Laryngeal Preservation Approaches: Considerations for New Selection Criteria Based on the DeLOS-II Trial

Abstract

In the locoregional advanced group of larynx and hypopharyngeal squamous cell carcinomas (LHSCC), there are two kinds of patients: those who are candidates for functional larynx organ preservation (LP) by avoiding ablative surgery and those who are not. Currently, the distinction between them is depending on the patient's needs and desires, the experience and recommendation of the surgeon, the philosophy of the institution and others. The milestone VA trial established non-surgical LP in advanced LHSCC utilizing induction-chemotherapy (IC) with PF (cisplatin, P plus 5-fluorouracil, F) followed by irradiation (IC+RT) as appropriate alternative treatment to total laryngectomy (TL) already in the 1990s. Even thou the VA trial's findings were verified by the EORTC 24891 trial we have an ongoing debate about the best protocol balancing survival and laryngectomy-free survival (LFS) with acceptable late toxicity and good functional outcome. In advanced LHSCC without surgical options preserving the larynx, only IC+RT and primary concurrent chemo-radiotherapy (CRT) are accepted treatment options aiming to preserve a functional larynx. In the US, cisplatin-based CRT is still recommended as best protocol to achieve cure of the disease and LP. But current views on long term survival with functional organ preservation and still high failure rates are addressing the need of better selection of patients which will be discussed as follows taking the current debate in literature and in particular the recently published data of the DeLOS-II trial in consideration.

Keywords: decision-making; early response evaluation; head and neck cancer; head and neck squamous cell carcinoma (HNSCC); hypopharyngeal cancer; induction chemotherapy; laryngeal cancer; larynx organ preservation.

Figure 1

Ten-years outcome data of patients treated with concomitant cisplatin radiotherapy (CRT) vs. induction-chemotherapy with cisplatin and 5-fluorouracil followed by radiotherapy (IC+RT) in the Radiation Therapy Oncology Group (RTOG) phase III randomized clinical trial RTOG 91–11 demonstrates superior long-term survival and survival with larynx despite increased frequency of total laryngectomies (TL). Modified representation of data from Forastiere et al. (1) according to Licitra et al. (2).

Figure 2

The Cox proportional hazard model for laryngectomy-free survival (LFS) developed in responders (p = 6.28 × 10–4) contains 4 independent significant covariates and predicts the LFS, overall (OS), and tumor- specific survival (TSS) of responders Forrest plot for the four covariates in the multivariate Cox model (1) suspect positive neck nodes (N+) ≤2 vs. >2, (2) residual volume of the primary tumor resVT ≤20 vs. >20%, (3) residual total tumor volume in CT-based volumetry resV≤5.6 vs. >5.6 ml, and (4) the ratio of the residual standard-uptake value maximum and the residual standard-uptake value mean resSUVmax/resSUVmean≤1.51 vs. >1.51. Fifty two consecutive patients with advanced laryngeal and hypopharyngeal carcinoma in the phase II larynx preservation trial DeLOS-11 treated in the University Hospital Leipzig (31); permission for reuse kindly provided by Elsevier.

Figure 3

Kaplan-Meier curves for laryngectomy-free survival (LFS; A), overall (OS; B), and tumor-specific survival (TSS; C) among responders stratified according their LFS score ≤16 vs. >16 are shown together with p-values from log-rank tests. Modified reproduction from Wichmann et al. (31); permission for reuse kindly provided by Elsevier.