Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 22188

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Guest Editor
Department of Otorhinolaryngology, Careggi University Hospital, Florence, Italy
Interests: head & neck cancer; surgery; clinical oncology
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Special Issue Information

Dear Colleagues,

Head and neck (HN) cancer, which mainly presents in the form of squamous cell carcinoma, was the seventh most common cancer worldwide in 2018, with approximately 890,000 new cases and 450,000 deaths. Its incidence is rising in both less-developed countries, due to the increased exposure to classical risk factors (tobacco smoking and alcohol); as well as in high-income nations, due to the spread of high-risk serotypes of human papillomavirus (HPV-16 and HPV-18). Survival rates range from 70% to 80% at five years for early HN cancer (i.e., with neither nodal metastasis at presentation nor evidence of extra-organ extension) to an estimated overall survival of 30–40% at advanced stages. Unfortunately, the latter is the most common clinical presentation, and recent studies from the USA showed that the age-adjusted incidence rates for stage IV HN cancer have significantly increased by 26.1% over the last two decades.

Overall, 50% to 60% of these patients develop a loco-regional recurrence within 2 years. In addition, 20% to 30% develop distant metastases. Second primary risk is about 2% to 4% per year, representing a rate of about 10% to 20% overall lifetime risk.

Recurrent HN cancer can form at or near the original site of the tumor (recurrent locoregional cancer) or at distant sites throughout the body (recurrent metastatic cancer). As with all forms of cancer, the outcomes for head and neck cancer recurrences can be significantly improved with early detection and prompt treatment; however, the prognosis overall remains poor.

Depending on the type and location of the HN cancer recurrence, an individualized treatment plan may include: surgery, chemotherapy, or radiation therapy, or more frequently, a multimodal approach that incorporates some or all of the above. Despite the high rate of HN cancer failures, few reports have extensively investigated the specific problems linked to the diagnosis, staging, treatment and prognosis of HN recurrence. The great majority of available studies focus on newly diagnosed HN cancer. Furthermore, specific problems must be considered when treating an HN cancer recurrence following a surgical failure vs. radiotherapy relapsed case, and when the recurrence is limited to the primary or to the neck. Another crucial point is the HN primary tumor site, not only in terms of risk of recurrence but also because of different therapeutic approaches required.

Altogether, I believe that a Special Issue on “Head and neck cancer recurrence: Diagnosis, treatment and prognosis” would represent an interesting and innovative work including potential contributions from scientists such as radiologists, pathologists, oncologists, head and neck surgeons, and radiotherapists, frequently involved in multispecialty teams of experts for the treatment HN cancer recurrence.

Prof. Dr. Oreste Gallo
Guest Editor

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Keywords

  • head and neck cancer
  • recurrence
  • squamous cell carcinoma
  • HPV
  • larynx
  • oral cavity
  • oropharynx

Published Papers (10 papers)

