Surgery and/or Radiation Therapy

Surgery and/or Radiation Therapy

Surgery and radiation therapy have been the standards for the treatment of laryngeal cancer; however, outcome data from randomized trials are limited. Studies have attempted to address the question of whether to use surgery or radiation, but the studies have been underpowered.[1] Selection of primary surgery versus radiation therapy-based treatment should be made in a multidisciplinary setting with consideration of disease stage, comorbidities, and functional status, including voice and swallowing outcomes and lung capacity.


Small superficial cancers without laryngeal fixation or lymph node involvement are successfully treated by radiation therapy or surgery alone, including laser excision surgery. Radiation therapy may be selected to preserve the voice and to reserve surgery for salvaging failures. The radiation field and dose are determined by the location and size of the primary tumor. A variety of curative surgical procedures are also recommended for laryngeal cancers, some of which preserve vocal function. An appropriate surgical procedure must be considered for each patient, given the anatomic problem, performance status, and clinical expertise of the treatment team. Advanced laryngeal cancers are often treated by combining radiation with concurrent chemotherapy for larynx preservation and total laryngectomy for bulky T4 disease or salvage.[2-4]


Evaluation of treatment outcome can be reported in various ways: locoregional control, disease-free survival, determinate survival, and overall survival (OS) at 2 to 5 years. Preservation of voice is an important parameter to evaluate. Outcome should be reported after initial surgery, initial radiation, planned combined treatment, or surgical salvage of radiation failures. Primary source material should be consulted to review these differences.

A review of published clinical results of definitive radiation therapy for head and neck cancer suggests a significant loss of local control when the administration of radiation therapy was prolonged; therefore, lengthening of standard treatment schedules should be avoided whenever possible.[5,6]


Direct comparison of the results of radiation therapy versus endolaryngeal surgery (with or without laser) has not been made for patients with early-stage laryngeal cancer. The evidence is insufficient to show a clear difference in the results between treatment options regarding local control or OS. Retrospective data suggest that in comparison with surgery, radiation therapy might cause less perturbation of voice quality without a significant difference in patient perception.[7]

Concurrent Chemoradiation Therapy

Concurrent chemoradiation therapy is a standard treatment option for patients with locally advanced (stage III and stage IV) laryngeal cancer.

Evidence (concurrent chemoradiation therapy):

  1. A meta-analysis of 93 randomized prospective head and neck cancer trials published between 1965 and 2000 showed the following:[8][Level of evidence: 2A]
    • The subset of patients receiving chemotherapy and radiation therapy had a 4.5% absolute survival advantage.
    • Patients who received concurrent chemotherapy had a greater survival benefit than those who received neoadjuvant chemotherapy.
  2. In a randomized trial of patients with locally advanced head and neck cancer, curative-intent radiation therapy alone (213 patients) was compared with radiation therapy plus weekly cetuximab (211 patients).[9] The initial dose of cetuximab was 400 mg/m2 of body-surface area 1 week before radiation therapy was started, followed by a weekly dose of 250 mg/m2 of body-surface area for the duration of the radiation therapy. This study allowed altered-fractionation regimens to be used in both arms.[9,10][Level of evidence: 1iiA]
    • At a median follow-up of 54 months, patients treated with cetuximab and radiation therapy demonstrated significantly higher progression-free survival (PFS) (hazard ratio [HR] for disease progression or death, 0.70; P = .006).
    • Patients in the cetuximab arm experienced higher rates of acneiform rash and infusion reactions, although the incidence of other grade 3 or higher toxicities, including mucositis, did not differ significantly between the two groups.

(Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information about oral toxicities.)

Neoadjuvant Chemotherapy Followed by Concurrent Chemoradiation Therapy

In a meta-analysis of five randomized trials, a total of 1,022 patients with locally advanced head and neck squamous cell cancer were randomly assigned to receive either neoadjuvant chemotherapy with TPF (docetaxel, cisplatin, and fluorouracil) followed by concurrent chemoradiation therapy or concurrent chemoradiation therapy alone. The analysis failed to show an OS (HR, 1.01; 95% confidence limits [CLs], 0.84–1.21; P = .92) or PFS (HR, 0.91; 95% CLs, 0.75–1.1; P = .32) advantage for neoadjuvant chemotherapy using the TPF regimen over concurrent chemoradiation therapy alone.[11][Level of evidence: 1iA]

Evidence (neoadjuvant chemotherapy followed by concurrent chemoradiation therapy):

