 when I was first diagnosed that I wouldn't be surprised by the unexpected.

Dr. Meyers met me as I was being wheeled into my hospital room to get moving on exploring treatment options. Chemo is one possibility, but given how much of it I received in 2013, there's the worry of resistance, so he's also looking at trials that involve vaccines or drugs that stimulate an immune response against tumors. We last spoke yesterday; he told me he was still investigating, and that I should for the moment go home, as I was sufficiently healed and capable of resuming my normal life. I'll hear from him when the pathology report is in and when he's finished looking at options. I don't know where treatment will be or how disruptive it will be to my daily routine, but here's hoping for something that is not too disruptive and also in Northern California.

I was able to find a reasonably priced flight that left New York late in the afternoon, so I headed back home and resumed work this morning. It's an eerie feeling, though, knowing what's inside me. I have no symptoms now, but if I do nothing, they'll eventually develop and intensify and, well, I don't want to go there. I'm doing my best to think happy thoughts. Hopefully whatever second-line treatment I pursue ends up working.