De-escalation of Cancer Therapy Should Be Celebrated, Not Criticized

Mark A. Lewis, MD


September 28, 2023

This transcript has been edited for clarity.

Hello. It's Mark Lewis for Medscape, and I am coming to you in the summer of 2023 after the ASCO annual meeting. I attended this conference with great expectations that it would change my practice, and indeed it has. Although what I wanted to talk about today was some controversy that arose around one of the most prominent studies presented.

This was the second year in a row that we saw the convergence of coverage of the conference in both the scientific press and the mainstream media — in this case, The New York Times. Curiously enough, in both instances, it was around the management of rectal cancer.

In 2022, The New York Times ran this headline: "A Cancer Trial's Unexpected Result: Remission in Every Patient." This was a massive, attention-grabbing headline around a small but significant study run by colleagues at Memorial Sloan Kettering looking at the role of dostarlimab in locally advanced, MSI-high rectal cancer, with the really remarkable finding that all of the patients in the study, although it was the low double digits in terms of the end, responded to that immunotherapy and then did not require chemotherapy, radiation, or surgery. As we know, this is traditionally a disease — arguably the GI malignancy par excellence — that requires a trimodality approach.

This year, things weren't all that different. On Sunday, June 4, The New York Times headline read, "Rectal Cancer Patients Could Be Spared the Brutal Effects of Radiation." By the next day, after considerable uproar, the word "brutal" had been diplomatically omitted from further editions, but the editorialization was already there in the original title.

Now, with all due respect to the paper of record, I think the proper word here is "de-escalation," and the unfortunate phrasing threatens to overshadow the fact that this is exactly the kind of difficult work that we should rightly be celebrating on our largest stages. Dr Schrag, in her plenary presentation, did a beautiful job explaining the rationale of the PROSPECT trial. In fact, I'll quote her here:

Neoadjuvant chemoradiation has been the standard treatment for the past two decades because it has lower toxicity and yields lower rates of pelvic recurrence than post-operative therapy. The prevailing approach for curative intent treatment for locally advanced rectal cancer when PROSPECT began in 2012 was 5.5 weeks of pelvic chemoradiation, next was surgery with a total mesorectal excision, and finally, after recovery, adjuvant chemotherapy, typically 8 cycles of FOLFOX or 6 cycles of CAPOX.
This approach achieves cure in around three quarters of patients, and local recurrence rates in the single-digit range, but this treatment comes at a cost. There is considerable long-term toxicity from pelvic chemoradiation, including impaired bowel, bladder, and sexual function, and also increased risk of pelvic fracture, second malignancy, impaired marrow reserve and fertility, and also premature menopause. And these are extremely problematic because of the increasing diagnosis of rectal cancer before the age of 50.

I think Dr Schrag was actually very fair and balanced in how she presented our desire to trade off lower toxicity and preserved efficacy. As a medical oncologist, I tell my patients all the time that treatment has to be two things: effective, of course; but often, even before we can discern efficacy, treatment needs to be safe and tolerable.

One of the greatest practice-changing trials of my entire career was the IDEA study, now presented at the ASCO annual meeting more than 5 years ago, which looked at outcomes based on 3 vs 6 months of oxaliplatin-containing adjuvant therapy — whether FOLFOX or CAPOX — in stage III colon cancer.

The discovery that a significant number of my patients could receive half the duration of adjuvant chemotherapy, with their rates of chemotherapy-induced neuropathy being cut by two thirds, was immediately practice-changing for me and for thousands of oncologists across the country and across the world.

We should also not penalize investigators when such trials do take years to accrue, knowing that standards of care will change even during enrollment and the maturation of data. Dr Schrag, again, acknowledged this:

Over the past two decades, there have been advances in chemotherapy, development of FOLFOX, surgical techniques with total mesorectal excision, dissemination of screening leading to fewer T4 and large symptomatic tumors, and pelvic MRI, increasing the accuracy of staging.
Taken together, these advances led them to hypothesize that they could de-escalate treatment and use chemoradiation selectively without compromising outcomes.

Again, a well-explained rationale. Dr Schrag also recognized that, even at the very same ASCO meeting, the PRODIGE 23 investigators were presenting data about FOLFIRINOX as part of a total neoadjuvant therapy approach prior to total mesorectal excision, again, in rectal cancer.

I think this de-escalation work is incredibly important because less can be more, or at least noninferior, in terms of cancer-related outcomes while improving the quality of life for our patients. It's also crucial that — The New York Times "brutal" headline aside — we advertise these findings because I think they truly and authentically demonstrate to the public that we're not interested in doing more for more's sake. We're interested in doing less if it harms our patients less. Again, back to primum non nocere as our key medical precept.

All in all, I think PROSPECT is a practice-changing study. As Dr Schrag said it best from the plenary stage, it does not obviate the need to discuss cases of rectal cancer in multidisciplinary fashion. Again, I do not manage locally advanced rectal cancer without discussing each and every case with the radiation oncologist and a surgical oncologist.

I know there's other coverage that will go into more granular detail about the schema of PROSPECT and its generalizability in terms of your patients. I think the overarching message here is that de-escalation is something to be celebrated, not criticized. Rather than describing the omission of brutal therapies, we should be celebrating the fact that we can do just as well for our patients cancer-wise, while inflicting less harm upon them regardless of the modality.

Mark Lewis for Medscape, signing off.

Mark A. Lewis, MD, is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City, Utah. He has an interest in neuroendocrine tumors, hereditary cancer syndromes, and patient-physician communication.

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