Episode 159: Head and Neck Cancer Series, Pt. 2 – Locoregional Disease
This week we get into treatment. Building on Part 1's workup and staging, we walk through three cases to highlight the important distinguishing details: an oral cavity cancer, a locally advanced oropharynx cancer, and a larynx cancer. We discuss how treatment modality is chosen by stage and subsite, the impact of high risk features, the cisplatin dosing, induction chemotherapy actually helps, larynx preservation, and the brand-new perioperative immunotherapy data.
If you haven’t done so already, we highly recommend checking out Episode 158 first!
This episode is sponsored by Primum! To learn more, sign up for your free account, and to ask questions to Primum experts, click here!
How do you decide treatment modality in head and neck cancer?
The organizing principle is stage and subsite.
Early-stage disease (roughly T1–T2, N0) is treated with a single modality — surgery or radiation alone — because one modality cures these and adding a second just stacks toxicity.
Locally advanced disease is multimodality - some combination of surgery, radiation, and systemic therapy. Remember from Part 1: "locally advanced / Stage IV" is frequently still curable.
Subsite steers the default:
Oral cavity → surgery first, with adjuvant radiation or chemoradiation based on pathology.
Oropharynx → definitive chemoradiation is the typical backbone (with a separate, evolving algorithm for p16+ disease), though surgery/TORS has a growing role.
Larynx / hypopharynx → organ-preservation chemoradiation, because the goal is to avoid total laryngectomy and its morbidity.
Overarching theme for the whole episode: in head and neck cancer, locoregional control is the dominant driver of overall survival. Most of what we do is in service of controlling disease in the neck.
Case 1: Oral cavity.
A 58-year-old man with a heavy smoking and alcohol history develops an ulcer under the anterior tongue and has lost 30 pounds over two months. Biopsy of the floor of mouth shows invasive squamous cell carcinoma, and staging CT shows sclerosis of the left mandible but no metastatic disease. How are you treating this?
Default is surgery up front — primary resection with attention to margins, and because there's concern for cortical bone erosion of the mandible, a mandibulectomy plus neck dissection.
Radiation as the primary modality for oral cavity is uncommon and reserved for patients who can't have surgery — surgery is the workhorse here.
He's clinically node-negative. Do you still dissect the neck, or watch it?
Electively dissect the neck
The practice-changing trial wasD'Cruz and colleagues from Tata Memorial (NEJM 2015): in clinically node-negative early oral cavity cancer, elective neck dissection improved both overall and disease-free survival compared to therapeutic dissection at relapse.
Why this appears to be effective: micrometastatic nodal disease is common, and finding and clearing it early and identifying who needs adjuvant therapy — beats waiting for it to declare itself.
Board pearl: elective neck dissection improves survival in the cN0 oral cavity patient.
(Sentinel lymph node biopsy is an option in select early oral cavity cancers in experienced hands, but the data are more limited than for melanoma or breast.)
Final pathology shows two left level II nodes with extranodal extension, plus one right level II node. Margins are negative. Radiation alone, or chemoradiation?
This is high yield - pay attention to the pathology report!
The answer here is adjuvant concurrent chemoradiation, because he has extranodal extension.
The two landmark adjuvant trials, both from 2004, are worth knowing cold:
EORTC 22931 (Bernier et al., NEJM 2004): adding concurrent cisplatin to postoperative radiation improved overall survival in high-risk patients and improved locoregional control.
RTOG 9501 (Cooper et al., NEJM 2004): same question; concurrent chemoradiation improved locoregional control and disease-free survival, but the overall survival benefit did not reach significance in the overall trial population.
The two trials seemed to disagree, so Bernier, Cooper, and colleagues did apooled/comparative analysis (Head & Neck 2005) and found the resolution: the patients who clearly benefit from adding chemotherapy are those with extranodal extension and/or positive margins. Those two features are the "must-treat-with-chemo" adverse features.
Other adverse features (multiple positive nodes, pN2/N3, perineural or lymphovascular invasion, level IV/V nodes, pT3/T4) push you toward chemoradiation but are softer indications — the hard, board-level triggers are ENE and positive margins. Our patient has ENE → adjuvantconcurrent chemoradiation it is.
Which chemo? This is where the board answer and the real-world answer famously diverge.
The board answer is high-dose cisplatin, 100 mg/m² every three weeks for three cycles, given concurrently with radiation. That's the regimen used in the pivotal trials, especially the MACH-NC meta-analysis (Pignon et al., Radiother Oncol 2009)
A massive individual-patient meta-analysis showing that adding concurrent chemotherapy to radiation produced an absolute overall survival benefit of roughly 6–8%, with concurrent clearly beating induction or adjuvant timing. Crucially, that benefit shrank with increasing age and largely disappeared in the elderly.
