Traditional risk factors and nodal yield-still relevant with high-quality risk-adapted adjuvant treatment for locally advanced head and neck cancer?

OBJECTIVE: Patients with locally advanced head and neck cancer (LAHNC) often undergo multimodal therapy including radical resection of the primary tumor and neck dissection (ND) followed by risk-adapted adjuvant radio(chemo)therapy (R(C)T). Quality parameters influencing local control and survival of these patients have been postulated: resection status (R status), extranodal extension (ENE), interval to adjuvant treatment ≤6 weeks, R(C)T given when indicated, and nodal yield (NY) ≥18 lymph nodes per neck. For other solid tumors the trend is towards less extensive lymph node surgery to avoid toxicity such as lymphedema, damage to peripheral nerves, dysesthesia, or paresthesia. The present study aims to investigate whether the number of nodes removed during neck dissection for LAHNC is still predictive for outcome when patients receive risk-adapted adjuvant treatment according to current guidelines. METHODS: Between 2008 and 2015, 468 patients with LAHNC undergoing R(C)T with curative intent were prospectively registered in a database (UICC III/IV). Among them, 359 patients received adjuvant treatment and 295 underwent neck dissection. There were 119 (40%) patients with an oropharyngeal primary, 49 (17%) with cancer of the larynx/hypopharynx, 88 (30%) of the oral cavity, and 39 (13%) of the nasal/paranasal sinuses and cancer of unknown primary (CUP). Median follow-up was 45.6 months. Histopathology revealed an R1 status in 65 (22%) cases and ENE in 93 (31%) cases. 150 (51%) patients received RCT; the median time to adjuvant treatment from the day of tumor resection was 44 days (35-54) and overall treatment time (OTT; time from surgery to the last day of R(C)T) was 90 days (82-101). Factors influencing disease-free survival (DFS) were adjusted and analyzed using CART analysis (removed nodes, number of positive nodes, body mass index (BMI), ENE, T and N classification, R status, and primary site). Local control (LC), distant metastases-free survival (DMFS), and overall survival (OS) were analyzed using Kaplan-Meier statistics and multivariate analysis (MVA) for factors predictive for DFS and OS. RESULTS: CART analysis (Classification and Regression Trees) showed that T classification (T3/4) is the most important predictor for DFS, followed by age (> 61 years) and BMI (< 17.4). Primary site (OPC vs. other) and number of removed nodes (< 17) were shown to be less important for DFS, while ECE, N classification, and R status seem to be of little relevance. MVA revealed number of positive nodes, non-OPC, and T3/4 to be negative predictive factors for DFS. For OS, the number of positive nodes and non-OPC primary were predictive. Five-year rates were 86.1% for LC, 87.9% DMFS, 76.5% DFS, and 67.2% for OS. CONCLUSION: In this patient cohort, the number of removed nodes is not relevant for DFS and OS, while the number of positive nodes and T classification have a negative impact on these endpoints. The high-risk factors positive resection margin and ECE seem to lose their negative impact on DFS and OS. High-quality care in head and oncology is only possible within a close multidisciplinary team and network.

Influence of radiation dose to pharyngeal constrictor muscles on late dysphagia and quality of life in patients with locally advanced oropharyngeal carcinoma.

