Simultaneously Integrated Boost Affects Survival in Locally Advanced p16-Negative Oropharyngeal Squamous Cell Carcinoma

Discussion

Survival outcomes after concomitant CRT using SIB technique for patients with p16-negative locally advanced oropharyngeal cancer were largely superior compared to those who received sequential boost technique. Both 5-year OS and 5-year DFS were significantly in favor of SIB group. To better understand the role of SIB technique on clinical outcomes, we analyzed the frequencies of acute and late toxicities. All patients experienced some degree of acute toxicity, mainly of mild severity. The acute toxicity profile was similar between the two boost techniques, whereas SIB group experienced higher frequencies of late xerostomia, dysgeusia and dysphagia graded as mild to moderate. Nevertheless, there were no reported late severe radiation-related toxicities in all cases, indicating that as long as the dose constraints to organs at risk were limited to below the recommended dose, regardless of using SIB or sequential technique, the severe late toxicity remained non significant. We postulated that the observed improvement in mild/moderate late toxicity seen clinically with SIB boost was due to the summation of different intensity radiation exposure on a per-fraction basis, suggesting that beam coverage by balancing the overall throughput may contribute to late toxicity rates.

This descriptive analysis allows one to question whether slightly higher dose per fraction – 2.25 Gy instead of conventional 1.8-2 Gy per fraction – used to achieve curative dose of radiation to macroscopic disease for patients with p16-negative disease may be beneficial to reduce the risk of locoregional failure. Our favorable survival outcomes encourage the use of SIB given its safety and efficacy. The rationale for IMRT SIB approach is to short treatment time, intensifying total dose with a slightly hypofractionated dose per fraction to macroscopic disease while maintaining acceptable toxicity profile. It is assumed that reduction of overall treatment time may reduce the risk of tumor clonogens’ regrowth during the late phase of radiotherapy and improve tumor control probability. The slightly higher fraction size might have a positive effect on cellular death and regeneration of acute responding normal tissue surrounding gross target volume.

At present, there is no strong evidence in scientific literature supporting the role of SIB technique in p16-negative oropharyngeal cancer. Although there is agreement that IMRT is needed in head and neck cancer treatment, the optimal boost technique is not known (1). Results of prospective trials with direct comparison of the two boost techniques in p16-negative locally advanced oropharyngeal cancer are still awaited and retrospective results are controversial. It should be considered that heterogeneity of population, mainly due to different primary tumor location and absence of p16 status, impede data extraction and comparison among published studies, thus limiting the applicability of those results.

A randomized phase III study compared SIB-IMRT versus sequential boost IMRT technique in newly diagnosed stage I-IVB nasopharyngeal carcinoma patients (7). Overall late toxicities were more common in patients treated using SIB technique. Survival outcomes were promising, accounting 3-year regional progression-free survival (RPFS), OS and PFS of 100% 83.6% and 73.4%, in SIB technique group and 95.7%, 86.3% and 72.7% in sequential technique, respectively (7).

A single institutional retrospective matched cohort analysis on 209 patients with locally advanced head and neck cancer treated with definitive chemoradiotherapy reveled no statistically significant differences in survival outcomes (OS and DFS) between the two techniques (8). Of note, 129 cases were oropharyngeal cancer in origin, but no HPV status was considered, and no subgroup analysis was performed.

These results and limitations also parallel those of Spiotto et al. experience (9). They did not observe any differences in survival outcomes for squamous cell carcinomas of the head and neck series examining SIB and sequential IMRT technique. Still, only a fraction of oropharyngeal patients was tested for HPV and no specific data can be extrapolated.

Recently, a meta-analysis of 7 studies involving a total of 1,049 patients was carried out to compare treatment outcomes and severe acute toxicity of the SIB-RT versus the sequential technique in head and neck cancer patients (10). Results concluded that survival outcomes, including OS, PFS, locoregional-free survival and distant metastasis-free survival, as well as toxicity frequencies were similar between the two IMRT boost techniques. The studies included in the meta-analysis did not address exactly the same outcomes (multiplicity). In addition, results suffered from other confounding factors and potential bias, such as different study design, various primary tumor sites and diverse radiation treatment plan and chemotherapy regimens, precluding sufficient statistical power (10).

Although we focused on p16-negative oropharyngeal cancer, we acknowledge that the single-institution retrospective design limits the generalizability of our results. The strength of our study is that, to our knowledge, it represents the largest cohort of patients with p16-negative locally advanced oropharyngeal cancer treated with a uniform and consistent treatment strategy, thereby excluding a center bias. Additional analysis and validation in an independent study with preregistered protocols are necessary to confirm our results. Incorporation of baseline and longitudinal patient-reported outcomes should be encouraged. There is also a critical need to identify molecular markers at diagnosis to further guide the selection of therapy.