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Chemotherapy and Immunotherapy

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what is chemotherapy?

Last reviewed: October 4, 2026

Introduction

Medicines are used in three main ways in head and neck cancer: given at the same time as radiation to make it more effective, given before or after surgery for cancers at high risk of coming back, and given on their own for cancer that has returned or spread. The medicines fall into three groups: standard chemotherapy (most often cisplatin), targeted therapy (most often cetuximab), and immunotherapy (checkpoint inhibitors such as pembrolizumab and nivolumab) [1].

The strongest evidence is for cisplatin given during radiation, which improves survival [2]. Immunotherapy has become the first treatment for most cancers that have returned or spread [3], and in 2025 pembrolizumab given before and after surgery became an option for some newly diagnosed advanced cancers [4]. The sections below explain each type of treatment, the main trials behind it, and how side effects are managed. A numbered reference list is at the end of the page.

Chemotherapy is treatment by medicines that damage cancer cells by interfering with their ability to divide and make more cancer cells. There are several different types of chemotherapy that may be used in the treatment of your Head and Neck Cancer. These are most often given in combination with radiation therapy. Less often, for more advanced cancer that have spread or for recurrent cancer, chemotherapy may be given by itself. For some cancers, such as melanoma, chemotherapy may be given after surgery to help reduce the risk of cancer coming back. Almost all chemotherapies used to treat head and neck cancers are given intravenously. The three broad categories of chemotherapy are standard chemotherapy, targeted therapy, and immunotherapy.

Standard Chemotherapy

The most common chemotherapies are those given with radiation, usually cisplatin (Cis) or a similar drug called carboplatin (Carbo), which work by chemically connecting proteins, DNA, and RNA with themselves, literally tying these molecules up and causing the cell to die in a process called apoptosis. These are usually given either once a week or once every 3 weeks by IV infusion. Common side effects, more so with cisplatin, include fatigue, decreases in blood counts (anemia, low white cells, low platelets), nausea, decreased renal function, numbness/neuropathy, hair loss, hearing loss, tinnitus (ringing ears), and electrolyte changes. One other chemotherapy used in more advanced cancers is 5-fluorouracil (5-FU) which requires administration through a chemotherapy pump over several days. This requires placement of a mediport, which is and IV device that helps give better access for IV medications, that is surgically placed in the upper chest and usually is under the skin. Chemotherapy treatments generally take 1-3 hours and is given while you sit in a comfortable recliner chair in the cancer center and is administered by a medical oncologist and their team.

Why chemotherapy is given with radiation

The largest analysis of head and neck cancer trials (MACH-NC: 107 randomized trials and 19,805 patients) found that adding chemotherapy at the same time as radiation improved five-year survival by 6.5 percentage points. Chemotherapy given only before or only after radiation did not provide the same survival benefit, and the benefit became smaller with older age [2].

Weekly or every three weeks

The best-studied schedule is high-dose cisplatin (100 mg/m² of body surface area) every three weeks, usually three doses during radiation. A lower dose given weekly (40 mg/m²) is easier to tolerate, and two randomized trials support it:

In the Japanese JCOG1008 trial of 261 patients receiving radiation after surgery, weekly cisplatin was at least as effective for survival, with less severe infection, kidney injury and hearing loss [5].
In the Indian ConCERT trial of patients treated with radiation without surgery, weekly cisplatin was not inferior for control of the cancer in the head and neck and caused fewer severe side effects [6].

The dose matters, however. An earlier trial that used a lower weekly dose (30 mg/m²) found that control of the cancer was better with the every-three-weeks schedule [7]. The NCCN guidelines list both high-dose and weekly 40 mg/m² cisplatin as options [1].

