What Is the Best Initial Treatment for Stage 4 or Recurrent Head and Neck Cancer?

Recurrent or metastatic (stage 4) head and neck squamous cell cancer generally has a poor prognosis (disease course). In most studies, median survival is 6 to 15 months, but this varies with factors related to the patient, cancer status and selected treatment regimens.

Systemic treatment (not local, affecting the whole body) should be given alongside best supportive care for most patients with metastatic or recurrent head and neck cancer. However, which systemic medicines to choose for these patients has long been debated.

In the image below, head and neck cancers can arise in the classified anatomical regions shown:

Treatment options for stage 4 or recurrent squamous cell head and neck cancer include;

• Conventional cytotoxic (cell-killing) chemotherapies,
• A molecularly targeted medicine called cetuximab (Erbituks), often combined with chemotherapy,
• Best supportive care (palliative care) and
• Checkpoint immunotherapies .

The most commonly used medicines in head and neck cancer are;

• Platinum compounds (cisplatin, carboplatin),
• Taxanes (docetaxel, paclitaxel, nanoparticle albumin-bound paclitaxel [nabpaclitaxel]),
• Fluorouracil (5FU),
• Methotrexate,
• Cetuximab, and
• The anti-PD-1 checkpoint immunotherapies pembrolizumab (Keytruda) and nivolumab (Opdivo).

Immunotherapy in head and neck cancer received, in August (Pembrolizumab) and November (Opdivo) 2016, FDA approvals. Under these approvals, in patients with metastatic or recurrent squamous cell head and neck cancer progressing after previous platinum-based chemotherapy, second-line immunotherapy shows activity and provides significant benefit.

This raised the question of whether immunotherapies would also be effective as first-line treatment in these patients, and the results, at the ESMO 2018 Congress, were presented for the clinical study called KEYNOTE-048.

In the phase III KEYNOTE-048 study, the immunotherapy pembrolizumab, compared with standard treatment, was examined for whether it controlled disease and extended lifespan.

For metastatic or recurrent head and neck cancer, the current standard initial treatmentis platinum-based chemotherapy [cisplatin or carboplatin with 5-fluorouracil (5-FU)] plus the EGFR inhibitor cetuximab.

This study enrolled 601 patients, randomly assigned in equal proportions to 3 groups:

1. Standard treatment: platinum-based chemotherapy (cisplatin or carboplatin with 5-FU) and cetuximab (control group)
2. Pembrolizumab alone
3. A new combination of pembrolizumab plus platinum-based chemotherapy.

Results for the immunotherapy pembrolizumab compared with standard treatment were presented for all patients regardless of PD-L1 positivity.

• According to the study results; PD-L1-positive patients (combined positive score [CPS]> 20) had overall survival of 14.9 months with pembrolizumab compared with 10.7 months with standard treatment.
• Regardless of PD-L1 level;
  • Overall survival was 13 months with the immunotherapy plus chemotherapy combination and 10.7 months with standard treatment.
  • The immunotherapy-containing regimen reduced the risk of death by % 23.

This study showing first-line immunotherapy activity can be compared with the study published in NEJM in 2008 that defined the current standard treatment for metastatic or recurrent head and neck cancer, the EXTREME study . EXTREME first showed that the platinum + 5FU + cetuximab triplet regimen was superior to the platinum + 5FU doublet regimen, increasing median life expectancy in this group from 7 months to around 10 months.

Now, comparing the results of these two landmark studies in the history of head and neck cancers;

Conclusion

Although immunotherapies have not yet received, for first-line systemic treatment of stage 4 or recurrent squamous cell head and neck cancer, FDA approval, the survival improvement shown in KEYNOTE-048 indicates that immunotherapies are moving toward becoming standard initial treatment for this disease stage. This clinical study is also the first in the past decade to show superior survival over standard first-line treatment. Particularly in the PD-L1-positive group, pembrolizumab alone appears superior to all other treatments.