Approach

The treatment of laryngeal cancer is dictated by the TNM stage. Modalities include surgical resection, radiotherapy, chemotherapy, or any combination of these.[1]​ Goals of therapy are eradication of cancer with organ preservation. While glottic and supraglottic tumours are distinct pathological subsites, management of these tumours is similar. In this topic, glottic and supraglottic tumours are discussed together and the differences are highlighted, where appropriate. Speech therapy is appropriate after surgery, radiotherapy, chemoradiotherapy, or any combination of these modalities.[1]​ All patients should be screened for dysphagia during intake, treatment course, and survivorship. There are validated dysphagia tools for assessment.[41]

Glottic and supraglottic tumours: T1 and T2

Treatment in T1 and T2 N0 M0 tumours involves single-modality treatment with surgery or radiotherapy.[1]​ Larynx-sparing surgery (e.g., endoscopic laser resection, transoral robotic surgery, laryngofissure, cordectomy, vertical partial laryngectomy) or radiotherapy are equally effective in terms of tumour control and survival.[42]​ Neck dissection is usually performed in addition to surgery in T1-T2 N0 M0 supraglottic tumours, although some patients may elect not to do a neck dissection for T1 N0 M0 tumours. Neck dissection may also be needed in addition to surgery in certain T1-T2 N0 M0 glottic tumours.[1]

In glottic tumours, larynx-sparing surgery is reported to have local cancer control rates ranging from 86% to 98% and a 5-year disease-specific survival rate of 92% to 97%.[43][44]​ Although the data vary, larynx-sparing surgery and radiotherapy for treatment of T1 and T2 laryngeal cancers show similar survival rates.​[45][46]​ In experienced hands, endoscopic resection of T1 lesions has been shown to yield better outcomes than definitive radiotherapy.[46] However, one systematic review showed similar voice outcomes between surgery and radiotherapy.[42]​ Single-mode treatment of T1 laryngeal cancer with radiotherapy has a similar survival rate to surgery. For carcinoma in situ, endoscopic resection is preferred if possible.[1]​ For patients with adverse features on final pathology (i.e., close or positive margins, extranodal extension, etc.), adjuvant therapy is also recommended.

In supraglottic tumours, open or endoscopic surgery is comparable to radiotherapy alone, although some report that there is a higher local control rate with open surgery.[46] For patients with T1 and T2 cancers, transoral microlaser surgery or transoral robotic surgery should be offered where possible as a treatment option in addition to open surgery, other larynx-sparing surgeries, and radiotherapy.[1]​ There is insufficient evidence to determine whether the endoscopic surgical techniques are superior to radiotherapy, but the vocal and quality of life outcomes for radiotherapy and transoral laser surgery appear to be equivalent.[47][48][49]

Patients with T1 or T2 tumours with N1-N2c M0 staging (N1 M0, N2a M0, N2b M0, or N2c M0) have more deeply invasive lesions with regional lymph node metastases ≤6 cm in size but no distant metastases. Laryngeal surgery (with partial or total laryngectomy) or radiotherapy or concurrent chemotherapy and radiotherapy is recommended.[1] Cisplatin or carboplatin may be given with or without fluorouracil.[1]​ In cases of excessive toxicity, patients may be treated with the monoclonal antibody cetuximab. Cetuximab binds specifically to the epidermal growth factor receptor (EGFR) expressed on epithelial tissues and inhibits the growth of tumour cells that express EGFR. Adjuvant chemotherapy may be used postoperatively for certain unfavourable tumour characteristics (e.g., angiolymphatic or perineural invasion, extracapsular spread).[50]

Neck dissection is recommended for patients undergoing laryngectomy prior to adjuvant radiotherapy or chemoradiotherapy. A systematic review using a number-needed-to-treat cut-off of 5 has provided recommendations on the appropriate lymph node level for dissection.[51]

Glottic and supraglottic tumours: T3 (N0-N2c M0)

