Effect of Fluorescence Visualization–Guided Surgery on Local Recurrence of Oral Squamous Cell Carcinoma

Key Points Question Is the use of fluorescence visualization (FV) during surgery associated with reduced local recurrence of localized oral squamous cell carcinoma? Findings In this multicenter randomized clinical trial of 443 patients, compared with those who underwent non–FV-guided conventional surgery, 227 patients who received FV-guided surgery had no significant difference in 3-year local recurrence. Meaning In this study, under a controlled environment, patients with localized oral squamous cell carcinoma who underwent FV-guided surgery had a similar risk of local recurrence to those who received conventional non–FV-guided surgery.

reduction of local recurrence for localized OSCC. This result suggests that attention be directed to strategies other than improving definitions of nonapparent disease at clinical margins to identify the sources of local recurrence.

Summary statements:
This study randomized 261 patients undergoing primary surgery for T1-T2N0 oral cavity squamous cell carcinoma and 182 patients with high-grade premalignant oral lesions to undergo surgical margin planning either by clinical assessment alone or with assistance by the Velscope, a portable device that detects changes in tissue autofluorescence to detect high-risk tissues.
• No significant differences were observed between groups in the primary outcome, 3-year local recurrence, nor in any secondary outcomes (failure of fist pass margin, regional failure, overall survival, disease-specific survival)

Strengths:
Prospective, randomized multi-center trial design provides high level evidence about the role of fluorescence visualization in guiding surgical margins • Trial design includes power analysis, clearly outlined randomization procedures, blinding protocols where possible, photo documentation, and auditing processes to minimize bias • Discussion appropriately recognizes study limitations, including imbalanced use of adjuvant therapy between groups that may account for differences in local control, as well as lower than expected event rate that may impact study power

Weaknesses:
Multiple covariates that may impact the primary or secondary outcomes are not delineated, including perineural invasion, lymphovascular invasion, depth of invasion, or oral cavity subsite • Supplement describes that training of study "fluorescence visualization specialists FVS", however it is not clear what training was performed or whether results were similar across study sites • The study conclusion states that "to improve local recurrence, attention should be directed to strategies other than improving definitions of nonapparent disease at clinical margins", however, the study demonstrates no difference in first pass margin rates between groups, and while first-pass margins are reported, final margin status is unclear. It may a more valid conclusion to state that the Velscope was ineffective in defining nonapparent clinical margins and that it may remain valuable to continue efforts to improve detection of nonapparent disease. Purpose: Sentinel node (SN) biopsy is accurate in operable oral and oropharyngeal cT1-T2N0 cancer (OC), but, to our knowledge, the oncologic equivalence of SN biopsy and neck lymph node dissection (ND; standard treatment) has never been evaluated. Methods: In this phase III multicenter trial, 307 patients with OC were randomly assigned to (1) the ND arm or (2) the SN arm (experimental arm: biopsy alone if negative, or followed by ND if positive, during primary tumor surgery). The primary outcome was neck node recurrence-free survival (RFS) at 2 years. Secondary outcomes were 5-year neck node RFS, 2-and 5-year diseasespecific survival (DSS), and overall survival (OS). Other outcomes were hospital stay length, neck and shoulder morbidity, and number of physiotherapy prescriptions during the 2 years after surgery.

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Results: Data on 279 patients (139 ND and 140 SN) could be analyzed. Neck node RFS was 89.6% (95% CI, 0.83% to 0.94%) at 2 years in the ND arm and 90.7% (95% CI, 0.84% to 0.95%) in the SN arm, confirming the equivalence with P < .01. The 5-year RFS and the 2-and 5-year DSS and OS were not significantly different between arms. The median hospital stay length was 8 days in the ND arm and 7 days in the SN arm (P < .01). The functional outcomes were significantly worse in the ND arm until 6 months after surgery.

Conclusion:
This study demonstrated the oncologic equivalence of the SN and ND approaches, with lower morbidity in the SN arm during the first 6 months after surgery, thus establishing SN as the standard of care in OC.