High-dose cisplatin is brutal. Is all that toxicity necessary if the goal is locoregional control?
High-dose cisplatin causes substantial toxicity — grade 3/4 neutropenia in roughly a third of patients, meaningful ototoxicity and nephrotoxicity, and dose modification or discontinuation in a large minority.
Is there data for alternative regimens
Weekly cisplatin 40 mg/m²: JCOG 1008 (Kiyota et al., JCO 2022) tested weekly 40 mg/m² against q3-week 100 mg/m² in the adjuvant setting and found weekly dosing non-inferior with a better toxicity profile. This is why you'll see weekly cisplatin widely in the community.
But cumulative dose matters: the Tata Memorial trial (Noronha et al., JCO 2018) compared weekly 30 mg/m² to q3-week 100 mg/m² and found the low weekly dose inferior for locoregional control. The likely explanation: 30 mg/m² weekly delivers a lower cumulative cisplatin dose. JCOG 1008's 40 mg/m² weekly held up because it reaches a higher cumulative dose.
Bottom line — if you go weekly, dose and cumulative exposure matter.
Another induction approach you may see is weekly carboplatin (AUC 1) plus paclitaxel (~30–40 mg/m²) as the radiosensitizer
The rationale traces to a phase II study (Carter et al., Invest New Drugs 2008) and a larger Vanderbilt retrospective experience (Vlacich et al., The Oncologist 2012) showing 3-year overall survival in the mid-70% range, comparable to cisplatin series, with markedly less late xerostomia, nephropathy, and GI toxicity, and very high treatment completion rates.
The argument: since locoregional control drives survival, and carbo/taxol radiosensitizes effectively with far less collateral damage, you can preserve efficacy while sparing cisplatin's ototoxicity and nephrotoxicity.
The caveat: the highest-level evidence (and the board answer) remains cisplatin; carbo/taxol weekly is institutional preference supported by phase II and retrospective data.
For a cisplatin-ineligible patient (poor renal function, hearing loss, neuropathy, poor performance status, significant cardiac disease), reasonable options include weekly carbo/taxol, single-agent carboplatin, cetuximab + radiation, or — in older/frail patients — radiation alone (recall the MACH-NC point that chemo's benefit fades with age).
Is there a role for “induction chemotherapy,” for instance in a patient with a rapidly enlarging base-of-tongue mass with pooling secretions and airway concern?
Who would be someone to consider this in? A patient with bulky, threatening disease where you want rapid cytoreduction (impending airway compromise, very bulky nodes) before definitive local therapy.
Although here we are discussing this in the oral cavity case, this could theoretically be applied to other HNC regions, as well.
The induction regimen to know is TPF (docetaxel, cisplatin, 5-FU). TPF beat the older PF doublet in TAX 324 (Posner et al., NEJM 2007), establishing the taxane-containing triplet as the better induction option.
The crucial caveat: trials of routine induction-then-chemoradiation versus chemoradiation alone (PARADIGM (Haddad et al., Lancet Oncol 2013) and DeCIDE) did not show an overall survival benefit for adding induction.
So induction is not standard for everyone; it's a selective tool for bulky/threatening disease, and many oncologists will use more tolerable carbo/taxol-based induction rather than full TPF.
After induction, reassess (exam + imaging) and proceed to definitive chemoradiation or surgery induction does not replace local therapy, it sets it up.
What's new: neoadjuvant/adjuvant immunotherapy.
The newest entrant is perioperative pembrolizumab, based on KEYNOTE-689 (Uppaluri et al., NEJM 2025). In resectable locally advanced HNSCC, neoadjuvant pembrolizumab, then surgery, then adjuvant pembrolizumab combined with (chemo)radiation improved event-free survival versus standard surgery-plus-adjuvant therapy.
Note that MOST patients (60%) were oral cavity patients
What if they are progressing
Other data for iO:
NIVOPOST-OP (Bourhis et al., Lancet 2026): Assessing nivolumab.
No pre-operative nivolumab, but after surgery treated with lead-in (pre-adjuvant) nivolumab, then 3 concomitant cycles of nivolumab with adjuvant cisplatin-based chemoradiotherapy, followed by 6 maintenance doses of nivolumab every 4 weeks positive study.
