Immunotherapy is moving earlier in the cancer pathway, from a salvage option for advanced disease to a tool used before and after surgery in select tumor types. A synthesis of evidence spanning seven cancer areas highlights both momentum and unresolved questions as health systems weigh benefits, risks, and costs of bringing immune checkpoint inhibitors into the operating room timeline.
“We see that immunotherapy in early stages of disease is developing rapidly across many tumor areas. By bringing together studies from many cancer types, it becomes clearer how the field is evolving and what experiences can be shared between different specialties,” says last author Hildur Helgadottir, researcher at the Department of Oncology-Pathology at Karolinska Institutet.
What “earlier use” means in practice
- Neoadjuvant therapy: checkpoint inhibitors delivered while the primary tumor remains in place, often combined with chemotherapy; aims to prime systemic anti-tumor immunity, downstage disease, and improve surgical outcomes.
- Adjuvant therapy: checkpoint inhibitors started after curative-intent surgery to lower risks of recurrence in high‑risk patients by targeting residual microscopic disease.
- Perioperative strategies: integrated courses before and after surgery, tested across melanoma, lung, head and neck, breast, gastrointestinal, gynecologic, and urologic cancers, reshaping the traditional boundary between medical and surgical oncology.
Selected U.S. regulatory milestones shaping perioperative care
In the United States, perioperative immunotherapy is now moving from trial settings into routine practice, guided by a series of cancer‑specific approvals from the U.S. Food and Drug Administration, which operates under the core statutory framework of the Federal Food, Drug, and Cosmetic Act. These decisions, in turn, influence coverage policies by public and private payers and are beginning to inform national cancer strategies.
| Indication & regimen | Setting | U.S. regulatory status | Pivotal evidence |
|---|---|---|---|
| Non‑small cell lung cancer: pembrolizumab + platinum chemo (neoadjuvant), then pembrolizumab (adjuvant) | Resectable stage II–IIIB (AJCC 8e) | Approved October 16, 2023 (FDA perioperative approval) | KEYNOTE‑671 (OS and event‑free survival benefit) |
| Non‑small cell lung cancer: nivolumab + platinum chemo (neoadjuvant), followed by nivolumab (adjuvant) | Resectable tumors ≥4 cm and/or node‑positive | Approved October 3, 2024 | CHECKMATE‑77T (reduced perioperative disease events) |
| Head & neck squamous cell carcinoma: pembrolizumab as neoadjuvant, continued post‑op with RT ± cisplatin, then pembrolizumab | Resectable, locally advanced; PD‑L1 CPS ≥1 | Approved June 12, 2025 (FDA perioperative approval) | KEYNOTE‑689 (longer event‑free survival; higher major pathologic response) |
Who may benefit — and why results vary
- High‑risk, resectable disease: Evidence signals benefit in tumors where relapse risk after surgery is substantial, including subsets of lung and head & neck cancers, and in selected patients with melanoma and urothelial carcinoma.
- Underlying biology: Tumors with immune‑responsive features (e.g., PD‑L1 expression in some settings; mismatch‑repair deficiency in parts of colorectal cancer research) show greater signal, though predictive biomarkers remain imperfect and not yet harmonized across indications.
- Treatment combinations: Combination strategies (chemo‑immunotherapy) can improve pathologic response before surgery, a surrogate linked to long‑term outcomes in certain cancers, but translation to overall survival differs by tumor type and by regimen intensity.
- Patient selection: Age, comorbidities, performance status, and surgical risk all shape who is likely to benefit from perioperative immunotherapy without unacceptable toxicity.
Clinical and system risks that health leaders are weighing
As immunotherapy moves into the perioperative window, the clinical risks intersect directly with organizational risk and accountability for outcomes.
- Immune‑related adverse events (irAEs): pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic and renal toxicities can be serious; management requires rapid recognition and coordinated specialty support, with clear escalation plans that include surgeons and anesthesiologists.
- Surgical timing: rare but consequential delays or missed operations can occur if toxicity emerges during neoadjuvant therapy; multidisciplinary scheduling, “stop rules” for treatment, and defined decision‑rights between oncology and surgical teams are essential.
