Immunotherapy Gains Use in Head and Neck Cancer
In recent years, the inclusion of immunotherapy in the therapeutic algorithm of patients with PD-L1-positive advanced head and neck cancer has significantly increased the survival of these patients, which is known to coincide with World Head and Neck Cancer Daywhich is celebrated on July 27. And this is a non-trivial question, since This tumor is the seventh most diagnosed cancer in our environment, with an estimated 10,700 new cases and 3,660 deaths registered in Spain in 2024.according to the report “Cancer rates in Spain in 2024” of the Spanish Society of Medical Oncology SEOM.
He tobacco and alcohol are the main causative agents of head and neck cancer. responsible for approximately 75-85% of casesalthough there is a progressive increase in tumors associated with human papillomavirus (HPV), which may be the cause of 30-35% of cases, although there is great geographic variability, these tumors represent a different clinical and molecular entity.
These tumors arise in anatomically complex areas, Local treatment for curative purposes is associated with significant, highly stigmatizing physical consequences. and has a major impact on the quality of life and functionality of the triple sphere of phonation, swallowing and breathing. In addition, these patients often have problems with malnutrition due to the tumor, treatment and comorbidities, which must be addressed and treated from the time of diagnosis.
Big steps
Under the auspices of a communications campaign called “In oncology, every achievement is written in capital letters”SEOM acknowledges the medical advances that have occurred over the past decades in the treatment of various head and neck tumors.
Local and locally advanced disease
IN maxillofacial and otolaryngological surgery It has evolved from Hasted techniques to reconstructions and grafts, and to the advent of robotic surgery, particularly transoral, which allows resections that were previously technically unachievable. Conservative techniques such as supraglottic laryngectomy have been refined, allowing phonation to be preserved and a tracheostomy to be avoided. In radiotherapy, advances have been made in techniques that allow dose concentration with less toxicity, such as intensity-modulated radiotherapy (IMRT) and radiosurgery, and techniques for very precise dose delivery are being developed using technologies that allow very high-resolution planning. Similarly, deintensification techniques are being tested in HPV-associated tumours.
In most cases of stage I or II cancer, surgery or radiotherapy is the treatment of choice. Treatment of locally advanced stage III or IV (M0) tumors is currently multimodal and includes surgery, radiotherapy, and chemotherapy depending on the stage, location, and clinical factors. In some cases, induction chemotherapy and subsequent radiotherapy can preserve the larynx.
Treatment of patients with locally advanced head and neck cancer has evolved, and concurrent radiotherapy and cisplatin remains the standard of care today. In 2006, Bonner demonstrated that the efficacy of radiotherapy was increased when combined with cetuximab without increasing toxicity, making it now a good alternative to concomitant cisplatin except in patients with HPV-related tumors. In 2022, the Treatment of Tumors in the Head and Neck (TTCC) published a phase III trial that attempted to demonstrate non-inferiority of cetuximab radiotherapy to cisplatin radiotherapy, but failed to achieve its non-inferiority goal.
Studies of immunotherapy combined with radiotherapy have been negative in the general population. We are currently waiting to learn the role of immunotherapy in the induction phase, whether or not associated with chemotherapy, and in the adjuvant phase after surgery or radiotherapy.
Recurrent or metastatic disease
In the area of relapses it is possible salvage surgery or radiation therapy in combination with chemotherapy or cetuximabIn cases already irradiated, re-irradiation will be considered, but salvage is not always possible at this stage of the evolution. Patient selection is the key to achieving long-term survival; salvage treatment is indicated depending on the extent of the relapse, the time since previous radiotherapy, and the patient’s initial condition.
Concerning systemic treatmentthe addition of cetuximab to standard chemotherapy represented a significant advance for these patients. In recent years, the EXTREME (cisplatin, 5-fluorouracil, and cetuximab) and TPEX (cisplatin, docetaxel, and cetuximab) regimens have been promoted as treatment options for patients with advanced head and neck cancer. TPEX has established itself as a less toxic alternative to EXTREME, eliminating the need for a fluorouracil pump. ERBITAX (paclitaxel and cetuximab) is an effective therapeutic option for frail patients who are not candidates for cisplatin.
A major advance in the treatment of head and neck tumors has been the inclusion of immunotherapy in the therapeutic algorithm. Previously, there was a therapeutic gap in cisplatin-refractory cases, especially in patients refractory to EXTREME treatment, until 2016, when the FDA approved immunotherapy for these cases with two anti-PD-1 agents, the main benefit of which is long-term survival of responders. The FDA accelerated approval of nivolumab in April 2016 after presentation of data from the first pivotal phase III CHECKMATE 141 trial, in which nivolumab demonstrated an overall survival (OS) benefit versus investigator’s choice chemotherapy in patients who crossed over to platinum for localized disease. There was an improvement in OS (7.7 vs 3.3 months), but most striking was that more than 10% of patients in the nivolumab group were alive at 3 years.
On September 1, 2016, the FDA granted accelerated approval to pembrolizumab based on data from the nonrandomized Phase Ib KEYNOTE-012 trial. Most patients in the study had previously received at least two different cycles of treatment. A median overall survival of 8 months was achieved, with 38% of patients still alive one year after starting treatment. A Phase II trial (KEYNOTE-055) subsequently confirmed these data in a 2017 publication in the Journal Clinical Oncology.
In 2018, the results of the KEYNOTE-048 study were published, demonstrating the superiority of pembrolizumab as monotherapy and pembrolizumab in combination with cisplatin-based chemotherapy in first-line patients with recurrent and/or metastatic disease with platinum-sensitive disease and a positive PD-L1 result. Since 2021, it has been included in the standard treatment of this group of PDL1-positive patients, and this is reflected in the SEOM Guidelines for the treatment of these tumors. But perhaps the most impressive aspect is the reduction in the risk of mortality that is observed with the introduction of these drugs. In an updated study published in 2023, with a 4-year follow-up period, treatment with pembrolizumab showed a reduction in the risk of death compared with standard chemotherapy by 26-39% depending on PD-L1 expression and a combination of chemotherapy and pembrolizumab by 38%.