Treatment in T3 tumours (N0-N2c M0) involves either concurrent chemotherapy and radiotherapy or surgery. Patients with N0-N2c M0 staging have either no regional or distant lymph node metastases (N0 M0) or regional lymph node metastases ≤6 cm in size but no distant metastases (N1 M0, N2a M0, N2b M0, or N2c M0). Partial laryngectomy or total laryngectomy can be used depending on location and size of the tumour; partial laryngectomy allows for preservation of speech and swallowing function in highly selected cases.[44] The choice between surgery and concurrent chemoradiotherapy for patients with primary T3 tumours is a matter of debate.[52][53]​ Chemoradiotherapy has the advantage of allowing better preservation of speech and swallowing function if the alternative option requires total laryngectomy. However, a retrospective observational cohort study of over 7000 patients from the National Cancer Database found that, in patients with T3 laryngeal cancer, those treated with chemoradiotherapy had a significantly increased risk for death compared with those treated with total laryngectomy (hazard ratio=1.18; P=0.03).[52] Radiation alone, however, has been shown to be inferior to the above-mentioned therapies for T3 and T4 tumours.​[52][54][55]

Cisplatin (preferred) or carboplatin may be given with or without fluorouracil.[1]​ In cases of excessive toxicity, patients may be treated with the monoclonal antibody cetuximab. The addition of cetuximab to cisplatin in combination with radiation does not improve outcome compared with radiation plus cisplatin only.[56] Similarly, altered fractionated radiation plus cisplatin does not confer any advantage over standard cisplatin chemoradiation.[57]

Other chemotherapy options for T3 tumours to be given concurrently with radiotherapy include:[1][58]

  • Fluorouracil/hydroxycarbamide

  • Carboplatin/paclitaxel

  • Cisplatin/paclitaxel

  • Docetaxel

  • Docetaxel/cetuximab.

Neck dissection is recommended for persistent neck disease after chemoradiotherapy and in patients undergoing laryngectomy with clinically positive neck disease.[51] The role of neck dissection following chemoradiotherapy, however, remains controversial.[59]

Adjuvant chemotherapy may be used postoperatively for certain unfavourable tumour characteristics (e.g., positive margins, >4 lymph nodes, extracapsular spread).[50] See local specialist protocol for dosing guidelines.

Locoregional control and larynx preservation were found to be significantly improved with concomitant chemoradiation compared with induction chemotherapy followed by radiotherapy or compared with radiotherapy alone.[60] However, induction chemotherapy, with management based on response, remains an option for all but T1-T2 N0 glottic and supraglottic cancer.[1]

Glottic and supraglottic tumours: T4 or N3 or M1, suitable for definitive treatment

Patients with N3 staging have regional lymph node metastases >6 cm. Patients with M1 staging have distant metastases. Treatment involves either concurrent chemotherapy and radiotherapy or surgery. Neck dissection and adjuvant (postoperative) radiotherapy may also be required. For M1 disease, surgery is not usually first-line treatment.

Chemoradiotherapy or surgery are equally effective if cartilage is not involved. Total laryngectomy is recommended over concurrent chemotherapy and radiotherapy if cartilage is involved.​[61] In cases of cartilage invasion, positive or close margins, multiple positive cervical lymph nodes, or extracapsular extension of disease, adjuvant (postoperative) chemoradiotherapy is recommended. Neck dissection after chemoradiotherapy is recommended for persistent neck disease after and in patients undergoing laryngectomy with clinically positive neck disease.[51] The role of neck dissection following chemoradiotherapy in an N0 neck; however, remains controversial.[59] Good local control has been demonstrated after open partial laryngectomy in patients with radiorecurrent laryngeal cancer, although the technique is not widely practised in this setting.[62]

The choice of chemotherapy agents for patients receiving definitive treatment is the same as for T3 tumours.[1] Adjuvant chemoradiotherapy may be used postoperatively for certain unfavourable tumour characteristics (e.g., angiolymphatic or perineural invasion, extracapsular spread).[50]

The preferred regimen is high-dose cisplatin, or a combination of carboplatin plus fluorouracil. Other recommended regimens include weekly cisplatin, or carboplatin plus paclitaxel. In addition, the following regimens may be potentially useful: a combination of fluorouracil plus hydroxyurea; cetuximab; a combination of cisplatin plus fluorouracil or paclitaxel; or docetaxel (if cisplatin ineligible).[1]​​​ Immunotherapy with pembrolizumab or nivolumab may also be recommended for patients with unresectable tumours.[1] Subcutaneous nivolumab/hyaluronidase may be substituted for intravenous nivolumab.​[1]