BACKGROUND AND OBJECTIVE: Patients with oropharyngeal carcinoma (OPC) often have difficulty swallowing, which may affect quality of life (QoL). Radiation dose to constrictor muscles plays an important role. METHODS: 54 patients with locally advanced OPC were evaluated after intensity-modulated radiotherapy. Data were collected at standardized intervals using the EORTC questionnaires QLQ-C30 and QLQ-HN35 within two years. The pharyngeal constrictors (superior, middle, and inferior) were each contoured as an organ at risk. Influence of dose to the constrictors (≥55 Gy vs. <55 Gy) on late dysphagia and QoL was analyzed using the t­test. RESULTS: Late radiation-induced dysphagia depends significantly on the dose to the lower pharyngeal constrictor. At a dose of ≥55 Gy, 14 (64%) patients developed dysphagia grade ≤2 and 8 (36%) patients grade ≥3. At a dose of <55 Gy, the distribution at the end of radiotherapy (RT) was similar: 22 (69%) patients with dysphagia grade ≤2, 10 (31%) with grade ≥3. There was no dose-dependent difference in the severity of dysphagia in the acute phase (p = 0.989). There were differences 18 months after the end of RT: ≥55 Gy: 19 (86%) patients showed dysphagia grade ≤2; 3 (14%) grade ≥3. At <55 Gy, 31 (97%) patients developed grade ≤2, 1 (3%) grade ≥3 (18 months: p = 0.001; 24 months: p = 0.000). Late dysphagia is also dependent on the dose level of the middle constrictor muscle (6 months: p = 0.000; 12 months: p = 0.005, 18 months: p = 0.034). After 24 months, there was no significant difference (p = 0.374). CONCLUSION: Radiation dose to the upper constrictor muscle appears to be of little relevance. The middle and lower constrictor should be given special consideration to avoid late dysphagia. Long-term QoL is independent on radiation dose.

[Update on HPV-associated head and neck cancer-highlights from the 2019 ASCO Annual Meeting]. / Update zu HPV-assoziierten Kopf-Hals-Karzinomen ­ Highlights der ASCO-Jahrestagung 2019.

At this year's Annual Meeting of the American Society for Clinical Oncology (ASCO), the keyword search "HPV-associated head and neck cancer" resulted in 920 hits-74% of the hits on human papillomavirus (HPV). This underlines the relevance of the topic. The spectrum ranged from validation and separation of the prognostic groups of patients with HPV-associated oropharyngeal carcinoma (OPSCC) according to TNM 8, to the characterization of new tumor markers and tumor mutational burden for possible de-escalation strategies to avoid toxicity of standard multimodal treatments. It has been shown that the separation of p16-positive OPSCC into Union for International Cancer Control (UICC) stages I and II with the current TNM 8 classification without further markers is not sufficiently successful to justify de-escalation strategies. Following publication of the results of the De-ESCALaTE- and RTOG-1016 trials in 2018, which confirm the current standard of care for p16-positive OPSCC, no further phase III studies on de-escalation were presented. In a presented prospective phase II study (NCT02281955), the radiotherapy dose was reduced to cumulative 60 Gy, whereby the simultaneous chemotherapy regimen with cisplatin 30 mg/m2 weekly is not standard of care and could be administered as an alternative to cisplatin cetuximab. Some work dealt with the oral and intestinal microbiota as prognostic markers or their treatment-related changes, particularly under immunotherapy. Modification seems to have a positive impact on the success of therapy. However, robust data are still lacking for the various modified treatments for HPV-associated OPSCC, which are needed before their implementation in daily practice.

[Studies on radiotherapy of head and neck cancer : Highlights of the 2019 ASCO Annual Meeting]. / Strahlentherapeutische Studien bei Kopf-Hals-Tumoren : Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: Radiotherapy is an important treatment option in patients with head and neck. At this year's annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, results of several studies on radiotherapy in patients with head and neck cancer were presented. MATERIALS AND METHODS: All abstracts and presentations from this year's ASCO Annual Meeting on radiotherapy in patients with head and neck cancer were screened and the most interesting results selected for further review. RESULTS: The ORATOR trial compared primary surgery in patients with oropharyngeal carcinoma (OPSCC) with primary radiochemotherapy (RCT), particularly in terms of swallowing, for which superiority of RCT was demonstrated. Furthermore, results were presented on the question of optimal cisplatin dosage in patients receiving adjuvant RCT. Higher cisplatin doses showed better outcome. In patients with nasopharyngeal carcinoma (NPC), neoadjuvant chemotherapy before RCT is a comparable alternative to RCT followed by adjuvant chemotherapy. In addition, results of studies were presented that examined the tolerability of combining immunotherapy with radiotherapy in the first-line setting. CONCLUSION: The data presented show promising approaches for the further development of radiotherapy, particularly in terms of combined RCT as well as the optimal sequencing and dosing of systemic therapies.

