Across the United States radiation oncologists will treat nearly 50,000 HNSCC patients with radiation therapy each year. During treatment, weekly or daily CBCT setup imaging data is acquired for each patient and the quality of this setup imaging continues to improve. However, this setup imaging data is not currently used for prognostication or therapeutic guidance. Here we analyzed CBCT imaging data from 64 patients and determined that changes in pathologically enlarged LN correlated with objective responses and patients with a ≥ 30% decrease in pathologically enlarged LN on the last day of radiation treatment had improved overall survival.
Interestingly, a prospective institutional study from Taipei Medical University utilized PET/CT during the 5th week of definitive chemoradiation and reported a higher local recurrence for patients with higher mid-treatment SUVm value.
This study contributes to a growing area of research into the utilization of radiation image guidance data to assess tumor response and outcomes. Previous studies have evaluated toxicity outcomes and tumor regression during the treatment period, though without correlation to overall survival [10
]. Interestingly, a prospective institutional study from Taipei Medical University utilized PET/CT during the 5th week of definitive chemoradiation and reported a higher local recurrence for patients with higher mid-treatment SUVm value[20
]. Additionally, several ongoing trials are evaluating de-escalation of therapy by utilizing PET or CT imaging at designated time points during the treatment window including Memorial Sloan Kettering’s Major Radiation Reduction for HPV + OPSCC (NCT03323463) and the Quarterback Trial (NCT01706939) at Mount Sinai. While insightful, PET/CT imaging during or immediately after a course of radiation therapy can be problematic to interpret due to edema, mucositis, and other inflammatory changes caused by radiation itself. The current standard of care used to determine therapeutic response is PET/CT or CT at 12–16 weeks post-therapy in conjunction with physical exam. Post-RT imaging is well-correlated to treatment outcomes with findings ultimately guiding management such as neck dissection for patients with residual FDG avid neck disease[18
]. Importantly PET imaging has a high negative predictive value of 90%, which, as demonstrated in the PET-NECK trial, can spare the patients the morbidity of neck dissection without compromising treatment outcomes[21
]. However, 3–4 months is a substantial time to wait to determine therapeutic response and earlier assessments would help inform patients and potentially guide adjuvant therapy.
When we analyzed demographics from our 64 patients with oropharyngeal HNSCC, we observed the vast majority (90%) were p16+, consistent with rising rates of HPV positivity as well as low rates of smoking in our region (Table 1). While CBCT imaging was originally designed to help setup patients using soft tissue as well as boney anatomy, improved algorithms and detection arrays now permit distinct identification of tumor masses and LNs. Nevertheless, for oropharyngeal HNSCC we were unable to obtain precise measurements of the primary tumor site using CBCT due to the lack of contrast between the primary tumor and surrounding normal mucosal and soft tissues. However, we were able to obtain accurate and robust measurements of LN and nodal conglomerates due to contrast with surrounding fat planes and more uniform shapes and used this for our analyses. We observed that changes in LN CC dimension at the end of treatment CBCT had the strongest correlation with complete response rate with a median change of 28.8% from CT simulation to end of treatment in patients with CR versus only 7.7% in non-complete responders. These data indicate that patients with rapid clinical responses to radiation are more likely to have complete responses at 3-month post-treatment PET/CT.
Of tremendous interest is the molecular basis for the radiographic findings observed, which highlights the value of molecular profiling. For example, mutations in the NOTCH pathway have been associated with poorer prognosis in HNSCC, which is consistent with the molecular profile of a patient in our cohort who experienced local failure after therapy. Similarly, PI3K family mutations, also seen in our cohort, have been associated with up to 60% of HNSCC and confer resistance to therapies, particularly EGFR inhibitors. Unlike NOTCH, however, PI3K family mutations are potentially targetable representing an actionable mutation for further treatment. From RTOG 0129, we have long understood that HPV-associated HNSCC is a distinct entity from HPV-negative malignancies. Recent literature including molecular studies from the University of Michigan have further divided the HPV-positive cohort by molecular and immunologic features including immune infiltration and gene expression that establish higher risk subgroups within HPV-associated HNSCC. Ultimately, the next steps for precision radiation medicine involve correlation of molecular and radiomic findings with treatment outcomes to guide therapeutic recommendations.
There are multiple limitations of this retrospective study. The use of CBCT imaging is a novel technique and standards for measurements of tumors and LN have not been established. CBCT is also prone to artifacts due to the wide incident cone-beam field and reconstruction and filtering algorithms required. Additionally, there are patients who have a partial response or stable disease at end of treatment that go on to have a durable complete response. Furthermore, prospective studies would be needed to confirm whether patients with decreased size of pathologic LN at the end of radiation treatment have improved overall survival. Nevertheless, we believe that these results identify end of treatment CBCT as a novel imaging tool to identify rapid responders who are likely to manifest durable complete responses with improved outcomes.
Ultimately an early predictor of treatment response would be beneficial to help to guide management such as de-escalation or treatment intensification. This would be especially useful in light of multiple ongoing Phase III studies using checkpoint blockade immunotherapy either concurrently during chemoradiation or adjuvantly after completion of chemoradiation [27–29]. For example in the Phase III Pacific study consolidative anti-PD-L1 immunotherapy was administered to patients between 1–42 days after completion of chemoradiation for lung cancer. Given that the standard post-treatment imaging for HNSCC is routinely obtained around 90 days post-treatment, this creates a significant delay in the initiation of a potentially beneficial therapy. Additionally, because outcomes are relatively favorable for intermediate risk HPV + HNSCC patients additional treatments such as immunotherapy after completion of chemoradiation may be needed in some patients and unnecessary in others. When we analyzed survival in our patients, we found that those patients who manifested a ≥ 30% reduction in LN CC at the CBCT performed on the last day of radiation treatment had significantly improved overall survival (Fig. 3). Taken together, these findings represent one of the first examples correlating end of treatment CBCT imaging data with response to radiation therapy and overall survival of HNSCC patients.