西野 宏

The interim analysis of JCOG1008 demonstrated that chemoradiotherapy with cisplatin 40 mg/m ² once a week for seven cycles (weekly cisplatin) was noninferior in terms of overall survival (OS) compared with chemoradiotherapy with cisplatin 100 mg/m ² once every 3 weeks for three cycles (3-weekly cisplatin) for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). This report presents the long-term follow-up results of JCOG1008. In this phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin or with weekly cisplatin. A total of 261 patients were enrolled. At the final analysis, with a median follow-up of 5.6 years, 5-year OS was 58.7% in the 3-weekly arm and 71.2% in the weekly arm (hazard ratio, 0.76 [95% CI, 0.52 to 1.12 [<1.32]]), confirming the noninferiority of the weekly regimen. Both 5-year relapse-free survival (RFS) and 5-year local RFS were numerically better in the weekly arm. No late adverse event showed more than a 10% difference between the two arms. In conclusion, 5-year follow-up confirmed that chemoradiotherapy with weekly cisplatin is noninferior in OS to chemoradiotherapy with 3-weekly cisplatin in patients with postoperative high-risk LA-SCCHN. These results further support the use of weekly cisplatin plus radiotherapy as a reasonable alternative for this patient population.

6015 Background: For patients with post-operative high-risk locally advanced head and neck squamous cell carcinoma (LA-HNSCC), initiation of chemoradiotherapy (CRT) within 6 weeks after surgical resection is recommended based on previous reports. However, the guideline-defined 6-week threshold for initiating post-operative radiotherapy (PORT) is derived mainly from data in patients treated with PORT alone. Therefore, its relevance in patients receiving post-operative CRT remains uncertain. Methods: This supplementary analysis used data from the JCOG1008 trial (jRCTs031180135), which compared post-operative CRT with weekly cisplatin versus 3-weekly cisplatin. Associations between the surgical-to-PORT interval (S-PORT) and locoregional relapse-free survival (LRFS), overall survival (OS), and relapse-free survival (RFS) were evaluated using restricted cubic spline analyses, Kaplan–Meier methods, and Cox proportional hazards models. Treatment package time (TPT), defined as the sum of S-PORT and radiotherapy duration, was also assessed. Results: Among 261 enrolled patients, 251 were eligible for this analysis (median age, 62 years; 16.3% female; 45.8% with oral cavity primaries). The median S-PORT and TPT were 7.0 weeks (range, 2.9–10.0) and 13.9 weeks (range, 7.6–16.9), respectively. Restricted cubic spline analyses demonstrated minimal variation in risk across the observed S-PORT range, with hazard ratios (HRs) remaining close to 1 for LRFS, OS, and RFS. Kaplan–Meier analyses using the guideline-defined 6-week cutoff showed similar 5-year LRFS between patients with S-PORT ≤6 weeks and &gt;6 weeks (64.0% vs 64.9%; HR 0.91, 95% CI 0.60–1.37; Table), with no significant differences in OS or RFS. In multivariable Cox models adjusting for clinical covariates, S-PORT was not independently associated with outcomes. Findings for TPT closely paralleled those for S-PORT, with no significant associations observed between TPT and treatment. Conclusions: In this supplementary analysis of JCOG1008, no prognostic disadvantage was observed when PORT was initiated within the range observed in this trial (6–10 weeks after surgery) among patients receiving post-operative CRT. These findings support individualized S-PORT timing rather than rigid cutoff-based decision-making in contemporary standardized CRT. Clinical trial information: jRCTs031180135. Kaplan–Meier analyses according to guideline-defined 6-week surgical-to-postoperative radiotherapy interval (S-PORT) cutoff. <table> <tbody><tr> <th colspan="1" rowspan="1"></th> <th colspan="1" rowspan="1">S-PORT ≤ 6 weeks</th> <th colspan="1" rowspan="1">S-PORT &gt; 6 weeks</th> </tr> </tbody><tbody> <tr> <td colspan="1" rowspan="1">5y LRFS (95% CI)</td> <td colspan="1" rowspan="1">64.0% (52.1%–73.7%)</td> <td colspan="1" rowspan="1">64.9% (57.3%–71.5%)</td> </tr> <tr> <td colspan="1" rowspan="1">HR (95% CI), p-value</td> <td colspan="1" rowspan="1">1</td> <td colspan="1" rowspan="1">0.91 (0.60–1.37), 0.65</td> </tr> <tr> <td colspan="1" rowspan="1">5y OS (95% CI)</td> <td colspan="1" rowspan="1">65.3% (53.4%–74.9%)</td> <td colspan="1" rowspan="1">66.6% (59.1%–73.1%)</td> </tr> <tr> <td colspan="1" rowspan="1">HR (95% CI), p-value</td> <td colspan="1" rowspan="1">1</td> <td colspan="1" rowspan="1">0.88 (0.58–1.34), 0.54</td> </tr> <tr> <td colspan="1" rowspan="1">5y RFS (95% CI)</td> <td colspan="1" rowspan="1">60.0% (48.0%–70.1%)</td> <td colspan="1" rowspan="1">60.2% (52.6%–67.0%)</td> </tr> <tr> <td colspan="1" rowspan="1">HR (95% CI), p-value</td> <td colspan="1" rowspan="1">1</td> <td colspan="1" rowspan="1">0.98 (0.66–1.46), 0.93</td> </tr> </tbody> </table>

Abstract Antibody-dependent cellular cytotoxicity (ADCC) is a key player in the antitumor immunity elicited through molecular targeted therapy of oncogenic receptors using monoclonal antibodies (mAb). Oncolytic viruses represent an alternative therapeutic means that selectively replicate in and destroy tumor cells, as well as induce specific antitumor immune responses. This study investigates whether oncolytic virus therapy using G47Δ, a third-generation oncolytic herpes virus with enhanced induction of antitumor immunity, can augment the efficacy of molecular targeted therapy with ADCC using the anti–epidermal growth factor receptor (EGFR) mAb cetuximab. Due to the species specificity of cetuximab, we developed a human EGFR-expressing immunocompetent murine tumor model specific to the ADCC activity of cetuximab. Intratumoral G47Δ administration combined with systemic cetuximab treatment was significantly more effective in suppressing tumor growth than G47Δ monotherapy. This phenomenon was dependent upon the activation of both innate and adaptive immune cells, as antitumor responses were abrogated upon natural killer cell and CD8+ T-cell depletion. Further studies investigating the draining lymph node dendritic cells (DC) indicate that the destruction of cetuximab-coated tumor cells by G47Δ promotes uptake of tumor cells by DCs, enhances the priming of immune responses, and subsequently stimulates tumor-specific CD8+ T cells. These results suggest that the combination of G47Δ therapy and molecular targeted therapies with ADCC activity may represent a useful therapeutic strategy for enhancing antitumor immune responses, even after the emergence of acquired resistance.