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Research

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21 pages, 3740 KiB  
Article
The Role of the p16 and p53 Tumor Suppressor Proteins and Viral HPV16 E6 and E7 Oncoproteins in the Assessment of Survival in Patients with Head and Neck Cancers Associated with Human Papillomavirus Infections
by Andrejs Lifsics, Maksims Cistjakovs, Liba Sokolovska, Renars Deksnis, Modra Murovska and Valerija Groma
Cancers 2023, 15(10), 2722; https://doi.org/10.3390/cancers15102722 - 11 May 2023
Cited by 4 | Viewed by 2103
Abstract
The role of HPV in the survival prognosis of patients with head and neck squamous cell carcinoma, especially patients with laryngeal squamous cell carcinoma (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC), is still somewhat ambiguous. The present study aimed to explore the significance [...] Read more.
The role of HPV in the survival prognosis of patients with head and neck squamous cell carcinoma, especially patients with laryngeal squamous cell carcinoma (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC), is still somewhat ambiguous. The present study aimed to explore the significance of tumor suppressor proteins and HPV16 E6 and E7 oncoproteins in the assessment of survival in patients with oropharyngeal squamous cell carcinoma (OPSCC), LSCC, and HPSCC associated with high-risk (HR-) and low-risk (LR-) HPV infections. By utilizing molecular and immunohistochemical investigations of HNSCC samples and patient data, univariate and multivariate survival analyses were conducted. The presence of HPV DNA (LR- and HR-HPV) was associated with a better 5-year OS and DSS for OPSCC and LSCC. The IHC overexpression of HPV16 E6 protein and p16 protein was associated with better survival in the univariate (for OPSCC) and multivariate (OPSCC and HPSCC) survival analyses. The overexpression of p53 was associated with better survival in OPSCC. HPV infection plays a significant role in the tumorigenesis of HNSCC, and the immunohistochemical assessment of HPV16 E6 protein expression should be interpreted as a useful prognostic marker for OPSCC and HPSCC. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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12 pages, 7387 KiB  
Article
CD44, PDL1, and ATG7 Expression in Laryngeal Squamous Cell Carcinomas with Tissue Microarray (TMA) Technique: Evaluation of the Potential Prognostic and Predictive Roles
by Lidia Puzzo, Maria Rita Bianco, Lucia Salvatorelli, Giordana Tinnirello, Federico Occhiuzzi, Daniele Latella and Eugenia Allegra
Cancers 2023, 15(9), 2461; https://doi.org/10.3390/cancers15092461 - 25 Apr 2023
Cited by 1 | Viewed by 1422
Abstract
We focus on the new prognostic and predictive factors CD44, PDL1, and ATG7 in our study of surgical samples of patients with laryngeal squamous cell carcinoma (LSCC) using tissue microarray (TMA). Thirty-nine previously untreated patients affected by laryngeal carcinoma who then underwent surgical [...] Read more.
We focus on the new prognostic and predictive factors CD44, PDL1, and ATG7 in our study of surgical samples of patients with laryngeal squamous cell carcinoma (LSCC) using tissue microarray (TMA). Thirty-nine previously untreated patients affected by laryngeal carcinoma who then underwent surgical treatment were considered in this retrospective study. All surgical specimens were sampled, embedded in paraffin blocks, and stained with hematoxylin and eosin. A representative sample of the tumor was chosen and transferred into a new block of paraffin, the recipient block, to perform immunohistochemical analysis with the primary antibodies anti-CD44, PD-L1, and ATG7. At follow-up, 5-year disease-free survival (DFS) for negative and positive tumors was determined as 85.71% and 36% for CD44, 60% and 33.33% for PDL1, and 58.06% and 37.50% for ATG7, respectively. Multivariate analysis revealed that CD44 expression is an independent predictive factor of low-grade tumors (p = 0.008), lymph node metastasis at the time of diagnosis, and AGT7 negativity. Thus, CD44 expression is a potential marker for more aggressive forms of laryngeal cancer. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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14 pages, 1097 KiB  
Article
Clinical Significance of the Lymph Node Ratio of the Second Operation to Predict Re-Recurrence in Thyroid Carcinoma
by Joonseon Park, Il Ku Kang, Ja Seong Bae, Jeong Soo Kim and Kwangsoon Kim
Cancers 2023, 15(3), 624; https://doi.org/10.3390/cancers15030624 - 19 Jan 2023
Cited by 4 | Viewed by 1380
Abstract
The purpose of this study was to establish the risk factors for re-recurrences and disease-specific mortality (DSM) in recurrent thyroid cancer. Patients with recurrent thyroid cancer who underwent initial thyroid surgery from January 2000 to December 2019 at Seoul St. Mary’s Hospital (Seoul, [...] Read more.