Carboplatin, often combined with fluorouracil or paclitaxel, is used for patients who cannot safely receive cisplatin because of kidney function, hearing loss, neuropathy or frailty. It causes less kidney and ear damage but lowers blood counts more [1]. Chemotherapy given before radiation (induction chemotherapy, usually docetaxel, cisplatin and fluorouracil, called TPF) is used in selected situations, such as for larynx preservation or very bulky cancers (see the larynx and hypopharynx pages).

what is immunotherapy?

Immunotherapy generally involves treatments that are designed to help the immune system better recognize and attack cancer cells. Currently, these treatment are predominantly a class of medications called immune-checkpoint inhibitors. One way cancers grow is by escaping the normal mechanisms that the immune system uses to clear damaged/bad cells. The immune system has checkpoints, or brakes, that are present to help prevent it from being overactive. Checkpoint inhibitors remove these brakes and let the immune system be more active and clear the damaged cell. This can help to also create memory T-cells that may continue to recognize and react to the cancer cells even after treatments have been completed. Currently, all of these treatments are given intravenously. The most common types are called PDL1/PD1 inhibitors, and include nivolumab (Opdivo), pembrolizumab (Keytruda) and cemiplimab (Libtayo). For squamous cell carcinomas of the head and neck, these are given in patients that have relapsed and/or metastatic disease that are not candidates for further surgery or radiation. They are often given in combination with chemotherapy. For cutaneous squamous cell carcinomas (primary skin cancers), these may be given in patients with recurrent disease again when surgery and radiation are not options. For patients with melanomas, these may be given to high-risk patient post operatively or in patients with metastatic disease. In that situation, another common treatment is combined immunotherapy with nivolumab and ipilimumab (Yervoy).

The side effects of immunotherapy are primarily related to the autoimmune toxicities that occur by allowing the immune system to be more active. The most common of these are rash if the immune system attacks the skin and diarrhea if it attacks the colon. However, since the immune system is active throughout the body, multiple systems can be affected including pituitary, thyroid, heart, lungs, kidneys, liver, pancreas, adrenals, and joints. Many patients can be supported with less aggressive interventions like imodium or topical steroids. However, some may require steroids to help suppress the immune system or even discontinuation of the medication.

The evidence for immunotherapy

First treatment for recurrent or metastatic cancer. In the KEYNOTE-048 trial of 882 patients, pembrolizumab alone (for tumors with PD-L1 expression) or pembrolizumab with chemotherapy improved survival compared with the previous standard, chemotherapy with cetuximab. For tumors with higher PD-L1 expression (combined positive score of 20 or more), median survival with pembrolizumab alone was 14.9 months compared with 10.7 months [3]. PD-L1 testing of the tumor helps decide whether pembrolizumab is given alone or with chemotherapy.
After platinum chemotherapy stops working. In the CheckMate 141 trial of 361 patients, nivolumab improved median survival (7.5 compared with 5.1 months) and caused fewer severe side effects than standard chemotherapy [8].
Before and after surgery. In the KEYNOTE-689 trial of 714 patients with newly diagnosed, resectable stage III or IVA cancer, adding pembrolizumab before surgery and after surgery (with radiation or chemoradiation) improved three-year event-free survival from 44.9% to 58.2% in patients whose tumors expressed PD-L1 (combined positive score of 1 or more) [4]. Overall survival results are still maturing.
Not every approach has worked. Adding the checkpoint inhibitor avelumab to standard chemoradiation did not improve outcomes in the JAVELIN Head and Neck 100 trial, which was stopped early [9].

In KEYNOTE-689, immune-related side effects of any severity occurred in 43% of patients given pembrolizumab, and severe ones in 10% [4]. Underactive thyroid is among the most common, so thyroid blood tests are checked during treatment. Any new rash, diarrhea, cough, shortness of breath or unusual fatigue should be reported promptly. More information is on the immunotherapy for head and neck cancers page.

What is targeted therapy?