- Overtreatment: a subset of patients might be cured with surgery alone; without precise risk stratification, some will incur toxicity and cost without added benefit, raising questions for hospital ethics committees and payer medical‑necessity reviews.
- Equity: earlier infusions add travel, time, and coordination burdens that can disproportionately affect rural patients and those with limited paid leave or transportation, potentially widening survival gaps unless health systems invest in navigation and supportive services.
Operational implications for hospitals and cancer centers
For hospital executives and cancer service line leaders, perioperative immunotherapy is less a single drug decision and more a redesign of the perioperative pathway.
- Capacity planning
- Infusion chair time and nursing coverage must expand to meet pre‑op demand, often within fixed physical footprints.
- Pathology throughput for standardized assessment of pathologic response, including timely reporting that can inform adjuvant decisions.
- Operating room windows aligned to neoadjuvant cycles to avoid unnecessary delays, with contingency planning for patients experiencing irAEs.
- Safety infrastructure
- Shared irAE protocols spanning oncology, pulmonology, gastroenterology, endocrinology, anesthesia, and surgery, with clear ownership for perioperative risk assessment.
- 24/7 triage to capture early toxicity signals during the pre‑surgical period, supported by electronic alerts, standardized order sets, and access to urgent diagnostics.
- Data systems
- Prospective perioperative registries to track event‑free survival, surgical outcomes, readmissions, and long‑term functional status at the institutional level.
- Integration of biomarker reporting (PD‑L1, mismatch repair status) into treatment pathways and tumor board workflows so that eligibility decisions are transparent and auditable.
Payment, coverage, and oversight considerations
Because these regimens are high‑cost and delivered in a curative setting, payers and regulators are scrutinizing how quickly perioperative use scales beyond clinical trials.
- Coverage: on‑label perioperative uses under Medicare Part B and commercial plans generally reimburse drug and infusion services; off‑label neoadjuvant use often hinges on compendia support, prior authorization, and documentation that alternatives are inadequate.
- Benefit design: patient out‑of‑pocket exposure shifts earlier in the care episode, requiring financial navigation to prevent treatment abandonment, especially for patients who have not yet met deductibles at the time of surgery.
- Value assessment: outcomes‑based contracts and real‑world evidence may be leveraged as systems adopt perioperative protocols at scale, with boards and quality committees increasingly asking whether incremental survival gains justify cumulative toxicity, infrastructure investment, and budget impact.
Evidence gaps that call for coordinated research
The rapid regulatory uptake contrasts with still‑evolving evidence on who should receive perioperative immunotherapy, for how long, and at what cost to quality of life.
- Biomarker precision: validated markers beyond PD‑L1 to identify who truly benefits from neoadjuvant and adjuvant courses across tumor types, and to distinguish patients who may safely avoid treatment.
- Optimal sequencing and duration: defining when to stop treatment in major pathologic responders, how to manage incomplete responders post‑op, and whether de‑escalation strategies can preserve benefit while reducing toxicity and cost.
- Timing logistics: clarifying how infusion timing relative to surgery, circadian considerations, and recovery intervals influence outcomes without overburdening clinics or extending waiting times for operating rooms.
- Long‑term safety: characterizing late irAEs in patients treated with curative intent, including impacts on survivorship, return‑to‑work, and long‑term use of immunosuppression for chronic toxicities.
“It is valuable that we have come together from so many different tumor areas. This gives a broader understanding of how immunotherapy is used across cancer care and can, in the long term, support both clinical decision-making and future research,” says Hildur Helgadottir.
For public and private providers, the shift to earlier immunotherapy is as much a systems challenge as a scientific one. The opportunity is clear: reduce recurrence and improve long‑term outcomes for precisely defined patient groups. Realizing that promise will depend on measured implementation, robust data collection, and equitable access as perioperative protocols move from trials to everyday care, with governance structures in hospitals and health plans keeping pace with the speed of therapeutic innovation.
