COMMENTARY

'Immuno-Revolution' Has Oncologists 'Forgetting About Chemo'

Ravi B. Parikh, MD, MPP

Disclosures

April 10, 2019

I was embarrassed.

After my first year of fellowship, primarily caring for patients with leukemia and lymphoma, I was relatively seasoned when it came to modifying chemotherapy dosing based on liver and kidney dysfunction. It was a point of pride when first-year fellows like me could put in our chemotherapy orders without a pharmacist sitting right next to us. By the end of my first year of fellowship, putting in chemotherapy orders and making my own adjustments (eg, extra fluids, an extra antiemetic, dose reduction for elevated kidney function, etc) was easy to me.

So it was embarrassing when, as a second-year, the pharmacist called me, wondering about an order for etoposide that I had entered for a man with small cell lung cancer.

"Are you sure you want to give him full-dose?" the pharmacist questioned. "His creatinine clearance is kind of low..."

I was forgetting some things about chemotherapy.

Of course I should have dose-reduced his etoposide. If unchecked, my error could have resulted in an increased risk for side effects: cytopenias, nausea/vomiting, or worse.

Quickly fixing the dose, I realized that recalling which chemotherapies were cleared by the liver versus the kidney wasn't coming to me as easily as it had during my first year. Over the previous past few weeks, I had needed to look up dosing schedules of several chemotherapy regimens that I hadn't used for some time. It was harder to remember side-effect profiles for certain chemotherapies when discussing with patients.

In short, I was forgetting some things about chemotherapy. And when treating cancers for which immunotherapy and other newer drugs are becoming an increasing—and sometimes predominant—form of therapy, perhaps the reason was that I wasn't using chemotherapy too often.

In cancers like lung cancer, melanoma, prostate cancer, and renal cell carcinoma, use of chemotherapy is, in some cases, becoming an exception rather than a norm. A study published in 2018 using real-world data showed that within 4 months of FDA approval of immunotherapies in various metastatic solid cancers, over 60% of eligible patients received immunotherapy.[1] Our group recently presented data at the ASCO Genitourinary Cancers Symposium showing that by the beginning of 2018, approximately half of all patients with newly diagnosed advanced urothelial cancer received checkpoint inhibitors.[2]

Even in 1 year of fellowship, the pace of use has been astonishing. As I learned in my melanoma clinic, the fantastic efficacy of CTLA-4- and PD-L1-based treatments for this disease—where median overall survival used to be under a year—means that we shouldn't even be thinking about chemotherapy as initial treatment.

This shift requires understanding a new expanse of side-effect profiles. Indeed, the spectrum of adverse events associated with immunotherapies and chemotherapies is entirely different. This often means dredging up knowledge from medical school immunology classes that, 10 years ago, many oncologists would never have had to know. And many immunotherapy adverse effects are subtle—for example, a headache signaling hypophysitis, or new fatigue signaling adrenocortical dysfunction. These side effects, which may be passed off with patients on chemotherapy, are taken much more seriously in the immunotherapy era.

It has taken significant time, but I've become more comfortable identifying and managing endocrine and nonendocrine effects of checkpoint inhibitors, and the advent of immunotherapy has required specialty expertise within fields like neurology, dermatology, rheumatology, and endocrinology.

In most cases, however, immunotherapy is much better tolerated than chemotherapy, and the incidence of serious adverse effects is real but relatively rare compared with cytotoxic chemotherapy. There are similar analogies for nonchemotherapies, such as novel hormonal agents in prostate cancer. And naturally, many oncologists and patients wish to avoid chemotherapy at all costs when there is another option available. I know I often do.

But that familiarity can come with downsides.

Early in my first year, my attending and I met an older man in the hospital with metastatic prostate cancer. He had a prostatectomy a few years ago but experienced a rapid rise in his PSA over the past year. Scans before his hospitalization had shown a couple of bony metastases in his lumbar vertebrae, one of which was causing him dull pain. But perhaps most worrisome was a 3-cm liver lesion that, while not biopsied, was probably metastatic prostate cancer. He was in the hospital because his back pain had worsened.

Chemotherapy still has a major role to play, even in a disease revolutionized by immunotherapy.

In light of the diagnosis, his local oncologist had prescribed enzalutamide, which he was now taking. However, given his symptomatic disease and visceral metastasis, he clearly needed chemotherapy.

We never found out why he hadn't gotten chemotherapy earlier. But, now that I primarily rotate in genitourinary or lung cancer clinics, I regularly see patients who I believe would have a hard time tolerating chemotherapy—even if they don't have a strict contraindication to chemotherapy. Sometimes we rationalize giving less toxic therapies, even when it isn't strictly within clinical guidelines.

This has been a focus of research in our group at the University of Pennsylvania. In the research previously mentioned, we found that immunotherapy use was very prevalent, even among a group that, based on diagnosis codes, should have been eligible for cisplatin therapy—the standard of care. Related research showed that use of immunotherapy in the past few weeks of life in advanced bladder cancer was extremely high, probably because it carries fewer side effects.[3]

In short, immunotherapy, and many other novel therapies with low toxicity, has been a boon to much of solid tumor oncology. But we need to recognize situations where we are using such therapies without clear evidence, situations where chemotherapy may be a better option.

This has recently come to a head in bladder cancer: In May 2018, the FDA released data suggesting that many patients using first-line immunotherapy had poorer survival when compared with first-line chemotherapy.[4] This led to the first FDA label restriction on a checkpoint inhibitor in oncology—a sober reminder that chemotherapy still has a major role to play, even in a disease revolutionized by immunotherapy.

Granted, many trials in diseases like lung, prostate, and renal cancer have shown that novel therapies outperform traditional chemotherapies. While it is tempting to forgo chemotherapy in these diseases, often because of patient preferences, it is important to verbalize to patients when we are using immunotherapy outside the bounds of evidence. A good example is a patient with non–small cell lung cancer with low PD-L1 expression: Often I am trying to explain to patients why they need chemotherapy in this scenario. I rarely face such a situation when justifying immunotherapy.

Many attendings and trainees are starting on a similar playing field of experience.

Perhaps one of the most concerning effects of the immuno-revolution is that today's trainees may be less and less comfortable with dosing, administration, and side effects of traditional chemotherapies.

That's okay when chemotherapy doesn't have a role to play. But it's not okay when we shy away from chemotherapy because we are less comfortable using it.

Granted, there are many diseases, like hematologic malignancies, where chemotherapy probably will always play a central role in therapy. Indeed, I learned most of what I know about chemotherapy side effects from my liquid oncology rotations. There was some reassurance in knowing that the regimens we were using in leukemia and lymphoma had decades of evidence behind them. Plus, my attendings were extremely comfortable with such chemotherapies, as they were often the same ones they had used in training.

As one preceptor told me, with immunotherapy and other novel therapies, many attendings and trainees are starting on a similar playing field of experience. That is often great for my learning, but it's concerning when things don't go right.

In these situations, I sometimes think to myself, What would have happened if we used chemotherapy instead? I hope that, in the future, we are using novel therapies because they are the best drugs for patients, and not because we wish to avoid chemotherapy.

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