The most common targeted therapy used in treatment of head and neck cancer is cetuximab (Erbitux). This is a medication known as a monoclonal antibody that targets a receptor on the surface of the cells called epidermal growth factor receptor (EGFR). It is most often given in combination with radiation treatments, but is also frequently given in late-stage cancers in combination with other chemotherapies or sometimes by itself. It is most often given intravenously on a weekly basis. Common side effects include fatigue, skin rash (similar to acne) on the face and chest, and decreases in magnesium levels, which require IV infusions to replace.

There are also targeted therapies used in treatment of patients with melanoma who have a BRAF mutation in their cancer cells. This treatment is given by pill, and typically consists of two different medications, one targeting BRAF and the other targeting MEK. There are several similar drugs available and the choice is primarily based on individual preferences. These are most often used in patients with Stage IV melanomas, but may also be recommended for some patients post-operatively that are deemed to be at higher risk of recurrence. Side effects include mouth sores, fever, diarrhea, rash, and small risk of non-melanoma skin cancers. A less commonly used targeted therapy for advanced basal cell skin cancers are the hedgehog inhibitors, vismodegib (Erivedge) and sonidegib (Odomzo). These are oral medications that target the hedgehog pathway. Side effects include muscle spasms, hair loss, nausea, rash, and other skin cancers.

While not technically chemotherapy, the third common type of targeted therapy is used in patients with thyroid cancer. After surgery, patients are placed on thyroid replacement therapy (typically levothyroxine) which is use both to replace missing thyroid hormone and to suppress production of thyroid stimulating hormone (TSH) by the pituitary gland. This is to prevent TSH from stimulating any residual cancer cells. Side effects of thyroid replacement therapy can include palpitations, weight loss, and decreased bone density. Some patients with thyroid cancer that has metastasized are treated with BRAF inhibitors as well, as above.

The evidence for cetuximab

In a trial of 424 patients, adding cetuximab to radiation improved median survival from 29.3 to 49.0 months compared with radiation alone [10], and five-year survival was 45.6% compared with 36.4% [11]. However, when cetuximab was compared directly with cisplatin in HPV-related oropharyngeal cancer, cetuximab was less effective [12], so it is now used with radiation mainly for patients who cannot receive cisplatin [1] (see the oropharynx page). For cancer that has returned or spread, adding cetuximab to platinum and fluorouracil chemotherapy (the "EXTREME" regimen) improved median survival from 7.4 to 10.1 months [13]; this was the standard first treatment until immunotherapy surpassed it [3].

managing side effects of platinum-based chemotherapy (cis-platin, carbo-platin, “platinol”)

In a practical sense, the key to getting through platinum based chemotherapy is a matter of determination and remembering that while the treatment feels like it is kicking your butt, it’s kicking cancer’s butt even more. As for limiting specific side effects, your individual care will be through your medical oncologist, and may consist of the following:

Nausea is treated with medication (like ondansetron and corticosteroids). Since nausea can lead to decreased fluid intake, I.V. rehydration may be used from time to time.
Kidney damage is limited by staying hydrated. Since head and neck cancer and its treatments can affect swallowing, and since nausea can also limit fluid intake, the key is to stay as well-hydrated as possible and use I.V. rehydration when needed.

Cisplatin is one of the chemotherapy drugs most likely to cause nausea and vomiting. The ASCO antiemetic guideline recommends preventing it, rather than treating it after it starts, with a combination of four medicines for high-dose cisplatin: an NK1 blocker (such as aprepitant), a 5-HT3 blocker (such as ondansetron or palonosetron), dexamethasone and olanzapine [14]. Kidney function and blood minerals such as magnesium and potassium are checked before each dose, and fluids are given by vein before and after each treatment [1].

Go to hearing loss treatments >>

Inner ear damage (hearing loss, tinnitus) is common, but of variable extent from one patient to another. Recent data suggests that a lower dose of platinum-based therapy given once a week may have less inner ear injury than a higher dose given every three weeks, without compromising the effect on cancer treatment. Hearing tests (audiograms) are usually performed before chemotherapy is begun and mid-way through the treatment course. If hearing is significantly worse, the medical oncologist may decide to change from cisplatin to carboplatin (or vice-versa), as each affects inner ear cells slightly differently, and the change can spread the burden of toxicity. Hearing aids and possibly some balance therapy are helpful after treatment is complete for patients who lost some hearing and/or balance.