The purpose of this study was to establish the risk factors for re-recurrences and disease-specific mortality (DSM) in recurrent thyroid cancer. Patients with recurrent thyroid cancer who underwent initial thyroid surgery from January 2000 to December 2019 at Seoul St. Mary’s Hospital (Seoul, Korea) were assessed. Clinicopathological characteristics and long-term oncologic outcomes were compared between patients with one recurrence (n = 202) and patients with re-recurrences (n = 44). Logistic regression and cox-regression analyses were conducted to determine the risk factors for re-recurrences and DSM, respectively. Receiver-operating characteristic curve analysis was performed to determine the cutoff value for lymph node ratio (LNR) as a predictor of re-recurrences. DSM was significantly higher in the re-recurrence group compared with the single-recurrence group (6.8% vs. 0.5%, p = 0.019). Surgical treatment at the first recurrence significantly lowered the risk of re-recurrences. Age (≥55), male sex, and LNR (≥0.15) were independent significant risk factors for re-recurrences in patients who underwent surgery at the first recurrence. Surgical resection is the optimal treatment for initial thyroid cancer recurrence. LNR at re-operation is more effective in predicting re-recurrence than the absolute number of metastatic LNs. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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12 pages, 2905 KiB  
Article
The Same–Up–Down Staging System for Recurrent Early Glottic Cancer
by Giuseppe Licci, Luca Giovanni Locatello, Giandomenico Maggiore, Flavia Cozzolino, Saverio Caini and Oreste Gallo
Cancers 2023, 15(3), 598; https://doi.org/10.3390/cancers15030598 - 18 Jan 2023
Viewed by 1128
Abstract
(1) Background: The treatment of recurrent early glottic cancer (rEGC) remains challenging. We wanted to investigate how the oncological outcomes are affected by the initial and recurrent stages, in order to propose our newly developed Same–Up–Down (SUD) staging system. (2) Methods: In our [...] Read more.
(1) Background: The treatment of recurrent early glottic cancer (rEGC) remains challenging. We wanted to investigate how the oncological outcomes are affected by the initial and recurrent stages, in order to propose our newly developed Same–Up–Down (SUD) staging system. (2) Methods: In our cohort of 258 rEGC patients, we retrospectively assessed the prognostic performances of the rTNM (the TNM staging system for recurrence), CLRSS, CLRSS-2, and SUD staging systems by univariate and multivariate Cox analysis, comparing their predictive capability using Harrell’s C-index. (3) Results: The SUD classification satisfactorily predicted both overall survival (p = 0.022) and second-recurrence-free survival (p = 0.024, as same + down vs. upstage) in our cohort. It also outperformed the other three systems in terms of prediction of survival, with an improvement of 1.52%, 1.18%, and 3.96% in the predictive capacity of overall survival, disease-specific survival, and second-recurrence-free survival, respectively. (4) Conclusions: The SUD staging system can efficiently predict survival in rEGC patients, whose prognosis heavily depends on both the initial and recurrent locoregional extension. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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16 pages, 2023 KiB  
Article
Higher Risk of Recurrence in Patients Treated for Head and Neck Cancer with Low BMI and Elevated Levels of C-Reactive Protein
by Diana Spiegelberg, Christer Malmberg, Ylva Tiblom Ehrsson and Göran Laurell
Cancers 2022, 14(20), 5161; https://doi.org/10.3390/cancers14205161 - 21 Oct 2022
Cited by 1 | Viewed by 1565
Abstract
This prospective study identifies high-risk groups for recurrence of head and neck cancer by BMI and circulating inflammatory response markers. Head and neck cancer patients from three Swedish hospitals were included (n = 272). Leukocyte and thrombocyte counts, CRP levels, and BMI [...] Read more.
This prospective study identifies high-risk groups for recurrence of head and neck cancer by BMI and circulating inflammatory response markers. Head and neck cancer patients from three Swedish hospitals were included (n = 272). Leukocyte and thrombocyte counts, CRP levels, and BMI were measured pre-treatment and post-treatment. Associations between the four factors and treatment failure (residual tumor, loco-regional failure, general failure/distant metastasis) were assessed using a Cox proportional hazards model adjusted for sex, age at the initial visit, smoking status, cancer stage, and hemoglobin count. CRP level was the only significant single variable, with an average increase in risk of recurrence of 74% (p = 0.018) for every doubling. The predictive power of a combined model using all variables was highest during the initial months after treatment, with AUC under the ROC curve 0.75 at the 0–3 month timepoints. Patients with elevated pre- and post-treatment CRP levels are at higher risk for recurrence of disease. Male patients with low post-treatment BMI, advanced stage, and high CRP at any time post treatment are at high risk for recurrence. The combined model may be useful for stratifying post-treatment patients into low and high-risk groups, to enable more detailed follow-up or additional treatment regimens. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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Review