[Radiotherapeutic studies of head and neck cancer-highlights of the 2018 ASCO Annual Meeting]. / Strahlentherapeutische Studien bei Kopf-Hals-Tumoren ­ Highlights der ASCO-Jahrestagung 2018.

BACKGROUND: Radiotherapy is an important treatment option in patients with advanced head and neck cancer. At the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO), study results were presented that could further develop and modify existing therapy concepts in the future. MATERIALS AND METHODS: All ASCO abstracts and presentations concerning radiotherapy of head and neck cancer were screened and the most interesting abstracts were selected for further review. RESULTS: One major topic was the combination of radiation with immunotherapy. Presented trials included combination treatment of epidermal growth factor receptor (EGFR) antibodies and platin-based chemoradiotherapy, as well as programmed cell death protein 1 (PD-1) antibodies in combination with platin-based chemoradiotherapy or cetuximab radiotherapy. In one study, the impact of adjuvant (chemo)radiotherapy for overall survival of human papillomavirus (HPV)-associated head and neck cancer with low to intermediate risk was analyzed. Additionally, studies focusing on the prophylaxis or reduction of radiation-mediated oral mucositis were presented. CONCLUSION: The data presented do not justify a change of current treatment paradigms just yet. However, interesting developments can be expected in the coming years, particularly in the field of immunotherapy.

[Update on HPV-associated head and neck cancer-highlights of the 2018 ASCO Annual Meeting]. / Update zu HPV-assoziierten Kopf-Hals-Karzinomen ­ Highlights der ASCO-Jahrestagung 2018.

Rising incidence rates in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and a significantly improved prognosis have brought this entity into scientific focus. At this year's American Society of Clinical Oncology (ASCO) Annual Meeting, 291 studies with the keyword "HPV" were presented, the majority of which were in head and neck cancer. Due to high rates of late toxicities after conventional therapy, de-intensified treatment concepts are being increasingly discussed, although data from prospective phase III studies were not presented. Retrospective data on the latest TNM staging (downstaging in many HPV-associated patients) and other risk stratification systems were presented. HPV diagnostics based solely on p16 immunohistochemistry were discussed. Many groups presented work on the HPV association and its prognostic relevance not only in oropharyngeal carcinoma, but also in oral cavity, hypopharyngeal, and locally advanced laryngeal squamous cell carcinoma. New prognostic biomarkers such as methylation signatures appear to be promising. New data suggest equal survival rates in HPV-associated stage I OPSCC treated with surgery alone in comparison to patients who received adjuvant therapy after surgery. A possible negative effect on overall survival in stage III HPV-associated OPSCC with a cisplatin dose ≤200 mg/m2 was discussed. Results of de-escalation studies are urgently awaited, in order to be able to treat HPV-associated OPSCC patients as precisely and as specifically as possible and ensure long-term quality of life.

Socioeconomic status and quality of life in patients with locally advanced head and neck cancer.

PURPOSE: Socioeconomic aspects play an important role in health care. Patients with locally advanced head and neck cancer (LAHNC) experience detrimental effects on their quality of life (QoL). This prospective study examines QoL differences between patients with different socioeconomic status (SES) after intensity-modulated radiation therapy (IMRT). PATIENTS AND METHODS: In all, 161 patients were questioned at the end of IMRT and at 12 and 24 months follow-up using the questionnaires of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-30 and QLQ-HN35. Patients' QoL 2 years after IMRT was compared to a population reference sample and QoL of patients from lower, middle, and higher social class 2 years after IMRT was analyzed by ANCOVA using baseline QoL (end of radiation treatment) as a covariate. RESULTS: Patients with high SES report worse QoL at the end of IMRT in the domains global health status (-15.2; p = 0.005), role function (-23.8; p = 0.002), and social function (-19.4; p = 0.023) compared to patients with middle and low SES. QoL improved during the first 12 and 24 months. However, 2 years after IMRT, middle and low SES patients report lower QoL in the domains global health status, physical function, and role function, and report a higher general (fatigue, pain, dyspnea) and head and neck cancer-specific symptom burden (pain, swallowing, senses, speech, social eating, opening mouth, and felt ill) than patients with high SES. CONCLUSION: After IMRT for LAHNC, patients with high SES report worse QoL compared to patients with middle or low SES. There is a marked improvement within the first 24 months in many domains. However, the magnitude of improvement in patients with middle or low SES is significantly smaller compared to patients with high SES.

