[Retrospective analysis of papillary thyroid microcarcinoma cases treated between 2001 and 2010 in the Hungarian National Institute of Oncology]. / Pajzsmirigy-mikrokarcinómás eseteink retrospektív áttekintése a 2001­2010. közötti idõszakban.

The standard treatment of papillary microcarcinomas (mPTC; ≤1 cm) regardless of their size, was similar to the advanced ones till the recent past: immediate surgery ± radioactive iodine (RAI) therapy. However, the American Thyroid Association (ATA) 2015 guidelines accept the active surveillance in selected cases. We performed a retrospective analysis on the clinical data of 103 patients with PTmC in a single (62.1%) or multiple nodes (37.9%), treated with immediate surgery followed in most cases by postoperative RAI between 2001 and 2010. N stage of the neck was pN0 in 81, and pN+ in 22 patients. Survival probability was significantly related to age (p<0.001), TSH level (p=0.0347), N stage (p=0.0402) and need for neck dissection (p=0.0045). Overall survival at 5, 10, and 15 years was 95%, 89%, and 86%, while disease-specific mortality at 5 and 10 years was 3% and 5%, respectively. Our data show that immediate radical surgery with or without postoperative RAI yielded long-term survival similar to those published. Nevertheless, progression affecting mostly older men was not prevented by immediate surgery. Our findings do not contradict the acceptability of active surveillance recommended by the 2015 ATA Guidelines.

[First report on successful application of nivolumab in Hungary for the treatment of locally recurrent head and neck squamous cell carcinoma]. / Immunterápia elsõ hatékony alkalmazása Magyarországon lokálisan kiújult fej-nyaki laphámkarcinómás betegnél.

The prognosis for recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC) remains dismal and its treatment poses a challenge for oncologists. Nivolumab belongs to the class of immune checkpoint inhibitors (ICI) and is an antibody developed to target the programmed cell death protein 1 (PD-1) receptor. The CheckMate 141 randomized phase 3 trial proved the efficacy of nivolumab in the treatment of R/M HNSCC as it was shown to significantly increase overall survival and quality of life. We present the case of a 53-year-old woman with R/M HNSCC who was given nivolumab monotherapy, as third-line treatment due the progression of her tumor. After treatment with nivolumab, the size of her tumor decreased, then was stable, while she did not experience any adverse events or notable side effects. Our case report is the first to demonstrate the application of nivolumab in R/M HNSCC in Hungary.

[Role of MRI and CT in the evaluation of postirradiation status and complications in head and neck cancer]. / Az MRI és a CT szerepe a sugárterápia utáni státusz értékelésében, szövõdményeinek vizsgálatában, fej-nyaki daganatoknál.

Most head and neck cancer patients are treated with combined modalities such as surgery, radiotherapy (RT), chemotherapy (ChT). Concurrent chemo-radiation has improved treatment outcomes with increased toxic effects. Reactions after RT are divided into early and late changes. Early reactions are seen during the course of therapy or within 3 months; these are reversible in most cases. Late complications are observed 3 months to years after RT and they are generally irreversible. As typical late reaction radiation induced necrosis may occur in soft tissues, cartilage, bones and brain. Tumor recurrence and post-radiation necrosis typically appear at the same time, within 2-3 years after RT; the differentiation may be difficult. Computed tomography (CT) and magnetic resonance imaging (MRI) have become the gold standards not only for staging and assessing tumor response, but also to evaluate posttreatment status, to distinguish residual or recurrent tumor and RT complications. Using baseline CT or MRI between 2-3 months after treatment and performing standard follow-up imaging with strict clinical follow-up are required to establish early salvage treatment.

Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel (80 mg/m2 on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening and randomisation system with an interactive (voice and web) response system and stratification by number of previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat population, whereas safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01852292, and is ongoing but no longer enrolling patients. FINDINGS: Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months (95% CI 3·5-5·3) in the buparlisib group and 3·5 months (2·2-3·7) in the placebo group (hazard ratio 0·65 [95% CI 0·45-0·95], nominal one-sided p=0·011). Grade 3-4 adverse events were reported in 62 (82%) of 76 patients in the buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3-4 adverse events (occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 [22%] of 76 vs two [3%] of 78), anaemia (14 [18%] vs nine [12%]), neutropenia (13 [17%] vs four [5%]), and fatigue (six [8%] vs eight [10%]). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of 76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease progression and none were judged to be related to study treatment. INTERPRETATION: On the basis of the improved clinical efficacy with a manageable safety profile, the results of this randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. Further phase 3 studies are warranted to confirm this phase 2 finding. FUNDING: Novartis Pharmaceuticals Corporation.

Docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by chemoradiotherapy or chemoradiotherapy alone in stage III-IV unresectable head and neck cancer: Results of a randomized phase II study.