Summary Statements:
• Multicenter trial which randomly assigned 307 patients with oral or oropharyngeal cT1-T2N0 cancer to either neck dissection (ND) or sentinel node (SN) biopsy. Recurrence free survival (RFS) at 2 years was the primary outcome. • 279 patients were analyzed with 139 in the ND arm and 140 in the SN arm with no differences in 2-year RFS (89.6% vs 90.7%, P < 0.01). • Neck shoulder functional outcomes as assessed by self-reporting, an arm abduction test and physiotherapy course were worse in the ND arm until 6 months after surgery when this difference evaporated.

Strengths:
• The baseline clinical pathological characteristics were relatively evenly distributed among the two treatment arms. (However, note well and this is speculative there was a tendency towards more females in the SN group which questions how random the allocation was). • Despite the pooling of oral and oropharyngeal cancer patients, oncologic equivalence was established between the ND and SN arms in terms of 2-year RFS (89.6% vs 90.7%, P < 0.01). There was no statically significant difference regarding 5-year RFS, 2 and 5 year disease specific survival (DSS) and overall survival (OS). • Demonstrates quite well that functional outcomes for neck shoulder mobility are superior in the SN arm for at least the first 6 months following surgery.

Weaknesses:
• Oral and oropharyngeal cancer patients were pooled, with no mention regarding HPV status in the latter group (AJCC 7 th Edition Used). • Of the 140 SN patients there were 8 localization failures and 33 additional patients that went onto have ND (29.3%). Of this latter group 21 converted to ND at the same operation because of an intraoperative SN+ diagnosis, while 12 had a secondary ND following formal postoperative pathological analysis of the SN node that was initially deemed negative intraoperatively. However, depending on perspective this could also be considered a strength! • The extent of the ND was not commented on in the ND group nor in the positive SN group (pSN+) apart from to say "Level IIb dissection was performed in 26 of 33 pSN+ patients (79%). It is not clear if there were further levels dissected.

Purpose:
We performed an open-label randomized controlled phase III study comparing treatment outcome and toxicity between radiotherapy (RT) with concomitant cisplatin versus concomitant cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC; stage III-IV according to the Union for International Cancer Control TNM classification, 7th edition).

Materials and methods:
Eligible patients were randomly assigned 1:1 to receive either intravenous cetuximab 400 mg/m2 1 week before start of RT followed by 250 mg/m2/wk, or weekly intravenous cisplatin 40 mg/m2, during RT. RT was conventionally fractionated. Patients with T3-T4 tumors underwent a second random assignment 1:1 between standard RT dose 68.0 Gy to the primary tumor or dose escalation to 73.1 Gy. Primary end point was overall survival (OS) evaluated using adjusted Cox regression analysis. Secondary end points were locoregional control, local control with dose-escalated RT, pattern of failure, and adverse effects.

Conclusion:
Cetuximab is inferior to cisplatin regarding locoregional control for concomitant treatment with RT in patients with locoregionally advanced HNSCC. Additional studies are needed to identify possible subgroups that still may benefit from concomitant cetuximab treatment.

Strengths:
• Well-designed, adequately powered, multicenter phase III trial data comparing cetuximab to cisplatin based chemoradiotherapy. • Clear advantage in locoregional control for cisplatin despite only 48% of patients in that arm receiving the recommended dose. • Similar toxicity burden for the treatment arms.

Weaknesses:
• Largely a study of p16+ OPSCC patients (76%) thus confirming already seen inferior outcomes in HPV + oropharynx cancer with cetuximab-based chemoradiation in other phase III trials. Too few p16 negative patients to draw conclusions, but no major difference seen within that subgroup. Outcomes largely driven by the p16 + patients. • Prematurely stopped study prevented analysis of the secondary question whether dose escalation to 73 Gy at the primary site improved outcomes for advanced T stage patients. Dose escalation did, however, seem to help in the cetuximab arm which further substantiates that the tumor response is largely driven by the radiation in patients receiving that agent. • 7 th edition staging. From the Laryngoscope. January 2021.

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Background: The human papillomavirus (HPV) vaccine has been available in the United States (U.S.) since 2006 and was first approved by the Food and Drug Administration (FDA) for both men and women aged 9 to 26 years; this was increased to age 9 to 45 years in 2018. Despite FDA approval, the Advisory Committee on Immunization Practices (ACIP) did not recommend