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16 pages, 4451 KiB  
Review
The Histological Background of Recurrence in Laryngeal Squamous Cell Carcinoma: An Insight into the Modifications of Tumor Microenvironment
by Giorgia Arcovito, Annarita Palomba, Oreste Gallo and Alessandro Franchi
Cancers 2023, 15(12), 3259; https://doi.org/10.3390/cancers15123259 - 20 Jun 2023
Cited by 1 | Viewed by 1767
Abstract
Recurrent laryngeal carcinoma presents differences from the primary tumor that largely depend on the treatment. In this article, we review the histologic and molecular treatment-induced changes that may affect the diagnosis of recurrent laryngeal carcinoma, the assessment of predictive markers, and the response [...] Read more.
Recurrent laryngeal carcinoma presents differences from the primary tumor that largely depend on the treatment. In this article, we review the histologic and molecular treatment-induced changes that may affect the diagnosis of recurrent laryngeal carcinoma, the assessment of predictive markers, and the response to treatment with immune checkpoint inhibitors. Radiotherapy induces profound modifications that are strictly related to necrosis of different tissue components, fibrosis, and damage of the tumor vessels. Postradiotherapy recurrent/persistent laryngeal squamous cell carcinoma typically presents a discohesive growth pattern within a fibrotic background associated with significant changes of the tumor immune microenvironment, with both important immunosuppressive and immunostimulatory effects. Overall, the increase of immunoregulatory cells and immune checkpoints such as CTLA-4, TIM-3, PD-1, and PD-L1 induced by radiotherapy and chemotherapy strongly supports the use of immune checkpoint inhibitors in recurrent/persistent laryngeal carcinoma. Future studies aiming to identify predictive factors of the response to immune checkpoint inhibitors should consider such treatment-induced modifications. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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13 pages, 1536 KiB  
Review
Current Approaches to Salvage Surgery for Head and Neck Cancer: A Comprehensive Review
by Romina Mastronicola, Pauline Le Roux, Aurore Casse, Sophie Cortese, Emilie Beulque, Marco Perna and Gilles Dolivet
Cancers 2023, 15(9), 2625; https://doi.org/10.3390/cancers15092625 - 5 May 2023
Cited by 3 | Viewed by 2230
Abstract
Salvage surgeries of head and neck cancer are often complicated and do not always show decent results. This type of procedure is tough on the patient, as many crucial organs can be affected. A long period of reeducation usually follows the surgery because [...] Read more.
Salvage surgeries of head and neck cancer are often complicated and do not always show decent results. This type of procedure is tough on the patient, as many crucial organs can be affected. A long period of reeducation usually follows the surgery because of the need to rehabilitate functions such as speech or swallowing. In order to lighten the journey of the patients, it is important to develop new technologies and techniques to ease the surgery and limit its damages. This seems even more crucial since progress has been made in the past years, allowing more salvage therapy to take place. This article aims at showing the available tools and procedures for salvage surgeries, such as transoral robotic surgery, free-flap surgery, sentinel node mapping, and many others, that help the work of the medical team to operate or obtain a better understanding of the status of the cancer when taken in charge. Yet, the surgical procedure is not the only thing determining the outcome of the operation. The patient themself and their cancer history also play an important part in the care and must be acknowledged. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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16 pages, 2370 KiB  
Review
Implications and Emerging Therapeutic Avenues of Inflammatory Response in HPV+ Head and Neck Squamous Cell Carcinoma
by Lúcio Roberto Cançado Castellano, Sara Brito Silva Costa Cruz, Michael Hier, Paulo Rogério Ferreti Bonan, Moulay A. Alaoui-Jamali and Sabrina Daniela da Silva
Cancers 2022, 14(21), 5406; https://doi.org/10.3390/cancers14215406 - 2 Nov 2022
Cited by 3 | Viewed by 2088
Abstract
Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and [...] Read more.
Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and HPV18 being the most prevalent strains in HNSCC. Literature data reveal that the mutation profile as well as the response to chemotherapy and radiotherapy are distinct among HPV+ versus HPV-negative tumors. Furthermore, the presence of the virus induces activation of an immune response, in particular the recruitment of specific antiviral T lymphocytes to tumor sites. These T cells when activated produce soluble factors including cytokines and chemokines capable of modifying the local immune tumor microenvironment and impact on tumor response to the treatment. In this comprehensive review we investigated current knowledge on how the presence of an HPV can modify the inflammatory response systemically and within the tumor microenvironment’s immunological responses, thereby impacting on disease prognosis and survival. We highlighted the research gaps and emerging approaches necessary to discover novel immunotherapeutic targets for HPV-associated HNSCC. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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19 pages, 1599 KiB  
Review
It Takes Two to Tango: A Review of Oncogenic Virus and Host Microbiome Associated Inflammation in Head and Neck Cancer
by Mallory G. McKeon, Jean-Nicolas Gallant, Young J. Kim and Suman R. Das
Cancers 2022, 14(13), 3120; https://doi.org/10.3390/cancers14133120 - 25 Jun 2022
Cited by 9 | Viewed by 4002
Abstract
While the two primary risk factors for head and neck squamous cell carcinoma (HNSCC) are alcohol and tobacco, viruses account for an important and significant upward trend in HNSCC incidence. Human papillomavirus (HPV) is the causative agent for a subset of oropharyngeal squamous [...] Read more.
While the two primary risk factors for head and neck squamous cell carcinoma (HNSCC) are alcohol and tobacco, viruses account for an important and significant upward trend in HNSCC incidence. Human papillomavirus (HPV) is the causative agent for a subset of oropharyngeal squamous cell carcinoma (OPSCC)—a cancer that is impacting a rapidly growing group of typically middle-aged non-smoking white males. While HPV is a ubiquitously present (with about 1% of the population having high-risk oral HPV infection at any one time), less than 1% of those infected with high-risk strains develop OPSCC—suggesting that additional cofactors or coinfections may be required. Epstein–Barr virus (EBV) is a similarly ubiquitous virus that is strongly linked to nasopharyngeal carcinoma (NPC). Both of these viruses cause cellular transformation and chronic inflammation. While dysbiosis of the human microbiome has been associated with similar chronic inflammation and the pathogenesis of mucosal diseases (including OPSCC and NPC), a significant knowledge gap remains in understanding the role of bacterial-viral interactions in the initiation, development, and progression of head and neck cancers. In this review, we utilize the known associations of HPV with OPSCC and EBV with NPC to investigate these interactions. We thoroughly review the literature and highlight how perturbations of the pharyngeal microbiome may impact host-microbiome-tumor-viral interactions—leading to tumor growth. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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Other