  1. A direct comparison of chemotherapy followed by radiation therapy versus up-front surgery was made by The Department of Veterans Affairs (VA) Laryngeal Cancer Study Group in a trial in which 332 patients were randomly assigned to three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy.[12]
    • After two cycles of chemotherapy, the clinical tumor response was complete in 31% of the patients, and there was a partial response in 54% of the patients. Survival was similar in both arms; however, larynx preservation was possible in 64% of the patients in the chemotherapy-followed-by-radiation therapy arm.
  2. The VA study was followed up in a randomized study, RTOG 9111 (NCT00002496), in which the laryngeal preservation arm of the VA study was compared with the concurrent chemoradiation therapy and radiation therapy-alone arms, and the primary endpoint was laryngectomy-free survival.[4] The RTOG 9111 study evaluated 547 patients with locally advanced laryngeal cancer who were enrolled between August 1992 and May 2000, with a median follow-up for surviving patients of 10.8 years (range, 0.07–17 years). Three regimens were compared, including neoadjuvant chemotherapy plus radiation therapy, concurrent chemoradiation therapy, and radiation therapy alone.
    • Both chemotherapy regimens improved laryngectomy-free survival compared with radiation therapy alone (neoadjuvant chemotherapy vs. radiation therapy alone, HR, 0.75; 95% confidence interval [CI], 0.59–0.95; = .02; concurrent chemotherapy vs. radiation therapy alone, HR, 0.78; 95% CI, 0.78–0.98; P = .03).
    • Concurrent radiation therapy plus cisplatin resulted in a statistically significantly higher percentage of patients with an intact larynx at 10 years (67.5% for patients who had neoadjuvant chemotherapy; 81.7% for patients who had concurrent chemotherapy; and 63.8% for patients who received radiation therapy alone); 80% of laryngectomies were performed during the first 2 years (84 laryngectomies during year 1 and 35 laryngectomies during year 2).
    • Concurrent cisplatin with radiation therapy resulted in a 41% reduction in risk of locoregional failure compared with radiation therapy alone (HR, 0.59; 95% CI, 0.43–0.82; P = .0015) and a 34% reduction in risk compared with neoadjuvant chemotherapy (HR, 0.66; 95% CI, 0.48–0.92; P = .004). Both chemotherapy regimens had a lower incidence of distant metastases, although this did not reach statistical significance compared with radiation therapy alone.
    • The 10-year cumulative rates of late toxicity (grades 3–5) were 30.6% for neoadjuvant chemotherapy, 33.3% for concurrent chemotherapy, and 38% for radiation therapy alone, and were not significantly different between the arms.
    • OS was not significantly different between the groups, although there was possibly a worse outcome in the concurrent groups compared with the neoadjuvant chemotherapy group (HR, 1.25; 95% CI, 0.98–1.61; P = .08). The OS rates were 58% (5 year) and 39% (10 year) for neoadjuvant chemotherapy, 55% (5 year) and 28% (10 year) for concurrent chemoradiation therapy, and 54% (5 year) and 32% (10 year) for radiation therapy alone.
    • The number of deaths not attributed to larynx cancer or treatment were higher with concurrent chemotherapy (30.8% vs. 20.8% with neoadjuvant chemotherapy and 16.9% with radiation alone), because after approximately 4.5 years, the survival curves began to separate and favor neoadjuvant chemotherapy, although the difference was not statistically significant.

Altered Fractionation Versus Standard Fractionation Radiation Therapy

Radiation therapy alone with altered fractionation may be used for patients with locally advanced laryngeal cancer who are not candidates for chemotherapy. Altered fractionation radiation therapy yields a higher locoregional control rate compared with standard fractionated radiation therapy for patients with stage III and stage IV head and neck cancer.

Evidence (altered fractionation vs. standard fractionation radiation therapy):

  1. The randomized trial RTOG-9003 (NCT00771641) included four radiation therapy treatment arms:[13,14][Level of evidence: 1iiA]
    • Standard fractionation (SFX) to 70 Gy in 35 daily fractions for 7 weeks.
    • Hyperfractionation (HFX) to 81.6 Gy in 68 twice-daily fractions for 7 weeks.
    • Accelerated fractionation split course (AFX-S) to 67.2 Gy in 42 fractions for 6 weeks with a 2-week rest after 38.4 Gy.
    • Accelerated concurrent boost fractionation (AFX-C) to 72 Gy in 42 fractions for 6 weeks.
      In a long-term analysis, the three investigational arms were compared with SFX.
    • Only the HFX arm showed superior locoregional control and survival at 5 years compared with the SFX arm (HR, 0.79; 95% CI, 0.62–1.00; P = .05).
    • AFX-C was associated with increased late toxicity compared with SFX.
  2. The following results were shown in a meta-analysis of 15 randomized trials with a total of 6,515 patients and a median follow-up of 6 years involving the assessment of HFX or AFX-S for patients with stage III and stage IV oropharyngeal cancer:[15][Level of evidence: 1iiA]
    • There was a significant survival benefit with altered-fractionated radiation therapy and a 3.4% absolute benefit at 5 years (HR, 0.92; 95% CI, 0.86–0.97; P = .003).
    • Altered-fractionation radiation therapy improves locoregional control, with greater benefit shown in younger patients.
    • HFX demonstrated a greater survival benefit (8% at 5 years) than did AFX-S (2% with accelerated fractionation without total dose-reduction and 1.7% with total dose-reduction at 5 years, P = .02).

