Larynx-Preservation for T4a Laryngeal Squamous Cell Carcinoma: Where’s the Evidence?

For laryngeal squamous cell carcinoma, larynx preservation with maintenance of quality voice, swallowing, and respiratory functions is the hallmark endpoint of non-surgical management. However, for T4a tumors, upfront laryngectomy is the treatment of choice and prospective and randomized data on larynx-preservation outcomes in this cohort remains limited. The purpose of this short review is to evaluate the data regarding non-surgical management of T4a larynx cancers.

The sentinel VA Larynx study formed the foundation for larynx preservation treatment. The VA Larynx study randomized patients with larynx cancer to laryngectomy and post-operative radiation therapy or induction chemotherapy (3 cycles of cisplatin and fluorouracil) followed by radiation therapy for responders to chemotherapy. The study showed no difference in 2-year overall survival rates between the treatment arms, but 56% of T4 patients required a salvage laryngectomy [1].

Due to the poor outcomes for T4 tumors on the VA trial, the subsequent RTOG 91-1 trial, which randomized patients to induction cisplatin fluorouracil followed by radiation, radiotherapy with concurrent cisplatin, or to radiation alone, excluded patients with large-volume T4 disease, as defined as a tumor penetrating through the cartilage or extending more than 1cm into the base of the tongue. As a result, only 10% of the enrolled patients had T4a disease, and the specific result for this population were not reported [2].

In contrast, patients with T4 disease were included on the EORTC 24954 trial that compared chemotherapy (cisplatin with fluorouracil) followed by radiation (70Gy) against three alternating cycles of the same chemotherapy with 20Gy of radiation therapy (60Gy total). Although 30% of patients on this trial were T4, results specific to this subgroup were not reported and over 50% of patients enrolled had hypopharyngeal cancer making it difficult to draw conclusions in T4 larynx patients [3]. Likewise, data from two randomized phase II trials, the German multicenter DeLOS-II trial and the GORTEC TREMPLIN trial, provided limited evidence for larynx-preservation outcomes due to limited numbers of T4a patients (proportion of T4a: DeLOS 32%, TREMPLIN not reported) and a mix of laryngeal and hypopharyngeal cancers (proportion of hypopharyngeal tumors: DeLOS 50%, TREMPLIN 59%) [4, 5].

The remaining literature reporting laryngeal preservation outcomes for T4a tumors relies on single or small multi-institutional experiences, often using an induction or chemo-selection approach, with some being prospective protocols and others retrospective analyses [6-14]. Reported rates of larynx preservation in these studies range from 29% to 86% for chemoradiation approaches and less for RT alone techniques. In these reports the long-term tracheostomy rate was 23% to 45%, and the long-term feeding tube rate was 23% to 32%, highlighting some of the risks for aspiration, high-grade dysphagia, and airway compromise in this population [11, 15-16]. Many of these reports spanned decades and employed older radiation techniques and staging guidelines [2, 13, 14].

As a result, the current National Comprehensive Cancer Network (NCCN) guidelines recommend upfront laryngectomy followed by pathology-directed adjuvant therapy for T4a glottic cancers. For those who are not surgical candidates or refuse laryngectomy, NCCN recommends clinical trial enrollment, radiation with concurrent systemic therapy, or induction chemotherapy [17]. For any patient with T4a larynx cancer, careful consideration should be made prior to the start of any treatment to determine the likelihood of successful larynx-preservation and quality long-term functional outcomes.

Proper patient selection is vital, as several recent reports show inferior survival outcomes for T4a patients treated with nonsurgical approaches [13, 15-19]. One important selection criterion appears to the be volume of the primary tumor. Volumes less than 15cc to 21cc are associated with better outcomes, while patients with larger tumors may benefit from upfront laryngectomy followed by post-op radiation therapy with or without chemotherapy, based on final pathology [9, 10].

In general, when considering a non-surgical approach for T4a disease, multidisciplinary evaluation is critical to assess current and anticipated laryngeal function, airway management, and aspiration risks [17]. Additionally, patient’s reliability of follow-up - including distance from medical facility, patient resources, and general medical care-should also be considered to ensure that any recurrent or residual disease is detected early which optimizes the chances that the recurrent disease can be successfully salvaged with a laryngectomy. Patients with limited options for follow-up may still be best served with upfront laryngectomy.

In summary, there is limited data prospective or randomized evidence reporting the outcomes of T4a larynx cancer patients managed non-operatively. As such this approach should only be offered to select patients with limited volume of disease, likelihood of good functional outcomes, those with strong support, and the ability to meet follow-up and post-treatment surveillance protocols.

Table 1: Summary of studies treating T4a Squamous Cell Carcinoma of the Larynx.

None.

No Conflict of Interest.

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