It Was Supposed to Work

Immunotherapy. It seems everyone has heard about it, or at least seen the commercials on television. I was part of the team at ASCO that declared it to be the cancer advancement of the year in 2016. I still think it’s been an incredible discovery, and when James Allison and Tasuku Honjo were awarded the Nobel Prize in 2018 for their discoveries, the honor was truly deserved.

Yet, in all our talk of this breakthrough and our excitement in both the research and standard use of these agents, I think we’ve oversold its impact. It seems every woman facing a cancer diagnosis I meet for the first time wants immunotherapy. There’s an assumption that all are benefitting, and that it’s a less toxic alternative to standard chemotherapy. Yet, when it comes to most gynecologic and breast cancers, that’s not true. Immunotherapy—particularly immune checkpoint inhibition—is still experimental. It ends up being quite a difficult discussion for some who had hoped that they could stave off chemotherapy.

Still, there are some patients who should benefit from immune checkpoint inhibitors. For the women I treat, it’s those who have evidence that DNA repair is faulty—as evidenced by mismatch repair protein deficiencies (dMMR). Studies tell us that these women can respond to immune checkpoint inhibitors, and that for a fraction of these patients, treatment can be quite durable.

Perhaps that’s where I am as guilty as my colleagues, for when I find patients are eligible for immunotherapy due to dMMR, I cannot help but be excited for them, as if they’ve won the lottery. I excitedly speak about the option of pembrolizumab and tout what’s been reported, and my own anecdotal experience. I hope I do not give the expectation of a guarantee, but I would not be surprised if after our discussion, patients walk away not only hopeful, but assured that they will be okay.

Such was the case with June*. She had been diagnosed with early endometrial cancer years back. She underwent definitive surgery and didn’t need anything more. She did well for a few years, but then developed some vaginal bleeding. Tests showed her cancer had returned with disease in her liver and her lungs. A biopsy followed, which confirmed metastatic disease, and her tumor had dMMR.

I reacted positively to the news that she had dMMR, because it made her an excellent candidate for pembrolizumab, which had the approval for any tumor showing such features. I relayed how fortunate it was and looking back, I was pretty excited for her.

We started treatment the following week, both of us expecting good things. Yet, each week on treatment ended up being worse than the last. At first, the side effects were subtle—mild nausea, fatigue. But then, she had back pain that got worse at rest. While I had hoped it was a good sign- immunotherapy can cause tumor swelling, resulting in temporarily worse symptoms—the symptoms kept progressing. Following just three treatments I opted to proceed with imaging, and she and her family looked relieved. The scans shocked me. Not only were the tumors significantly larger, there were also more of them.

The visit to review images was perhaps one of my most difficult in recent times.

“Everything looks worse,” I said, choosing to confront the elephant in the room directly. “I wish I understood why… I had hoped—even expected—the exact opposite.”

She cried then. “I don’t get it. This was supposed to work. Why didn’t it work?!” She was angry, frustrated, and scared. I could see it in her, and I could see it in her family’s eyes. We spoke more and I offered them other options: other drugs, clinical trials, and—given how poorly she now felt—the option to stop.

“I wish I could tell you that I could give you more time with treatment,” I said, “but I think with or without, you will probably live as long.” Once said, her demeanor changed—as if it had brought her the clarity she needed. “Well, I hate being this sick, and I cannot fathom the thought of treatment and its side effects on top of how I feel now. I don’t want more.”

I looked at her and I looked at her family. “Okay. It’s a decision only you can make, and I will support you, as I promised you I would.”

She entered home hospice and died several weeks later. I learned quite a bit from June and her family when it comes to immunotherapy in gynecologic cancers. Importantly, immunotherapy can lead to profound results—and when it does, it is a thing to celebrate. But this does not happen with all of our patients, and for some, rapid progression still happens. So, I need to temper my enthusiasm for any treatment. Offering hope is one thing, but promising something I cannot guarantee is quite another.

* Patient name and details changed to protect patient privacy.