The current role of systemic chemotherapy in the primary treatment of head and neck cancer.

The treatment of patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) is still evolving into the perfect combination of the different multidisciplinary approaches. Induction chemotherapy (ICT) prior to planned definitive local therapy is widely used in this patient population for over 30 years but it is still unclear how to incorporate ICT into multimodality treatment the best. It appears to have a role in selected clinical situations especially for those patients with high risk for distant metastasis. However, since ICT protocols in different studies varies a lot, a comparative and consistent statement of benefits is difficult. We show the recent developments including randomized trials comparing radiochemotherapy (RCT) and ICT followed by definitive RCT here. This review summarizes how ICT has developed over the years, provides critical remarks of recent developments, and discusses how clinical trials including ICT should be conducted in the future.

[The most important study results of primary chemoradiation for head and neck squamous cell carcinoma : highlights of the ASCO Meeting 2013]. / Die wichtigsten Studienergebnisse der primären Radio-Chemo-Therapie von Kopf-Hals-Tumoren : Highlights des ASCO-Meetings 2013.

Primary concomitant and sequential chemoradiation is a commonly used therapeutic strategy for head and neck squamous cell carcinoma. At the annual meeting of the American Society of Clinical Oncology 2013 numerous trial results were presented. A selection of the most important trials will be summarized in this article. This year several results from phase II and III trials in concomitant and sequential therapy were demonstrated.

Xerostomia after radiotherapy. What matters--mean total dose or dose to each parotid gland?

PURPOSE: Xerostomia is a debilitating side effect of radiotherapy in patients with head and neck cancer. We undertook a prospective study of the effect on xerostomia and outcomes of sparing one or both parotid glands during radiotherapy for patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients with locally advanced squamous cell carcinoma of the head and neck received definitive (70 Gy in 2 Gy fractions) or adjuvant (60-66 Gy in 2 Gy fractions) curative-intent radiotherapy using helical tomotherapy with concurrent chemotherapy if appropriate. Group A received < 26 Gy to the left and right parotids and group B received < 26 Gy to either parotid. RESULTS: The study included 126 patients; 114 (55 in group A and 59 in group B) had follow-up data. There were no statistically significant differences between groups in disease stage. Xerostomia was significantly reduced in group A vs. group B (p = 0.0381). Patients in group A also had significantly less dysphagia. Relapse-free and overall survival were not compromised in group A: 2-year relapse-free survival was 86% vs. 72% in group B (p = 0.361); 2-year overall survival was 88% and 76%, respectively (p = 0.251). CONCLUSION: This analysis suggests that reducing radiotherapy doses to both parotid glands to < 26 Gy can reduce xerostomia and dysphagia significantly without compromising survival. Sparing both parotids while maintaining target volume coverage and clinical outcome should be the treatment goal and reporting radiotherapy doses delivered to the individual parotids should be standard practice.

Expression of insulin-like growth factor II mRNA-binding protein 3 in squamous cell carcinomas of the head and neck.

BACKGROUND: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) was found overexpressed in various cancer types suggesting its possible role in carcinogenesis. Analysis of IMP3 expression in head and neck squamous cell carcinomas (HNSCC) is rare so that we evaluated it using tissue microarray method. METHOD: Immunohistochemical analysis of IMP3 was performed on samples from over 400 patients. The expression was measured semiquantitative, subsequently divided into four categories (negative, weak, medium, or strong) and correlated with several available clinicopathologic parameters. RESULTS: For HNSCC, positive IMP3 expression was observed in patients with all tumor stages (pT1-4) and nodal stages (pN0-3), showing also significant statistical correlation (P=0.023 and P=0.0013, respectively). No further correlations were found. Separate analysis according to tumor localization (oral cavity, oropharyngeal, and laryngeal) showed a significant correlation of positive IMP3 expression and overall survival (P=0.038) only in patients with tumors of the oral cavity. Multivariate analysis showed IMP3 as an independent predictive marker for oral squamous cell carcinomas (OSCC). CONCLUSION: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression might be used as an independent prognostic factor in the subgroup of OSCC.