Locoregional control and larynx preservation were found to be significantly improved with concomitant chemoradiation compared with induction chemotherapy followed by radiotherapy or compared with radiotherapy alone.[60] ​

Some patients with limited metastases at initial presentation may be candidates for surgery, concurrent chemotherapy and radiotherapy, or radiotherapy alone.[1]

Some patients with T4 tumours that are unresectable, but with no metastases, may be candidates for concurrent chemotherapy and radiotherapy, or induction chemotherapy followed by radiotherapy, or radiotherapy alone.[1] If the patient’s performance status is poor, they may be offered palliative radiotherapy, single-agent systemic therapy, or best supportive care.[1]

Glottic and supraglottic tumours: T4 or N3 or M1, not suitable for definitive treatment, but candidate for systemic therapy

Patients who have unresectable or metastatic disease and no options for surgery or radiotherapy may nonetheless be candidates for systemic therapy. A patient’s performance status may limit the systemic options available to them. Those with a higher Eastern Cooperative Oncology Group (ECOG) score (i.e., >2) will have to weigh the risks and benefits of treatment toxicity. Regimens recommended by the US guidelines include:[1][37]​​​​​​

  • First line

    • Pembrolizumab with a platinum compound (cisplatin or carboplatin) and fluorouracil

    • Pembrolizumab monotherapy (for tumours that express programmed death-ligand 1 [PD-L1] with a combined positive score [CPS] ≥1).

  • Subsequent line (if not previously used)

    • Nivolumab (if disease progression on or after platinum therapy). Subcutaneous nivolumab/hyaluronidase may be substituted for intravenous nivolumab.

    • Pembrolizumab (if disease progression on or after platinum therapy).

Other recommended first- and subsequent-line regimens include combination therapy or single agents. Options for combination therapy include:[1]

  • Cetuximab with a platinum compound (cisplatin or carboplatin) and fluorouracil

  • Cisplatin with cetuximab

  • A platinum compound (cisplatin or carboplatin) with docetaxel or paclitaxel

  • Cisplatin with fluorouracil

  • A platinum compound (cisplatin or carboplatin) with docetaxel and cetuximab

  • A platinum compound (cisplatin or carboplatin) with paclitaxel and cetuximab

  • Pembrolizumab with a platinum compound (cisplatin or carboplatin) and docetaxel

  • Pembrolizumab with a platinum compound (cisplatin or carboplatin) and paclitaxel.

Single-agent options include:[1]

  • Cisplatin

  • Carboplatin

  • Paclitaxel

  • Docetaxel

  • Fluorouracil

  • Methotrexate

  • Cetuximab

  • Capecitabine

  • Afatinib (subsequent-line only, if disease progression on or after platinum therapy).

Subglottic tumours

Primary tumours of the subglottis are extremely rare resulting in limited data and lack of general guidelines. Treatment of these tumours should be discussed at a multidisciplinary tumour board and may be treated with chemoradiation or by total laryngectomy and neck dissection surgery (including thyroidectomy) followed by radiotherapy with or without chemotherapy.

Treatment not effective or appropriate

Patients for whom no treatment options have been effective or who are not candidates for therapy should be offered supportive care.

Chemotherapy can be used in combination therapy or as single agents in palliative circumstances. In addition, patients with advanced cancer who are not candidates for systemic chemotherapy may nonetheless benefit from immunotherapy or molecular targeted therapies, which may relieve symptoms and/or improve quality of life with fewer adverse effects than cytotoxic chemotherapy.[63]

Recurrence

Physical examination including laryngoscopy is most important in detection of recurrence.

Imaging and physical examination are vital in the setting of suspected recurrence or persistence of cancer. Various imaging modalities are available, but all require biopsy for a definitive result.[64] Surgical salvage is the standard of care in patients with recurrent disease that is considered resectable and who are medically fit for surgery.[65]​ Postoperative re-irradiation may be considered. In patients re-irradiated with curative intent, the addition of chemotherapy or immunotherapy is typically used.​[37][65]​​

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