CR 248: 26th infusion

I officially am halfway through my two-year clinical trial with nivolumab. During my meeting with Dr. Hahn, his fellow, and two clinical trial nurses, they gave me a cupcake and sang "happy clinical trial birthday to you.' Just kidding. But I did ask them about dermatologic toxicity. They noted how my rash had subsided, although the nodules on my legs were still visible. Dr. Hahn said that he was unable to predict whether I would see a recurrence of the rash after today's and future infusions. based upon the limited experience of other patients who had taken Opdivo (including those with other types of cancer), he said that rashes did not follow any set pattern. Most commonly, patients whose immune systems reacted to nivolumab with a rash did so early on, within the first few cycles. Cases like mine -- a significant rash after more than 20 infusions -- were less common. And once a rash presented, there was little pattern to what happened next. Sometimes the rash did not recur. Other times it recurred in different locations. Other times it recurred in the same locations, but not as strong. Other times it repeated just as strongly. And in a minority of patients - less than 5% -- the rash increased in size and itchiness. The difference in reactions, Dr. Hahn explained, was due to the individual makeup of patients' immune systems. Frequently the T cells would figure out that it should not continue reacting to Opdivo with rashes. Only by waiting and seeing would we know. Dr. Hahn said that if the rash recurred in the same degree or worse, I could take an oral dose of over-the-counter Benadryl as well as continue using the corticosteroid. If the rash grew to grade 2 (less than 50% of the body surface area, or BSA), he might consider adding a steroid to the next infusion. If it got to grade 3, then he would discontinue the Opdivo until the rash resolved. I said I'd keep him informed if there was a (ahem) rash of problems.

I also was told by the clinical trial nurse that Bristol Myers Squibb was in the process of closing this specific trial, and is in the process of accruing data for an interim report that it will present at the Spring ASCO meeting. The hope is that the data will be broken down by cancer type and current status. The nurse told me that Hopkins had enrolled eight mets bladder cancer patients in this specific trial, and that there were between 60-80 mets BC patients in this trial at all locations. About half of those patients received combination therapies of nivolumab and ipilumumab, and the other half (including me) were monotherapy patients of nivolumab only. Dr Hahn is on the ASCO review committee for immunology, so he will get a sneak peek at the data. I'm eager to read the report and see the chart reflecting the durability of responses.

Earlier this week I signed up for Kaiser Permanente's Medicare Advantage plan for Fairfax County Virginia. It took several weeks of back-and-forth for me to find out whether Kaiser would be ok with my continued participation in my clinical trial at Hopkins. I was given at least four different answers before I found the definitive answer in Kaiser's 263 page long "Annual Notice of Changes for 2016." Sections 5.1 and 5.2 detail the conditions in which Kaiser will permit its members to participate in clinical trials outside of its coverage area. The short answer is yes, Kaiser is ok with my continuing in my trial, and might even agree to bear some of the standard of care expenses that accompany the trial. Before that happens, I need to get enrolled, meet with a GP, who will refer me to an oncologist, who will review the facts and (probably) will agree to work with Hopkins. And even if they don't, I'll have somewhere to go for any non-cancer health issues that may pop up, as well as a cheaper place to fill my prescriptions. In anticipation of a March 1 enrollment, I brought home three paper scrips. Hopefully this will all work out, but I won't be surprised if I hit some bumps.

In other news, a couple of days ago my youngest son Garrett learned he had been accepted to BYU. Yay! He's still waiting to hear from Carnegie Mellon and MIT. (He must have got the math gene from Jennifer, because it certainly did not come from me.) If he's accepted to more than one, we'll be looking at the financial aid packages offered by each before he makes his decision. I'm playing financial aid hardball: unemployed, totally disabled, receiving SSDI, fighting metastatic cancer with a 90%+ mortality rate. There are few silver linings to my cancer cloud, but getting college financial aid for one of my kids might be one of them.

CR 241: Itching for Opdivo

I've been taking nivolumab (Opdivo) for almost exactly a year. From time to time I've noticed that a rash forms a day or two after my infusion. I am aware that a rash is one of the most common side effects from Opdivo. The FDA safety information for Opdivo advises, "Immune-mediated rash can occur with Opdivo treatment. Monitor patients for rash." FDA's detailed prescribing information for Opdivo states on page 8 that a rash occurs in greater than 20% of patients. According to UpToDate,

Dermatologic toxicity is the most common immune-related adverse event (irAE) associated with checkpoint inhibitors (table 1). Approximately 50 percent of patients treated with ipilimumab will experience rash and/or pruritus, and approximately 30 to 40 percent of those treated with nivolumab or pembrolizumab will have dermatologic complications.

