Oncologists are increasingly reaching for the prescription pad before the scalpel, driving a dramatic rise in the use of neoadjuvant therapy for solid tumors, according to new research.
The second annual report from the American College of Surgeons (ACS) National Cancer Database (NCDB), published in the Journal of the American College of Surgeons, draws on data from more than 22 million cancer cases diagnosed at 1250 ACS Commission on Cancer hospitals between 2004 and 2022.
It found that the use of neoadjuvant systemic therapy for gynecologic cancers rose nearly fivefold from 2010 to 2022, jumping from 7% to 34%. During the same time frame, use of neoadjuvant therapy for pancreatic cancer more than tripled, from 12% to 40%. Usage for rarer abdominal cancers (peritoneum, omentum, and mesentery) nearly doubled, from 23% to 47%.
Among patients with melanoma, immunotherapy use also rose sharply, from 26% to 78% for stage III disease and from 9% to 67% for stage IV disease.
“Historically, when we thought about treating solid tumors, the first expected treatment was to have surgery to remove the tumor,” senior author Judy C. Boughey, MD, chair of the ACS Cancer Research Program, and chair of the Division of Breast and Melanoma Surgical Oncology at Mayo Clinic in Rochester, Minnesota, said in a press release. “Now, we are seeing treatment more frequently with targeted medication before surgery.”
‘Testing the Biology’
The shift toward neoadjuvant therapy is driven by the potential to improve long-term outcomes and the ability to assess how a tumor responds to drugs in real time.
“Neoadjuvant therapy is gaining momentum because it lets us treat the whole patient earlier, not just the tumor we plan to remove, while simultaneously testing the biology of the disease,” Ajay Maker, MD, chief of the Division of Surgical Oncology at UCSF Health, San Francisco, told Medscape Medical News. “We are seeing from many clinical trials that it can increase the likelihood of margin-negative surgery, and in some cases, allow less extensive operations, which supports a broader shift toward better patient selection and thoughtful de-escalation, recognizing that more treatment is not always better.”
By observing tumor response prior to surgery, clinicians can tailor subsequent treatments.
“If a patient’s tumor responds to systemic therapy, they generally will do well with treatment; if that doesn’t happen, it tells the clinical team that they need to think about different therapy,” Boughey noted in the press release.
Beyond tumor shrinkage, there may be an immunologic advantage to this approach.
Shailender Bhatia, MD, director of the Melanoma and Renal Cancer Team at Fred Hutch, Seattle, told Medscape Medical News that administering immunotherapy while visible tumors are still present, compared with removing visible tumors first, may create a “better training environment for immune cells against cancer proteins.”
“These data have spurred enthusiasm about neoadjuvant therapy amongst all disciplines involved in care of melanoma patients, including surgical, radiation, and medical oncologists,” Bhatia said.
Maker agreed and suggested that the broader trend has been driven by collaborative decision-making at a clinical level.
“The multidisciplinary cancer team who interprets and applies these data has likely been the most influential in this shift,” Maker said. “Centers and guideline panels can reinforce the shift, while payers have generally followed once evidence and guidelines solidify.”
Balancing De-escalation and Risk
While the NCDB report highlights the rising adoption of neoadjuvant therapy, this strategy is not without potential shortcomings, experts caution.
Maker noted, for example, that while a patient with melanoma who responds well to frontline immunotherapy may be a candidate for less intensive lymph node surgery, this approach is not without risks.
“There is a possibility that patients can progress or become too frail for surgery during neoadjuvant treatment,” Maker said. “Further, we are sometimes giving systemic therapy to people who might have done well with surgery alone. It can also blur the original staging and add logistical and cost complexity. So, the balance is using it where it truly adds value while avoiding overtreatment or loss of a surgical window.”
Beyond the risk for toxicity, Bhatia also pointed out the downside when a case responds poorly to neoadjuvant therapy.
“If the systemic treatment doesn’t work against the cancer, the tumors get even bigger and become hard to resect or completely inoperable,” he said. “The oncology community has to ensure, though, that the risks of toxicity with systemic therapies are justified by the risk of cancer spreading systemically; otherwise, a lot of our patients will suffer unnecessarily with minimal gains.”
Trend Likely to Advance, With Caveats
Bhatia suggested that the trend toward neoadjuvant therapy is likely to advance as systemic treatments continue to improve.
“What makes cancer such a formidable disease is the risk of cancer cells spreading systemically beyond their site of origin,” he said. “As our systemic treatments get better over time, these are likely to be used sooner and sooner in a patient’s journey, either before surgery as neoadjuvant therapy or after [surgery] as adjuvant therapy.”
Maker suggested that the trend may lag in disease types with mixed data.
“Pancreatic cancer is a good example,” Maker said, “in that retrospective data, real- world experience, and prospective trials do not always point in the same direction.”
He also predicted increasing usage of disease characterization tools, refining patient selection.
“Critically, as tumor assessment becomes more sophisticated and personalized, molecularly targeted and biology-driven therapies will likely play a larger role, including in the neoadjuvant setting, where they can be used to target disease biology, downstage tumors, potentially eradicate micrometastatic disease, and refine patient selection for surgery,” Maker said.
Overall, he said there will be a shift “toward more personalized sequencing of therapy rather than simply more preoperative treatment for everyone.”
Esophageal and Prostate Cancer Trends
In addition to the shifts in neoadjuvant therapy, the NCDB report provided in-depth analyses of esophageal and prostate cancer, revealing distinct changes in treatment patterns.
For esophageal cancer, the use of immunotherapy rose sharply, increasing from 8% in 2018 to 30% in 2022. However, the disease remains difficult to detect early; roughly half of patients are diagnosed at stage IV, and most (70.5%) do not undergo surgical resection.
“If patients with esophageal cancer are diagnosed at less advanced stages, we theorize that more patients could be treated with surgery or other less invasive treatment options,” first author Elizabeth B. Habermann, PhD, chair of the ACS Cancer Data Modeling Pillar and Robert D. and Patricia E. Kern Deputy Director of Research in the Mayo Clinic Kern Center for the Science of Health Care Delivery, Rochester, said in the press release.
In prostate cancer, the report documented a more modest move away from surgery. In 2022, roughly 60% of patients were treated with methods other than surgery — including radiation and/or hormone therapy — up from 54% in 2018. For those who did undergo surgery, prostatectomy remained the dominant procedure. The report noted that a prostate-specific antigen level over 20 ng/mL at diagnosis and a higher tumor grade were associated with worse survival.
The NCDB is a joint project of the Commission on Cancer of the ACS and the American Cancer Society. The investigators disclosed having additional relationships with Eli Lilly, SimBioSys, Quantum Leap Healthcare, and others. Bhatia disclosed having relationships with Bristol Myers Squibb, Replimune, Immunocore, and others. Maker reported having no relevant conflicts of interest.
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