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Journal ArticleDOI

Association of human papillomavirus and p16 status with mucositis and dysphagia for head and neck cancer patients treated with radiotherapy with or without cetuximab: Assessment from a phase 3 registration trial

TL;DR: Regardless of p16 status, the addition of cetuximab to RT did not alter the incidence, time to onset, severity, or duration of mucositis and dysphagia and did not impact the frequency of feeding tube use.
About: This article is published in European Journal of Cancer.The article was published on 2016-09-01 and is currently open access. It has received 27 citations till now. The article focuses on the topics: Mucositis & Head and neck cancer.
Citations
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Journal ArticleDOI
TL;DR: Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin, and cetuximab showed significant detriment in terms of tumour control.

661 citations

Journal ArticleDOI
TL;DR: In this article, the authors discuss about clinical presentation and pathogenesis of mucositis in relation to different kinds of treatments and discuss therapeutic and prevention strategies, describing past and present management according to international guidelines and the most promising new data about agents potentially able to further improve the treatment of the disease in the next future.
Abstract: Mucositis is a common complication of chemotherapy, radiotherapy and targeted agents. It often affects compliance to anticancer therapies as it frequently causes schedule delays, interruptions or discontinuations of treatment. Moreover, the economic impact related to the management of mucositis is topical and several estimations of additional hospital costs due to this clinical condition have been recently reported. The ability to determine risk factors for mucositis, to early detect its onset, to assess correctly the degree of this toxicity and to plan its multidisciplinary management are all key elements to guarantee the quality of life of patients and to avoid useless dose reduction or interruption of treatment. The pathogenesis of mucositis is multifactorial and it is classily subdivided into oral and gastrointestinal mucositis according to its anatomic presentation. Treatment and patients’ related factors might help in predicting the frequency and the potential degree of symptoms onset. Here we discuss about clinical presentation and pathogenesis of mucositis in relation to different kinds of treatments. Moreover, we focus on therapeutic and prevention strategies, describing past and present management according to international guidelines and the most promising new data about agents potentially able to further improve the treatment of mucositis in the next future.

162 citations


Cites background from "Association of human papillomavirus..."

  • ...Finally, they have also seen that patients with p16 negative seem to develop more frequently grade 3 or 4 mucositis (Bonner et al., 2016)....

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Journal ArticleDOI
TL;DR: This review provides the first available structured data on oral toxicities induced by the new recently FDA- and EMA-approved monoclonal antibodies targeting PD-1, and discusses clinical management of these targeted therapy-related oral changes.
Abstract: Development of biological targeted therapies and immune checkpoint inhibitors has redefined the treatment for many cancers; however, the increasing use of new protocols has led to physicians observing a new spectrum of toxicities. To date, oral adverse events induced by these new anticancer therapies have been mainly reported using nonspecific terminology ("stomatitis," "mucosal inflammation," "mucositis") and remain poorly characterized, with the exception of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis. Oral toxicities of targeted therapies often display very characteristic features which clearly differ from classic oral injuries observed with cytotoxic chemotherapy and/or radiotherapy. In addition, they frequently affect more than 20% of treated patients and can lead to a significant morbidity or permanent treatment discontinuation. Oral mucosal toxicities described in this review include mTOR inhibitor-associated stomatitis (mIAS); stomatitis, benign migratory glossitis, and osteonecrosis of the jaw associated with multi-targeted kinase inhibitors of the VEGF and PDGF receptors; mucositis induced by EGFR inhibitors (in monotherapy or in combination with head and neck radiotherapy and/or chemotherapy); hyperkeratotic lesions with BRAF inhibitors; pigmentary changes and lichenoid reactions secondary to imatinib; and more recent data on the "Osler-Weber-Rendu-like syndrome" described with the antibody-drug conjugate, TDM-1. Finally, we provide, to our knowledge, the first available structured data on oral toxicities induced by the new recently FDA- and EMA-approved monoclonal antibodies targeting PD-1. Clinical management of these targeted therapy-related oral changes is also discussed.

103 citations


Cites background from "Association of human papillomavirus..."

  • ...reported that, regardless of p16 status, the addition of cetuximab to cervical radiotherapy did not impact the incidence, time to onset, severity, or duration of mucositis [132] (Table 2)....

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  • ...Cetuximab in association with head and neck radiation therapy The incidence of high-grade (≥3) mucositis is high when cetuximab is combined with radiotherapy (about 60%) [73, 75, 132]....

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  • ...The main pivotal studies [73, 75, 132] (Table 2), however, indicate that the addition of cetuximab to radiotherapy does not have a significant impact on the incidence of high-grade (≥3) mucositis in comparison to radiotherapy alone [73–75] (Table 2)....