For me, the most common location of rash was on my calves, the back of my scalp, and around the base of my neck. In the past it has come and gone and not been much of an irritant. After my last infusion last week, however, I had a much more significant rash develop on my calves. It circled both lower legs from just above the ankle to a few inches below the knee, and comprised of hundreds of tiny red prickles that itched like crazy. After trying to control it with a Benadryl gel, on Tuesday I sent a midnight email to Dr. Hahn:

Since my last infusion on Feb. 11, I have developed a localized rash on both calves. I would categorize it as a grade 1 rash, being a localized maculopapular faintly erythematous rash with pruritis. I have been applying a Benadryl gel as a topical analgesic, but am wondering if I should apply a corticosteroid. Looking in my medicine cabinet, I see 3 different creams: lidocaine and prilocaine cream, 2.5/2.5%; clidamycin phosphate benzoyl peroxide gel, 1.2/5%; and fluticasone propianate cream, .05%.  Are any of those suitable? Or should I get a scrip for something else? Please advise on whether I should be seen before my next a scheduled infusion on Feb. 25. Many thanks for your ongoing excellent care.

The next morning, Dr. Hahn responded:

Normally, I would usually start with simple over the counter hydrocortisone 1% or 2% cream.  The fluticasone is stronger than the hydrocortisone and dermatologists usually reserve that for more severe cases.

I promptly went out and got some hydrocortisone, and it seems to be helping manage the rash. I also started researching why Opdivo can cause dermatologic toxicity, and what should be done about it. A post on Cure Today from July 2015 describes how to manage rashes caused by immunotherapy drugs such as Opdivo. A 2014 article entitled "Managing the Side Effects of Novel Cancer Immunotheraputics" described the function of Opdivo as sometimes contributing to dermatologic toxicity: 

PD-1 is expressed by T lymphocytes and, upon interaction with its ligands (PD-L1 or PD-L2), functions as a co-inhibitory receptor that dampens T-cell activation, thereby negatively regulating the immune response. Treatment with monoclonal antibodies that disrupt the interaction between PD-1 and PD-L1 results in significant antitumor activity.

A 2015 article published by ASCO entitled "Toxicities of Immunotherapy for the Practitioner" explained:

The basis for the majority of these adverse events is a hyperactivated T-cell response with reactivity directed against normal tissue, resulting in the generation of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells within normal tissues. The T-cell immune response is not tissue specific and may reflect a diffuse expansion of the T-cell repertoire that induces cross-reactivity with normal tissue, effectively breaking tolerance that is active with cytokines, vaccines, and checkpoint protein inhibitors and passive in the case of adoptive cell therapy.

The question for Dr. Hahn next week is what if anything we should do now that my skin has started protesting a little louder about Opdivo. I suspect that we'll continue on with the doses, dealing with the rash as long as it does not rise to grade 3 or 4. If this is the most significant side effect of Opdivo, then it's full speed ahead. It's a hundred times better than either of my chemotherapy regimens. If it gets to the point where all my hair falls out (again) and I feel like I'm climbing out of a hole each time I get an infusion, then maybe I'll start reconsidering it. But so far, so good.

CR 234: 25th infusion and more

It took a week for my flu symptoms to clear up. Had I not taken Tamiflu and Augmentin, I'm sure it would have taken at least seven days. After three weeks of coughing up my lungs, it's nice to be back to normal.

Two days ago I was eating a cheesesteak with Garrett, and I bit into something very had. I spit it out and was amazed to discover part of a tooth in my sandwich. I took it to the proprietor and said look what I found in my sandwich. He was befuddled, then said is it yours? I should have checked first - sure enough, a 30 year old crown had decided to escape. So on my way to Hopkins I stopped by my dentist in Silver Spring who slapped it back into place in about 5 minutes.

I spent the rest of the day at Hopkins. I had my labs drawn, then had to wait for nearly two hours while my bloodwork was done. Dr. Hahn was pleased to see that I was over the flu. We spoke about the lack of published data of nivolumab and bladder cancer. He said that he was the chair of an ASCO immunotherapy review panel and that in the next month or two he expected that he would see a lot of data about nivolumab, hopefully including some that was specific to bladder cancer, as well as overall durability data for patients who have had a complete response. I look forward to seeing those data.

Meanwhile, as I approached the one year mark for participation in this trial, I was asked to sign an updated clinical trial protocol. Bristol-Myers Squibb had amended it to include ovarian cancers, but otherwise it was unchanged from the previous protocols: up to two years of drug dosing, then ongoing monitoring. My plan is to continue to ride this horse as long as it will carry me.