[The most important results on primary chemoradiation for head and neck squamous cell carcinoma: highlights from the 2012 ASCO meeting]. / Die wichtigsten Studienergebnisse der primären Radiochemotherapie von Kopf-Hals-Tumoren: Highlights vom ASCO-Meeting 2012.

Primary concomitant and sequential chemoradiation is a commonly used therapeutic strategy for head and neck squamous cell carcinoma. At the annual meeting of the 2012 American Society of Clinical Oncology numerous trial results were presented. A selection of the most important trials will be summarized in this article. This year, several important results from phase III trials-including the long awaited comparison of sequential and concomitant chemoradiation-were demonstrated.

[Public awareness of human papilloma virus infection in the head and neck area: an appeal for precision in diagnostics and for public health awareness]. / Humane Papillomvirusinfektionen im Kopf-Hals-Bereich im öffentlichen Bewusstsein: Mahnung zu Präzision in Diagnostik und Öffentlichkeitsarbeit.

Infection with human papilloma virus (HPV) has been associated with head and neck carcinomas. Experts in HPV-positive carcinomas consider these carcinomas to be a new entity, because it has been shown that treatment outcome is excellent with significantly longer overall survival dependent of therapy. Despite this, in Germany public awareness of this development is rather low. A strategy for prophylactic vaccination against HPV-associated diseases has been available since 2007 but only to reduce the incidence of cervical cancer for girls between 12 and 17 years of age. There is an ongoing debate in Germany about the efficacy and safety of HPV vaccination. The results of epidemiological research in the USA which show that vaccination in young males is valuable are still not accepted in Germany. This article discusses the scientific and public awareness regarding this topic and calls for precision in diagnostics and public health awareness in order to establish a fertile ground for prevention and optimal treatment of HPV-associated diseases.

[New aspects of primary radiochemotherapy in head and neck cancer. Highlights from the 2011 ASCO Congress]. / Neue Aspekte der primären Radiochemotherapie bei Kopf-Hals-Tumoren. Highlights vom ASCO-Kongress 2011.

Primary radiochemotherapy is a treatment option for patients with locally advanced or unresectable head and neck cancer. Compared to conventional radiotherapy, intensity-modulated radiotherapy (IMRT) is associated with fewer long-term toxicities and better quality of life. Whether IMRT improves local control in these patients needs to be further investigated. The risk factors and treatment toxicities must be taken into consideration and discussed with the patients. New approaches combining radiotherapy and biological targets are a treatment option. The implementation of these substances in treatment protocols is increasing. Sensitive and specific prognostic biomarkers for patient identification to optimize treatment selection are important, but reliable parameters are still missing.

Global quality of life during the acute toxicity phase of multimodality treatment for patients with head and neck cancer: can we identify patients most at risk of profound quality of life decline?

PURPOSE: Treatment intensification has improved outcomes for patients with head and neck cancer (HNC), but little has been reported on health-related quality of life (QoL) consequences. We investigated changes in QoL after (chemo)radiotherapy to identify patient characteristics that predict those whose QoL deteriorates most profoundly in the acute post-treatment period. MATERIALS AND METHODS: Patients with locally advanced HNC treated with curative intent received intensity-modulated radiotherapy (60-70 Gy) in this prospective study. (Chemo)radiotherapy was either definitive or adjuvant. Induction chemotherapy consisted of three cycles of docetaxel, cisplatin, and 5-fluorouracil; responders received (chemo)radiotherapy; nonresponders underwent salvage surgery followed by (chemo)radiotherapy if appropriate. Patients completed the EORTC QLQ-C30 and HNC-specific HN35 module before and at the end of (chemo)radiotherapy and 6-8 weeks after therapy completion. RESULTS: Ninety-five patients participated. At baseline, patients reported significantly lower Global health status, functioning, and symptom scale scores than a reference German population (all p<0.001). At the end of (chemo)radiotherapy, patients had significantly lower QoL scores vs. baseline on all functioning scales (p<0.05). Most symptom and HN35 scores worsened during (chemo)radiotherapy but many recovered 6-8 weeks post-treatment. QoL deteriorated more in patients with high vs. low baseline QoL; no clinical or sociodemographic characteristics of patients most likely to experience a significant deterioration in QoL during treatment were identified. CONCLUSION: These standard QoL instruments did not predict patients at risk of profound global QoL impairments during acute treatment. Other than baseline QoL, no patient characteristics associated with significant QoL deterioration were identified.