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Journal ArticleDOI
TL;DR: A comprehensive review of the existing biomarkers to predict patient risk of developing oral mucositis and their role in early diagnosis concludes that non-coding RNAs might hold this potential.
Abstract: Inflammation response of epithelial mucosa to chemo- radiotherapy cytotoxic effects leads to mucositis, a painful side effect of antineoplastic treatments. About 40% of the patients treated with chemotherapy develop mucositis; this percentage rises to about 90% for head and neck cancer patients (HNC) treated with both chemo- and radiotherapy. 19% of the latter will be hospitalized and will experience a delay in antineoplastic treatment for high-grade mucositis management, resulting in a reduction of the quality of life, a worse prognosis and an increase in patient management costs. Currently, several interventions and prevention guidelines are available, but their effectiveness is uncertain. This review comprehensively describes mucositis, debating the impact of standard chemo-radiotherapy and targeted therapy on mucositis development and pointing out the limits and the benefits of current mucositis treatment strategies and assessment guidelines. Moreover, the review critically examines the feasibility of the existing biomarkers to predict patient risk of developing oral mucositis and their role in early diagnosis. Despite the expression levels of some proteins involved in the inflammation response, such as TNF-α or IL-1β, partially correlate with mucositis process, their presence does not exclude others mucositis-independent inflammation events. This strongly suggests the need to discover biomarkers that specifically feature mucositis process development. Non-coding RNAs might hold this potential.

99 citations

Journal ArticleDOI
20 Jun 2019-Cancers
TL;DR: This review focuses on the pathobiology and management guidelines for mucositis, a secondary effect of old and new anti-cancer treatments, highlighting recent advances in prevention and discussing future research options.
Abstract: Mucositis is one of the most common debilitating side effects related to chemotherapy (CT), radiation therapy (RT), targeted agents and immunotherapy. It is a complex process potentially involving any portion of the gastrointestinal tract and injuring the mucosa, leading to inflammatory or ulcerative lesions. Mechanisms and clinical presentation can differ according both to the anatomic site involved (oral or gastrointestinal) and the treatment received. Understanding the pathophysiology and management of mucosal injury as a secondary effect of anti-cancer treatment is an important area of clinical research. Prophylaxis, early diagnosis, and adequate management of complications are essential to increase therapeutic success and, thus, improve the survival outcomes of cancer patients. This review focuses on the pathobiology and management guidelines for mucositis, a secondary effect of old and new anti-cancer treatments, highlighting recent advances in prevention and discussing future research options.

71 citations


Cites background from "Association of human papillomavirus..."

  • ...In patients with HNC undergoing concomitant treatment with RT associated with cetuximab, a p16-negative status seems to be associated with a higher rate of grade 3–4 OM [87]....

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References
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Journal ArticleDOI
TL;DR: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoreGional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head andneck.
Abstract: BACKGROUND We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P = 0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P = 0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P = 0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant highdose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)

4,705 citations

Journal ArticleDOI
TL;DR: The Late Morbidity Scoring Criteria were developed as a joint effort between physicians with renewed interests in fast neutron therapy and Radiation Therapy Oncology Group (RTOG) staff to represent cumulative probabilities of late effects with methods similar to those for estimating local control and survival.
Abstract: The therapeutic use of ionizing radiations is predicated on sparing normal tissue effects while attempting to achieve lethal effects on tumor cells. From quite early in the history of radiation therapy, it was apparent that there were striking differences in effects in the panoply of normal tissues. Although there was early appreciation of some late effects in normal tissues, often not predicted by acute reactions, only in recent years has there been full documentation of the slow and progressive increase in severity of late damage. Pathophysiological mechanisms of acute and late radiation effects are better understood today (2), but interactions of other modalities with radiation therapy require constant monitoring to recognize and mitigate untoward sequelae. The work of Stone (3) is a classic example of unanticipated late effects, which resulted from irradiation with ‘fast neutrons. Acute reactions were moderate and tolerable, but the late sequelae were so marked that there was little interest in pursuing therapy with fast neutrons for nearly three decades. The Late Morbidity Scoring Criteria were developed as a joint effort between physicians with renewed interests in fast neutron therapy and Radiation Therapy Oncology Group (RTOG) staff. In the late 1970s the Neutron/Particle Committee was one of several modality committees of the RTOG. Recognizing the results of Stone, this committee, led by Lawrence Davis worked with RTOG staff to establish criteria and scoring for possible late effects from fast neutron radiation therapy. Investigators from the European Organization for Research and Treatment of Cancer (EORTC), led by William Duncan of the Western General Hospital of Edinburgh, wished to have common toxicity criteria in anticipation of joint studies. RTOG Protocol 7929, an international registry of patients treated with heavy particles, was started in 1980. At the annual meetings of the international participants in particle studies, there were attempts to monitor interobserver variations in scoring effects in normal tissues and to seek consistency in reporting toxicity, but no publications document these efforts. The first prospective trial to use the Late Morbidity Scoring Criteria was RTOG Protocol 8001, a study of fast neutron therapy for malignant tumors arising in salivary glands. Although the RTOG began to use these criteria in reporting toxicity in patients enrolled in all studies from 198 1 (beginning with RTOG Protocol 8 115), the criteria only became a published part of protocols in 1983. At that time, statistical methods began to be used, which presented time-adjusted estimates of late effects, the rationale for which was described by Cox (1). It is now considered standard to represent cumulative probabilities of late effects with methods similar to those for estimating local control and survival. The Acute Radiation Morbidity Scoring Criteria were developed in 1985 as complimentary to the Late Effects Scoring Criteria. The National Cancer Institute promulgated standard toxicity criteria in 1990, but late effects were not considered. An abbreviated version of the RTOG/EORTC toxicity criteria was published by Winchester and Cox in 1992 as part of the Standard for Breast Conservation Treatment. The current RTOG Acute Radiation Morbidity Scoring Criteria are presented in Table 1. The RTOG/EORTC Late Radiation Morbidity Scoring Scheme is detailed in Table 2. In both tables, 0 means an absence of radiation effects and 5 means the effects led to death. The severity

4,111 citations


"Association of human papillomavirus..." refers methods in this paper

  • ...Toxicity was assessed using the Radiation Therapy Oncology Group (RTOG) criteria [8]....