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15 pages, 326 KiB  
Perspective
Immunotherapy and Modern Radiotherapy Technique for Older Patients with Locally Advanced Head and Neck Cancer: A Proposed Paradigm by the International Geriatric Radiotherapy Group
by Nam P. Nguyen, Lyndon Kim, Juliette Thariat, Brigitta G. Baumert, Thandeka Mazibuko, Olena Gorobets, Vincent Vinh-Hung, Huan Giap, Tahir Mehmood, Felix Vincent, Alexander Chi, Trinanjan Basu, Gokoulakrichenane Loganadane, Mohammad Mohammadianpanah, Ulf Karlsson, Eromosele Oboite, Joan Oboite, Ahmed Ali and Brandi R. Page
Cancers 2022, 14(21), 5285; https://doi.org/10.3390/cancers14215285 - 27 Oct 2022
Cited by 1 | Viewed by 2480
Abstract
The standard of care for locally advanced head and neck cancer is concurrent chemoradiation or postoperative irradiation with or without chemotherapy. Surgery may not be an option for older patients (70 years old or above) due to multiple co-morbidities and frailty. Additionally, the [...] Read more.
The standard of care for locally advanced head and neck cancer is concurrent chemoradiation or postoperative irradiation with or without chemotherapy. Surgery may not be an option for older patients (70 years old or above) due to multiple co-morbidities and frailty. Additionally, the standard chemotherapy of cisplatin may not be ideal for those patients due to oto- and nephrotoxicity. Though carboplatin is a reasonable alternative for cisplatin in patients with a pre-existing hearing deficit or renal dysfunction, its efficacy may be inferior to cisplatin for head and neck cancer. In addition, concurrent chemoradiation is frequently associated with grade 3–4 mucositis and hematologic toxicity leading to poor tolerance among older cancer patients. Thus, a new algorithm needs to be developed to provide optimal local control while minimizing toxicity for this vulnerable group of patients. Recently, immunotherapy with check point inhibitors (CPI) has attracted much attention due to the high prevalence of program death-ligand 1 (PD-L1) in head and neck cancer. In patients with recurrent or metastatic head and neck cancer refractory to cisplatin-based chemotherapy, CPI has proven to be superior to conventional chemotherapy for salvage. Those with a high PD-L1 expression defined as 50% or above or a high tumor proportion score (TPS) may have an excellent response to CPI. This selected group of patients may be candidates for CPI combined with modern radiotherapy techniques, such as intensity-modulated image-guided radiotherapy (IM-IGRT), volumetric arc therapy (VMAT) or proton therapy if available, which allow for the sparing of critical structures, such as the salivary glands, oral cavity, cochlea, larynx and pharyngeal muscles, to improve the patients’ quality of life. In addition, normal organs that are frequently sensitive to immunotherapy, such as the thyroid and lungs, are spared with modern radiotherapy techniques. In fit or carefully selected frail patients, a hypofractionated schedule may be considered to reduce the need for daily transportation. We propose a protocol combining CPI and modern radiotherapy techniques for older patients with locally advanced head and neck cancer who are not eligible for cisplatin-based chemotherapy and have a high TPS. Prospective studies should be performed to verify this hypothesis. Full article
(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)
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