An additional late effect from radiation therapy is hypothyroidism, which occurs in 30% to 40% of patients who have received external-beam radiation therapy to the entire thyroid gland. Thyroid function testing of patients is a consideration before therapy and as part of posttreatment follow-up.[16,17]

Prospective data of two randomized controlled trials reported the incidence of hypothyroidism.[18]

  • At a median follow-up of 41 months, 55.1% of the patients developed hypothyroidism (39.3% subclinical, 15.7% biochemical).
  • Patients who underwent intensity-modulated radiation therapy (IMRT) had higher subclinical hypothyroidism (51.1% vs. 27.3%; P = .021), peaking around 1 year after radiation therapy.
  • Younger age, hypopharynx/larynx primary, node positivity, higher dose/fraction (IMRT arm), and D100 were statistically significant factors for developing hypothyroidism.[18][Level of evidence: 1iiC]

For patients with well-lateralized oropharyngeal cancer, such as a T1 or T2 tonsil primary tumor with limited extension into the palate or tongue base and limited ipsilateral lymph node involvement without extracapsular extension, elective treatment to the ipsilateral lymph nodes results in only minimal risk of spread to the contralateral neck.[19] For T3 and T4 tumors that are midline or approach the midline, bilateral nodal treatment is a consideration. In addition to the cervical lymph node chain, retropharyngeal lymph nodes can also be encompassed in the elective nodal treatment.


Surgery Followed by Postoperative Radiation Therapy (PORT) With or Without Chemotherapy for Patients With Locally Advanced Disease

New surgical techniques for resection and reconstruction that provide access and functional preservation have extended the surgical options for patients with stage III or stage IV laryngeal cancer. Specific surgical procedures and their modifications are not described here because of the wide variety of surgical approaches, the variety of opinions about the role of modified neck dissections, and the multiple reconstructive techniques that may give the same results. This group of patients is managed by head and neck surgeons who are skilled in the multiple procedures available and are actively and frequently involved in the care of these patients.

Depending on pathological findings after primary surgery, PORT with or without chemotherapy is used in the adjuvant setting for the following histological findings:

  • T4 disease.
  • Perineural invasion.
  • Lymphovascular invasion.
  • Positive margins or margins less than 5 mm.
  • Extracapsular extension of a lymph node.
  • Two or more involved lymph nodes.

The addition of chemotherapy to PORT for laryngeal cancer squamous cell carcinoma demonstrates a locoregional control and OS benefit compared with radiation therapy alone in patients who have high-risk pathological risk factors, extracapsular extension of a lymph node, or positive margins, based on a pooled analysis of the EORTC-22931 [NCT00002555] and RTOG-9501 [NCT00002670] studies.[20-23][Level of evidence: 1iiA]

For patients with intermediate pathological risk factors, the addition of cisplatin chemotherapy given concurrently with PORT is unclear. Intermediate pathological risk factors include:

  • T3 and T4 disease (or stage III and stage IV disease).
  • Perineural infiltration.
  • Vascular embolisms.
  • Clinically enlarged level IV–V lymph nodes secondary to tumors arising in the oral cavity or oropharynx.
  • Two or more histopathologically involved lymph nodes without extracapsular extension.
  • Close margins less than 5 mm.

The addition of cetuximab with radiation therapy in the postoperative setting for these intermediate pathological risk factors is being tested in a randomized trial (RTOG-0920 [NCT00956007]).

The risk of lymph node metastases in patients with stage I glottic cancer ranges from 0% to 2%, and for more advanced disease, such as stage II, the incidence is 10%, and for stage III glottic, the incidence is 15%. Thus, there is no need to treat glottic cancer cervical lymph nodes electively in patients with stage I tumors and small stage II tumors. Elective neck radiation is a consideration for T3 or T4 glottic tumors or T1 to T4 supraglottic tumors.[24]

For patients with cancer of the subglottis, combined modality therapy is generally preferred for the uncommon small lesions (i.e., stage I or stage II); however, radiation therapy alone may be used.

Patients who smoke during radiation therapy appear to have lower response rates and shorter survival durations than those who do not;[25] therefore, patients should be counseled on smoking cessation before beginning radiation therapy.


References

  1. Iyer NG, Tan DS, Tan VK, et al.: Randomized trial comparing surgery and adjuvant radiotherapy versus concurrent chemoradiotherapy in patients with advanced, nonmetastatic squamous cell carcinoma of the head and neck: 10-year update and subset analysis. Cancer 121 (10): 1599-607, 2015. [PUBMED Abstract]
  2. Silver CE, Ferlito A: Surgery for Cancer of the Larynx and Related Structures. 2nd ed. Saunders, 1996.
  3. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
  4. Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013. [PUBMED Abstract]
  5. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992. [PUBMED Abstract]
  6. Hansen O, Overgaard J, Hansen HS, et al.: Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiother Oncol 43 (1): 47-51, 1997. [PUBMED Abstract]
  7. Yoo J, Lacchetti C, Hammond JA, et al.: Role of endolaryngeal surgery (with or without laser) compared with radiotherapy in the management of early (T1) glottic cancer: a clinical practice guideline. Curr Oncol 20 (2): e132-5, 2013. [PUBMED Abstract]
  8. Pignon JP, le MaĆ®tre A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009. [PUBMED Abstract]
  9. Bonner JA, Harari PM, Giralt J, et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354 (6): 567-78, 2006. [PUBMED Abstract]
  10. Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007. [PUBMED Abstract]

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