Also, be aware that platinum-based chemotherapy is typically used with radiation therapy, and so one should consider the treatment effects of radiation as well.

The trials behind the weekly schedule are described above: in JCOG1008, hearing impairment was less frequent with weekly cisplatin [5]. Sodium thiosulfate, given several hours after cisplatin, roughly halved hearing loss in children treated with cisplatin in a randomized trial [15] and is approved for children, but it is not yet an established treatment for adults with head and neck cancer. Cisplatin-related hearing loss is usually permanent, so any change in hearing or ringing in the ears should be reported during treatment (see hearing).

Summary

Cisplatin given during radiation improves survival in head and neck cancer; chemotherapy given only before or after radiation does not provide the same benefit [2].
Weekly cisplatin at 40 mg/m² is an accepted alternative to high-dose cisplatin every three weeks, with fewer side effects; lower weekly doses are less effective [5, 6, 7].
Cetuximab with radiation is mainly for patients who cannot receive cisplatin [11, 12].
Immunotherapy is the first treatment for most recurrent or metastatic cancers, and perioperative pembrolizumab is an option for some resectable advanced cancers [3, 4].
Nausea, kidney injury and hearing loss from cisplatin can be reduced with preventive medicines, fluids and monitoring [14].

References

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 2.2026. nccn.org
Lacas B, Carmel A, Landais C, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group. Radiother Oncol. 2021;156:281-293. doi:10.1016/j.radonc.2021.01.013 PubMed 33515668
Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928. doi:10.1016/S0140-6736(19)32591-7 PubMed 31679945
Uppaluri R, Haddad RI, Tao Y, et al. Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer. N Engl J Med. 2025;393(1):37-50. doi:10.1056/NEJMoa2415434 PubMed 40532178
Kiyota N, Tahara M, Mizusawa J, et al. Weekly Cisplatin Plus Radiation for Postoperative Head and Neck Cancer (JCOG1008): A Multicenter, Noninferiority, Phase II/III Randomized Controlled Trial. J Clin Oncol. 2022;40(18):1980-1990. doi:10.1200/JCO.21.01293 PubMed 35230884
Sharma A, Choudhary MK, Bhasker S, et al. Concurrent chemotherapy and external radiation therapy (ConCERT): phase 3 noninferiority randomized clinical trial of cisplatin weekly vs every 3 weeks in locally advanced squamous cell carcinoma of the head and neck. J Natl Cancer Inst. 2026;. doi:10.1093/jnci/djag276 PubMed 42636269
Noronha V, Joshi A, Patil VM, et al. Once-a-Week Versus Once-Every-3-Weeks Cisplatin Chemoradiation for Locally Advanced Head and Neck Cancer: A Phase III Randomized Noninferiority Trial. J Clin Oncol. 2018;36(11):1064-1072. doi:10.1200/JCO.2017.74.9457 PubMed 29220295
Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-1867. doi:10.1056/NEJMoa1602252 PubMed 27718784
Lee NY, Ferris RL, Psyrri A, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021;22(4):450-462. doi:10.1016/S1470-2045(20)30737-3 PubMed 33794205
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-78. doi:10.1056/NEJMoa053422 PubMed 16467544
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21-8. doi:10.1016/S1470-2045(09)70311-0 PubMed 19897418
Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X PubMed 30449625
Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116-27. doi:10.1056/NEJMoa0802656 PubMed 18784101
Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020;38(24):2782-2797. doi:10.1200/JCO.20.01296 PubMed 32658626
Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(1):63-74. doi:10.1016/S1470-2045(16)30625-8 PubMed 27914822

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