Abstract
The neoadjuvant immunotherapy approach marks a significant shift in the treatment
paradigm of potentially curable HNSCC. Here, current therapies, despite being
highly individualized and advanced, often fall short in achieving satisfactory
long-term survival rates and are frequently associated with substantial
morbidity.
The primary advantage of this approach lies in its potential to intensify and
enhance treatment regimens, offering a distinct modality that complements the
existing triad of surgery, radiotherapy, and chemotherapy. Checkpoint inhibitors
have been at the forefront of this evolution. Demonstrating moderate yet
significant survival benefits in the recurrent-metastatic setting with a
relatively better safety profile compared to conventional treatments, these
agents hold promise when considered for earlier stages of HNSCC.
On the other hand, a significant potential benefit of introducing immunotherapy
in the neoadjuvant phase is the possibility of treatment de-escalation. By
reducing the tumor burden before surgery, this strategy could lead to less
invasive surgical interventions. The prospect of organ-sparing protocols becomes
a realistic and highly valued goal in this context. Further, the early
application of immunotherapy might catalyze a more effective and durable immune
response. The induction of an immune memory may potentially lead to a more
effective surveillance of residual disease, decreasing the rates of local,
regional, and distant recurrences, thereby enhancing overall and recurrence-free
survival.
However, neoadjuvant immunotherapy is not without its challenges. One of the
primary concerns is the safety and adverse events profile. While data suggest
that adverse events are relatively rare and manageable, the long-term safety
profile in the neoadjuvant setting, especially in the context of curative
intent, remains a subject for ongoing research. Another unsolved issue lies in
the accurate assessment of treatment response. The discrepancy between
radiographic assessment using RECIST criteria and histological findings has been
noted, indicating a gap in current imaging techniques’ ability to accurately
reflect the true efficacy of immunotherapy. This gap underscores the necessity
for improved imaging methodologies and the development of new radiologic and
pathologic criteria tailored to evaluate the response to immunotherapy
accurately.
Treatment combinations and timing represent another layer of complexity. There is
a vast array of possibilities in combining immunotherapy agents with
conventional chemotherapy, targeted therapy, radiation, and other experimental
treatments. Determining the optimal treatment regimen for individual patients
becomes an intricate task, especially when comparing small, single-arm,
non-randomized trials with varying regimens and outcome measures.
Moreover, one needs to consider the importance of pre- and intraoperative
decision-making in the context of neoadjuvant immunotherapy. As experience with
this treatment paradigm grows, there is potential for more tailored surgical
approaches based on the patient’s remaining disease post-neoadjuvant treatment.
This consideration is particularly relevant in extensive surgeries, where
organ-sparing protocols could be evaluated.
In practical terms, the multi-modal nature of this treatment strategy introduces
complexities, especially outside clinical trial settings. Patients face
challenges in navigating the treatment landscape, which involves coordination
across multiple medical disciplines, highlighting the necessity for streamlined
care pathways at specialized centers to facilitate effective treatment
management if the neoadjuvant approach is introduced to the real-world.
These potential harms and open questions underscore the critical need for
meticulously designed clinical trials and correlational studies to ensure
patient safety and efficacy. Only these can ensure that this new treatment
approach is introduced in a safe way and fulfils the promise it theoretically
holds.