The Hopkins pharmacy was backed up, and it took another couple of hours for the compounded Opdivo to be released. I passed the time by reading Jo Marchant's “Cure: A Journey Into the Science of Mind Over Body.” It's a well-researched exploration of the sometimes unexpected relationship between the brain and healing. Marchant's book is in some ways a counterpoint to Paul Offit's "Do You Believe In Magic?  The Sense and Nonsense of Alternative Medicine"which I blogged about in January 2014. I'm still mulling over some of Marchant's assertions, and likely will blog about it in the future.

The last drops of my infusion dribbled through the pump just before 4 pm. I was famished and jonesing for Popeye's, which fortunately is just across the street from the Weinberg Cancer Center. Two pieces of chicken and a large serving of red beans and rice kept me fortified for the two hour slog home in wreck hour traffic. I do not miss commuting.

This evening I saw that the more than 100 lawyers from my former law firm had been acquired by another firm in an asset acquisition. An announcement on my old firm's web site said that it "was no longer engaged in the practice of law." Although I had already retired, I nonetheless felt a moment of sadness upon learning of the death of a once-venerated 63 year old firm. The ending came not with a bang, but with a whimper. The firm died before it paid back all of the equity partnership capital that I had contributed. I hope I'll get it back, but I'm not holding my breath. C'est la vie.

CR 225: Clear scans, except for the mucus

After last Thursday's infusion, I started feeling fatigued. By Sunday I felt like I had just gone through dose dense MVAC chemo, which is saying something. It hurt to move, to walk, or do anything. I also started coughing up amazing amounts of mucus. By Monday I was running a fever of 101 degrees. Those combination of symptoms were highly uncommon for me - most colds or flus did not incapacitate me like that. Aware that Dr. Hahn had warned me to let him know if I developed a fever after an infusion, I emailed him and the clinical trial nurse:

Following my nivolumab infusion on Thursday, January 28, I have started running a fever (101 degrees), headaches, am constantly fatigued, have muscle and joint pain. In addition, the productive cough that I thought was resolved has returned with a vengeance. I've been trying to manage this with over-the counter remedies (ibuprofen, Mucinex, a decongestant), but the fever is increasing and symptoms are getting worse.

I am scheduled for a CT scan on Wednesday, Feb. 3 at 10:50 am. I know that is not your regular clinic day. Would it be possible to be evaluated on Wednesday, or do you want to work me in tomorrow?

I also called the Hopkins triage nurse, who asked some additional questions and consulted with my clinical trial nurse. I was advised to go to Hopkins the next day and be evaluated by their urgent care team in the oncology department. They also moved my CT scan from Wednesday.

So Tuesday morning I blearily left for Baltimore at 6:30 am, grateful it was raining and not snowing. I went to the CT department and was directed to the triage group, who after some confusion sent me back to CT, where my port was accessed and I had my scans. I then went back to triage, where I was hooked up to a saline IV and had an impressive amount of blood drawn from both my port and my arm (the latter to ensure that my port was not the source of the infection). I also gave a urine sample and had a long piece of plastic shoved into my sinuses for a mucus sample (that was unpleasant!).

Soon the results began to be posted. The good news first: The CT scans showed no new metastases or other evidence of the cancer growing or spreading. Yay for nivolumab! The chest scan noted "new tree in bud nodularity in the posterior  aspect of the left lower lobe, likely infectious/inflammatory etiology  such as bronchiolitis". The neck scan found "fluid accumulation in the maxillary sinuses, suggesting acute sinusitis". And the nasal swab tested positive for "Influenza virus type A RNA". The PA told me that I probably picked up the flu during my visit to Hopkins last Thursday. Lucky me. But at least it wasn't an adverse reaction to the Opdivo. There are a couple of reported cases of adverse drug events to nivolumab causing severe lung damage and even death. They are rare, but enough of a concern that the clinical trial doctors keep close watch on any possible such effects. I'm glad that it's just the flu, and that I can continue on with the trial. 

I was sent home with prescriptions for Augmentin and Tamiflu. When I went to CVS to pick them up, I had my first shock as a Medicare patient: because I had not yet signed up for a prescription drug plan, I was charged full price ($50 for the Augmentin, $147 for Tamiflu). Note to self: find a Medicare Advantage plan that lets me continue in the clinical trial at Hopkins but gives me some drug coverage.

After dosing myself with those drugs and a liberal amount of Nyquil, I actually got a decent night's sleep and am feeling somewhat better today. I am grateful for the continued excellent health care I am receiving, and thankful for each day I can spend with my loved ones. I am keenly aware of how narrow the precipice is between life and death, and take nothing for granted.