Improved DFS, but no improvement in OS
Answered question: Do we need to do induction or just in adjuvant setting - this has not been answered
That being said, pembrolizumab is an NCCN option, and the FDA approved perioperative pembrolizumab in June 2025 specifically for select PD-L1–positive (CPS ≥ 1) resectable patients.
Also an important note about IO trials - MOST patients are oral cavity cancer patients. So really - does all to all of head and neck cancer? Patient selection is important.
IO+ChemoRT for oropharynx - no surgery - in those patients there is no benefit (pembro and avelumab and atezo)
Case 2: Oropharynx.
A 58-year-old smoker with bulky bilateral neck nodes, FNA showing p16-positive squamous cell carcinoma, and an EUA revealing a tonsil primary cN3, p16+, locally advanced. How do you treat him?
For locally advanced oropharynx, especially with bulky/bilateral nodes, the backbone is definitive concurrent chemoradiation, with the same chemo discussion as above (board: cisplatin 100 q3wk).
Surgery (typically TORS) is reasonable for smaller primaries with limited nodal disease — our surgical guest will get into selection — but bulky bilateral nodal disease like this is generally a non-surgical, definitive-chemoradiation case.
If surgery is chosen for an oropharynx patient, the same adjuvant logic applies: ENE and/or positive margins → add chemo to postoperative radiation.
p16-positive disease does so much better, can we use a gentler radiosensitizer?
A cautionary tale. The logic was seductive: HPV+ patients are younger and cured at high rates, so why poison them with cisplatin? Cetuximab, an EGFR monoclonal antibody, looked like a gentler partner.
Cetuximab earned its place from the Bonner trial (NEJM 2006): cetuximab + radiation beat radiation alone for locoregional control and overall survival in locally advanced disease — so it became a legitimate option, particularly for cisplatin-ineligible patients.
Then came the de-escalation trials asking the real question: in p16+ oropharynx, can cetuximab replace cisplatin? Two big randomized trials, both 2019, gave a resounding no:
De-ESCALaTE HPV (Mehanna et al., Lancet 2019) and NRG/RTOG 1016 (Gillison et al., Lancet 2019): swapping in cetuximab for cisplatin led to inferior survival and worse locoregional control, without even delivering the hoped-for toxicity win in a meaningful way.
The lesson: in p16+ disease, cisplatin is still key.
Cetuximab is for the cisplatin-ineligible patient, not a de-escalation shortcut for fit patients. More on the broader de-escalation saga in the capstone.
Important practical tip: cetuximab can cause a severe allergic reaction/anaphylaxis in patients who have been exposed to the lone-star tick due to cross-reactivity between alpha-gal IgE antibodies
Lone star tick distribution. Image from: https://www.nature.com/articles/s41598-023-40397-x/figures/1
Case 3: Larynx. A 46-year-old woman who sings in her church choir develops hoarseness and a glottic mass with vocal cord fixation (T3 lesion, node-negative).
The goal is larynx preservation / laryngectomy-free survival keeping her voice and swallowing while curing her, because a total laryngectomy (permanent stoma, loss of natural voice) is life-altering.
Options: concurrent chemoradiation; induction chemo followed by radiation; surgery with larynx-preserving technique; or, for early T1–T2, radiation alone.
The defining trial is RTOG 91-11 (Forastiere et al., NEJM 2003; long-term JCO 2013), which compared induction cisplatin/5-FU → RT versus concurrent cisplatin + RT versus RT alone. The punchlines:
Concurrent chemoradiation gave the best larynx-preservation rate — better than induction or radiation alone.
No difference in overall survival across arms — because you can always salvage with total laryngectomy if organ-preservation therapy fails.
So for our T3 patient: concurrent chemoradiation for best larynx preservation, holding total laryngectomy in reserve as salvage.
If she had thyroid cartilage destruction (T4a) the calculus shifts toward upfront total laryngectomy. We discuss this more in our future surgery episode!
Quick recap / board pearls
Early stage → single modality; locally advanced → multimodality. Subsite drives the default (oral cavity = surgery; oropharynx = chemoRT; larynx = organ-preservation chemoRT).
cN0 oral cavity → elective neck dissection improves survival (D'Cruz, NEJM 2015).
Adjuvant chemo is mandatory for ENE and/or positive margins (EORTC 22931 + RTOG 9501, resolved by the Bernier/Cooper pooled analysis).
Board chemo = cisplatin 100 mg/m² q3wk ×3. Weekly cisplatin 40 is non-inferior (JCOG 1008); weekly 30 is inferior — cumulative dose matters (Noronha). Institutional option: weekly carbo/taxol. Concurrent chemo benefit fades with age (MACH-NC).