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Journal ArticleDOI
TL;DR: Overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients.
Abstract: Summary Background Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximabinduced rash and survival. Methods Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6–7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m² initial dose, followed by seven weekly doses at 250 mg/m². Randomisation was done with an adaptive minimisation technique to balance assignments across stratifi cation factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter . The trial is registered at www.ClinicalTrials.gov , number NCT00004227. Findings Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49·0 months (95% CI 32·8–69·5) versus 29·3 months (20·6–41·4) in the radiotherapy-alone group (hazard ratio [HR] 0·73, 95% CI 0·56–0·95; p=0·018). 5-year overall survival was 45·6% in the cetuximab-plus-radiotherapy group and 36·4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was signifi cantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0·49, 0·34–0·72; p=0·002). Interpretation For patients with LASCCHN, cetuximab plus radiotherapy signifi cantly improves overall survival at 5 years compared with radiotherapy alone, confi rming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash.

1,784 citations


"Association of human papillomavirus..." refers methods in this paper

  • ...The design of the phase 3, randomized IMCL-9815 cetuximab registration trial has previously been reported in detail [6,7]....

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Journal ArticleDOI
TL;DR: HPV-16-positive HNSCCs and HPV- 16-negative H NSCCs have different risk factor profiles, indicating that they should be considered to be distinct cancers.
Abstract: Background High-risk types of human papillomavirus (HPV), including HPV-16, cause a subgroup of head and neck squamous cell carcinomas (HNSCCs). We examined whether the risk factors for HPV-16-positive HNSCCs are similar to those for HPV-16-negative HNSCCs in a hospital-based case-control study. Methods Case subjects (n = 240) diagnosed with HNSCC at the Johns Hopkins Hospital from 2000 through 2006 were stratified by tumor HPV-16 status as determined by in situ hybridization. Two control subjects (n = 322) without cancer were individually matched by age and sex to each HPV-16-positive and HPV-16-negative case subject. Data on risk behaviors were obtained by use of audio computer-assisted self-interview technology. Multivariable conditional logistic regression models were used to estimate the odds ratios (ORs) for HPV-16-positive HNSCC and HPV-16-negative HNSCC associated with risk factors. All statistical tests were two-sided. Results HPV-16 was detected in 92 of 240 case subjects. HPV-16-positive HNSCC was independently associated with several measures of sexual behavior and exposure to marijuana but not with cumulative measures of tobacco smoking, alcohol drinking, or poor oral hygiene. Associations increased in strength with increasing number of oral sex partners (P trend = .01) and with increasing intensity (joints per month, P trend = .007), duration (in years, P trend = .01), and cumulative joint-years (P trend = .003) of marijuana use. By contrast, HPV-16-negative HNSCC was associated with measures of tobacco smoking, alcohol drinking, and poor oral hygiene but not with any measure of sexual behavior or marijuana use. Associations increased in strength with increasing intensity (cigarettes per day), duration, and cumulative pack-years of tobacco smoking (for all, P trend <.001), increasing years of heavy alcohol drinking (≥15 years of 14 drinks per week; P trend =.03), and increasing number of lost teeth (P trend =.001). Compared with subjects who neither smoked tobacco nor drank alcohol, those with heavy use of tobacco (≥20 pack-years) and alcohol had an increased risk of HPV-16-negative HNSCC (OR = 4.8, 95% confidence interval [Cl] = 1.8 to 12) but not of HPV-16-positive HNSCC (OR = 0.67, 95% Cl = 0.29 to 1.9). Conclusions HPV-16-positive HNSCCs and HPV-16-negative HNSCCs have different risk factor profiles, indicating that they should be considered to be distinct cancers.

1,436 citations


"Association of human papillomavirus..." refers background in this paper

  • ...Furthermore, HPV-negative patients were more likely to have greater tobacco exposure and more comorbidities than their HPV-positive counterparts [17], which may have contributed to the need for feeding tubes....

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Journal ArticleDOI
TL;DR: Mucositis is a frequent, severe toxicity in patients treated with RT for head and neck cancer and appears to lead to hospitalization and treatment interruptions, while its overall impact on outcomes has not been adequately investigated.

1,022 citations


"Association of human papillomavirus..." refers background in this paper

  • ...Radiotherapy (RT) for locally advanced head and neck squamous cell carcinoma (LA-SCCHN) can induce mucositis, pain, dysphagia, and diminished quality of life [1,2]....

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