De-escalating Cancer Therapy: More Talk Than Action?

At this year's American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, I attended a plenary session on optimizing the quality and value of prostate cancer treatment. The focus, per the panel's moderator, was the balance between escalation and de-escalation in prostate cancer therapy.

The moderator's words rang very true to me. She spoke of thinking critically about whether patients with prostate cancer need aggressive up-front surgery, radiation, or systemic therapy. She spoke about weighing quality of life and adverse effects against marginal survival gains. She even brought up the costs of treatment.

But as each of the panelists stepped forward to speak, no one argued for de-escalating treatment.

Instead, they spoke about definitive radiation, and even surgery, as up-front therapy in metastatic disease. Many brought up intensifying local therapy with up-front chemotherapy or antiandrogen therapy. One panelist identified himself as "a kitchen sink kind of guy," meaning that in high-risk localized disease, he preferred to "throw the kitchen sink" at patients with the hopes that he would improve downstream outcomes.

Of course, nobody could argue against these strategies. Many even had phase 3 evidence showing that they improved overall survival compared with the standard of care.

But coming out of that panel, I realized that de-escalation of therapy in oncology has been more talk than action. In an era where cancer-related expenditures are the fastest-growing component of healthcare spending,^[1] perhaps we need to renew our focus on this topic.

The Uphill Battle for De-escalation

To be fair, several recent trials on de-escalating systemic therapy have received significant press.

One, the TAILORx trial, was presented at last year's ASCO annual meeting and later published in the New England Journal of Medicine.^[2] TAILORx showed that women with hormone-positive early-stage breast cancer with an intermediate-risk 21-gene recurrence score may be able to avoid adjuvant chemotherapy.

Another, the IDEA trial, presented at ASCO 2 years ago,^[3] showed that for certain early-stage colorectal cancers, 3 months of adjuvant chemotherapy was noninferior to 6 months of therapy.

These trials are meaningful because they can save patients from both short-term and potentially lifelong adverse effects of therapy, along with the inconveniences of frequent clinic visits.

But the fact that these trials just came out now—more than a decade since the original trials supporting the 21-gene assay [4] and adjuvant chemotherapy in colon cancer^[5]—shows just how much of an uphill battle de-escalation is. In 2004, both of these original trials made several assumptions that then became standard practice. What was the basis for choosing 6 months of FOLFOX in the original adjuvant chemotherapy trial? The answer: It was what was the investigators chose. But it takes years or decades from that original trial to prove that another, less intensive regimen, is just as good. Meanwhile, millions of men with colon cancer were potentially exposed to 3 extra months of adjuvant chemotherapy that they didn't need.

Intensifying Trends

For every practice-changing de-escalation trial, there are many more trials that intensify up-front therapy.

The PACIFIC trial showed that adding maintenance immunotherapy in stage III non-small cell lung cancer improves overall survival.^[6] A recently published arm of the STAMPEDE trial suggested that definitive radiation to the prostate in low-volume metastatic hormone-sensitive prostate cancer may improve overall survival.^[7] For metastatic non-small cell lung cancer^[8] and extensive-stage small-cell lung cancer,^[9] recent trials suggest adding immunotherapy to up-front chemotherapy as part of first-line therapy.

A basic tour through the poster hall and oral sessions at ASCO makes it clear that escalating therapies will continue to be a trend. I saw countless trials adding agents reserved for advanced disease to localized or locally advanced settings.

However, as we move active therapies into earlier disease settings and as survival for many solid cancers increases, it becomes more difficult to provide good randomized evidence to de-escalate therapy.

Recent studies, including the JAVELIN trial in metastatic renal cell carcinoma,^[10] have even tested combination therapies (avelumab and axitinib) where neither of the two single agents was the frontline standard of care. It is unclear whether either single agent alone was better than the previous standard of care (sunitinib). However, in terms of trial design, it is much easier to combine two agents and compare it with one.

The prevailing bias among oncologists to offer more, rather than less, treatment if it provides a chance of benefit further complicates the discussion.

The most obvious elephant in the room is that large randomized trials need to be funded. It is much easier to fund an escalation trial than to fund a de-escalation trial. Will the National Institutes of Health, Agency for Healthcare Research and Quality, or private companies step up to fund de-escalation? So far, the answer is a resounding no.

Beyond funding, there are other ways to correct the trend against de-escalation. Better reporting of patient-reported outcomes and long-term side effects of intensified therapies will clarify the benefits they truly offer. As new treatments in later-line diseases become available, the relative efficacy of intensified first-line therapies must be reconsidered.

But perhaps most important, we need a better rationale for intensifying up-front therapy. And we need to realize that de-intensifying therapies is difficult. Maybe future trials could add treatment arms with options for therapy with decreased durations or lower doses of intensive therapy. Finally, we ought to be able to use real-world data to track in real-time whether different, lower-intensity treatment strategies can be effective.

Ultimately, a better balance between escalation and de-escalation can increase the likelihood that patients are only getting just as much therapy as they need—nothing more and nothing less. And as oncologists, we'd finally be doing more than simply talking the talk when it comes to de-escalating treatments for our patients.

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