[HPV infection in head and neck squamous cell carcinoma (HNSCC). Highlights from ASCO 2010]. / HPV-Infektion bei Kopf- und Hals-Malignomen. Highlights vom ASCO-Kongress 2010.

The human papillomavirus (HPV) is now understood to be important in the development of oropharyngeal cancers, particularly when other risk factors typically associated with this disease, such as smoking and nicotine abuse, are less evident. Case series have suggested that HPV-positive status is associated with better outcomes than HPV-negative status. The HPV status of patients with oropharyngeal cancer should be established before treatment commences. The risks and potential benefits of individual treatment modalities for patients with HPV-positive disease should be carefully considered with the aim of preserving quality of life, improving outcomes, and minimizing morbidity. The new data presented at ASCO will be discussed.

[Radiation therapy in head and neck cancer. Highlights from ASCO 2010]. / Strahlentherapie bei Kopf-Hals-Tumoren. Highlights vom ASCO-Kongress 2010.

In contrast to conventional radiotherapy, intensity modulated radiotherapy (IMRT) enables individually adjusted dose and intensity depending on tumor size and organs at risk, thus enabling radiotherapy of complex volumes in the head and neck area using high doses. Despite new data presented at the annual congress of the American Society of Clinical Oncology (ASCO), questions remain unanswered in two basic categories: (a) How do we use IMRT with other important advances in head and neck cancer treatment, such as altered fractionation, chemotherapy, and novel agents? (b) Does IMRT in its current form produce sufficient risk:benefit improvements in salivary gland sparing/less xerostomia, better targeting/local control and less late toxicity? Whether IMRT with its complex target volume definition and dose distribution leads to improved local control needs to be further investigated in relevant studies.

Human papilloma virus in locally advanced stage III/IV squamous cell cancer of the oropharynx and impact on choice of therapy.

Oropharyngeal cancers (OPCs) are now believed to arise from two distinct pathways: one influenced by alcohol and tobacco use and the other a result of genomic instability induced by the human papilloma virus (HPV). The incidence of HPV-associated OPC is increasing, particularly among younger males. Case series and clinical trials suggest that patients with HPV-positive OPC have better clinical outcomes than those with HPV-negative tumors. We evaluated efficacy data in published articles and meeting abstracts from clinical studies comparing response rates and survival outcomes in patients with HPV-positive and -negative locally advanced OPC. Eight clinical studies were identified: half were prospective analyses of outcome according to HPV status; the remaining four reports were retrospective analyses. The majority of these analyses showed that patients with HPV-positive tumors had significantly better responses to treatment than those with HPV-negative tumors. In the two studies in which the effect of treatment was also evaluated, patients with HPV-positive tumors did not benefit significantly from intensive therapy, unlike those with HPV-negative tumors. HPV-positive tumor status is an important prognostic factor associated with a favorable outcome in patients with locally advanced OPC. The HPV status of patients with locally advanced OPC should be established before treatment commences. Surgery is well accepted in the treatment of OPC, but the place of chemoradiotherapy has yet to be confirmed. Prospective, well-controlled clinical studies are required to establish whether chemoradiotherapy provides an acceptable risk-benefit balance versus high-quality radiotherapy alone in patients with HPV-positive OPC, in whom the goal is to maximize progression-free and overall survival, while preserving function and maintaining quality of life.