What is the role of induction chemotherapy in locoregionally advanced head and neck cancers?

Role of Induction Chemotherapy in Locoregionally Advanced Head and Neck Cancers

Induction chemotherapy is NOT standard treatment for most locoregionally advanced head and neck cancers, with the specific exception of organ preservation strategies in advanced larynx and hypopharynx cancer requiring total laryngectomy. 1

Standard Treatment Approach

Concurrent chemoradiation with high-dose cisplatin (100 mg/m² on days 1,22, and 43) remains the preferred standard treatment for locoregionally advanced disease. 1

• For resectable stage III-IV tumors, surgery with reconstruction plus postoperative radiotherapy (or chemoradiotherapy for high-risk features like extracapsular extension or positive margins) is the primary approach 1
• When anticipated functional outcomes with surgery are poor in resectable patients, concurrent chemoradiation is preferable to surgery 1
• For non-resectable patients, concurrent chemoradiation is the definitive standard treatment 1

Limited Role of Induction Chemotherapy

Where Induction Chemotherapy Has Evidence

The only established role for induction chemotherapy is organ preservation in advanced larynx and hypopharynx cancer in patients who would otherwise require total laryngectomy. 1

• TPF (docetaxel, cisplatin, fluorouracil) induction followed by radiotherapy in responsive patients allows larynx preservation 1, 2
• This approach has no negative impact on disease-free or overall survival due to successful salvage surgery 1
• Patients generally experience a slight increase in locoregional recurrence but reduction in distant metastases 1
• Patients with massive larynx cartilage invasion should be excluded from organ preservation approaches 1

Controversy and Lack of Consensus

The NCCN guidelines reveal significant disagreement among expert institutions regarding induction chemotherapy: 1

• Category 3 designation (major disagreement) for T3-4a, N0-1 oropharyngeal disease 1
• Category 2B designation (non-uniform consensus) for any T, N2-3 disease due to increased distant metastasis risk 1
• Only hypopharyngeal cancers less than T4a requiring total laryngectomy achieve Category 2A consensus for induction chemotherapy as part of larynx preservation 1

Evolution of Induction Regimens

While taxane-platinum-based combinations (TPF) have proven superior to platinum-fluorouracil (PF) schedules, this has not translated into making induction chemotherapy standard treatment. 1

• TPF demonstrates improved response rates, disease-free survival, and overall survival compared to PF in locoregionally advanced disease 1
• The FDA has approved docetaxel in combination with cisplatin and fluorouracil for induction treatment of locally advanced squamous cell carcinoma of the head and neck 2
• Despite improved chemotherapy regimens, most randomized trials from the 1980s-1990s showed no overall survival benefit when induction chemotherapy was added to locoregional treatment 1

Critical Limitations and Concerns

Sequential treatment with induction chemotherapy followed by chemoradiation (ICT-CRT) remains under evaluation, with substantial concerns about cumulative toxicity compromising final outcomes. 1

• The overall toxicity of sequential ICT-CRT can be substantial and may compromise treatment completion 1
• No clear advantage in overall survival has been demonstrated from adding induction chemotherapy to concurrent chemoradiation 1
• The RTOG 91-11 trial demonstrated that concurrent cisplatin/radiotherapy achieved superior laryngeal preservation (88% at 2 years) compared to induction chemotherapy followed by radiotherapy (74%) 1

Specific Clinical Scenarios

For T4a Disease

Induction chemotherapy is NOT preferred for T4a disease; surgery followed by adjuvant therapy or concurrent chemoradiation are the standard approaches. 3

• Total laryngectomy with partial/total pharyngectomy plus neck dissection followed by adjuvant chemoradiation is preferred for T4aN1M0 hypopharyngeal cancer 3
• Concurrent chemoradiation with cisplatin represents an alternative only for patients who decline surgery or are medically unfit 3

For Organ Preservation Candidates

When larynx preservation is the patient's priority and total laryngectomy would otherwise be required, TPF induction followed by radiotherapy in responders is an acceptable option. 1

• The choice between induction-based or concurrent chemoradiation-based organ preservation depends on anatomical subsite, anticipated treatment tolerance, and performance status 1
• Concurrent chemoradiation achieved higher initial larynx preservation rates but similar long-term survival compared to induction approaches 1

Important Caveats

• Multidisciplinary consultation is mandatory before initiating any treatment approach 3
• Safe administration of TPF requires treatment by an experienced multidisciplinary team at a specialized institution 4
• Response to induction chemotherapy predicts overall survival, locoregional control, and time to progression 5
• Post-induction treatment selection (radiotherapy alone versus chemoradiation, and choice of concurrent agent) remains controversial with no current consensus 4, 6
• Induction chemotherapy may reduce distant metastases but this benefit must be weighed against potential delays in definitive locoregional treatment 1