In p16+ disease, cisplatin beats cetuximab — De-ESCALaTE and RTOG 1016. Cetuximab is for cisplatin-ineligible patients (Bonner).
Induction (TPF; TAX 324) is selective — bulky/airway-threatening disease — not routine (PARADIGM/DeCIDE negative).
Larynx: concurrent chemoRT gives best larynx preservation; no OS difference because you can salvage with laryngectomy (RTOG 91-11; VA Larynx).
New: perioperative pembrolizumab for select resectable PD-L1+ disease (KEYNOTE-689).
Next up: our guest conversations — first with a head and neck surgeon on TORS, neck dissection, and reconstruction, then with a radiation oncologist on IMRT, fractionation, and toxicity. Then we tackle recurrent and metastatic disease.
References:
https://pubmed.ncbi.nlm.nih.gov/26027881/ — D'Cruz AK, et al. Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med. 2015;373(6):521–529.
https://pubmed.ncbi.nlm.nih.gov/15128894/ — Bernier J, et al. (EORTC 22931) Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945–1952.
https://pubmed.ncbi.nlm.nih.gov/15128893/ — Cooper JS, et al. (RTOG 9501) Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937–1944.
https://pubmed.ncbi.nlm.nih.gov/16161069/ — Bernier J, Cooper JS, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of EORTC 22931 and RTOG 9501. Head Neck. 2005;27(10):843–850.
https://pubmed.ncbi.nlm.nih.gov/19446902/ — Pignon JP, et al. (MACH-NC) Meta-analysis of chemotherapy in head and neck cancer: update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4–14.
https://ascopubs.org/doi/10.1200/JCO.21.01293 — Kiyota N, et al. (JCOG 1008) Weekly cisplatin plus radiation for postoperative head and neck cancer. J Clin Oncol. 2022;40(18):1980–1990.
https://pubmed.ncbi.nlm.nih.gov/29220295/ — Noronha V, et al. Once-a-week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer. J Clin Oncol. 2018;36(11):1064–1072.
https://pubmed.ncbi.nlm.nih.gov/18473121/ — Carter DL, et al. Carboplatin, paclitaxel, and concurrent accelerated hyperfractionated radiotherapy for locally advanced head and neck carcinoma. Invest New Drugs. 2008;26(5):473–481.
https://pubmed.ncbi.nlm.nih.gov/22550060/ — Vlacich G, et al. Intensity-modulated radiation therapy with concurrent carboplatin and paclitaxel for locally advanced head and neck cancer. The Oncologist. 2012;17(5):673–681.
https://doi.org/10.1056/NEJMoa053422 — Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–578.
https://pubmed.ncbi.nlm.nih.gov/30449623/ — Mehanna H, et al. (De-ESCALaTE HPV) Radiotherapy plus cisplatin or cetuximab in low-risk HPV-positive oropharyngeal cancer. Lancet. 2019;393(10166):51–60.
https://doi.org/10.1016/S0140-6736(18)32779-X — Gillison ML, et al. (NRG/RTOG 1016) Radiotherapy plus cetuximab or cisplatin in HPV-positive oropharyngeal cancer. Lancet. 2019;393(10166):40–50.
https://pubmed.ncbi.nlm.nih.gov/17960013/ — Posner MR, et al. (TAX 324) Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705–1715.
https://pubmed.ncbi.nlm.nih.gov/23414589/ — Haddad R, et al. (PARADIGM) Induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone. Lancet Oncol. 2013;14(3):257–264.
https://pubmed.ncbi.nlm.nih.gov/14645636/ — Forastiere AA, et al. (RTOG 91-11) Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349(22):2091–2098. Long-term results: https://pubmed.ncbi.nlm.nih.gov/23182993/ (J Clin Oncol. 2013;31(7):845–852).
https://doi.org/10.1056/NEJM199106133242402 — Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991;324(24):1685–1690.
https://pubmed.ncbi.nlm.nih.gov/40532178/ — Uppaluri R, et al. (KEYNOTE-689) Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer. N Engl J Med. 2025;393(1):37–50.
Regimen references (HemOnc.org): Concurrent cisplatin + RT · Carboplatin/paclitaxel + RT · TPF induction · Cetuximab + RT (historical) · Perioperative pembrolizumab
This episode is sponsored by Primum! To learn more, sign up for your free account, and to ask questions to Primum experts, click here!
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Vivek Patel, Dan Hausrath, Ronak Mistry
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Graphics, social media management: Ronak Mistry