PURPOSE: Concurrent chemoradiotherapy (CRT) is the standard treatment for advanced head and neck squamous cell carcinoma. In this phase II randomized study, the efficacy and toxicity of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy (ICT) followed by concurrent CRT was compared with those after standard CRT alone in patients with locally advanced, unresectable head and neck cancer. PATIENTS AND METHODS: Between January 2007 and June 2009, 66 patients with advanced (stage III or IV) unresectable squamous cell carcinoma of the head and neck (oral cavity, oropharynx, hypopharynx, and larynx) were randomly assigned to two groups: one receiving two cycles of docetaxel, cisplatin, and 5-fluorouracil ICT followed by CRT with three cycles of cisplatin and one treated by CRT alone. Response rate, local tumor control (LTC), locoregional tumor control (LRTC), overall survival (OS), progression-free survival (PFS), and toxicity results were assessed. RESULTS: Three patients from the ICT + CRT group did not appear at the first treatment, so a total of 63 patients were evaluated in the study (30 ICT + CRT group and 33 CRT group). Three patients died of febrile neutropenia after ICT. The median follow-up time for surviving patients was 63 months (range 53-82 months). The rate of radiologic complete response was 63% following ICT + CRT, whereas 70% after CRT alone. There were no significant differences in the 3-year rates of LTC (56 vs. 57%), LRTC (42 vs. 50%), OS (43 vs. 55%), and PFS (41 vs. 50%) in the ICT + CRT group and in the CRT group, respectively. The rate of grade 3-4 neutropenia was significantly higher in the ICT + CRT group than in the CRT group (37 and 12%; p = 0.024). Late toxicity (grade 2 or 3 xerostomia) developed in 59 and 42% in the ICT + CRT and CRT groups, respectively. CONCLUSION: The addition of ICT to CRT did not show any advantage in our phase II trial, while the incidence of adverse events increased. The three deaths as a consequence of ICT call attention to the importance of adequate patient selection if ICT is considered.

[The role of PET-CT in detecting unknown primary tumour in patients with cervical lymph node metastases]. / A PET-CT szerepe az ismeretlen primer tumorok kimutatásában manifeszt nyaki áttétes betegek esetében.

PET-CT examination was conducted with 440 patients treated at the Department of Head and Neck Surgery, National Institute of Oncology, Budapest, between January 1, 2006 and December 31, 2010. Out of them 77 patients were selected with whom no examination of any sort (physical, pan-endoscopy, or any of the conventional imaging techniques) succeeded in identifying the primary tumour. In each case the primary examination (aspiration cytology and histology) verified cervical metastases, most of them being squamous cell carcinoma. The significance of PET-CT was retrospectively evaluated in cases of unknown primary tumour with verified cervical metastases. We tested the sensitivity of PET-CT in detection of the primary malignant tumour, and possible distant metastases or a second primary in order to plan an optimal treatment schedule for the patient. Patients with whom the examinations specified in the treatment protocol (physical examination, pan-endoscopy, conventional imaging, biopsy) had failed to diagnose the primary tumour were referred to PET-CT. In each case 18F-FDG tracer was used. In 21/77 patients (27%), the PET-CT yielded unequivocal evidence for the primary tumour confirmed by histology, as well. With 10 others (13%), the precarious diagnoses by various imaging techniques were confirmed by the PET-CT. False positive findings with PET-CT that were not verified either by histology or control examination tests occurred but in 10 patients (13%). Concerning the primary tumour, false negative result was obtained only with 3 patients (4%). It should be noted that their retrospective evaluation proved diagnostic errors, the primary tumours were visible in all the scans. With 33 patients (43%) PET-CT furnished no additional information compared to the previous examinations. In 10 patients, asymptomatic distant metastases and in 3 patients synchronous tumours were diagnosed. We also acknowledge that the significance of PET-CT using 18F-FDG is unquestionable in the detection of unknown primary tumours. It is strongly recommended to re-include the detection of unknown primaries in the approved national indication list of PET-CT. (Note, until January 1, 2008 it had been included!) PET-CT is capable of detecting a primary tumour, after all unsuccessful diagnostic examinations till then, in 25-40% of the cases. One cannot disregard the role and significance of PET-CT in the detection of asymptomatic synchronous tumours, or distant metastases. These benefits make PET-CT a suitable tool for the refinement of individually tailored treatment strategies leading to better therapeutic results and more favourable cost-benefit ratio.

EGFR R521K Polymorphism Is Not a Major Determinant of Clinical Cetuximab Resistance in Head and Neck Cancer.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are among the most abundant malignancies worldwide. Patients with recurrent/metastatic disease undergo combination chemotherapy containing cetuximab, the monoclonal antibody used against the epidermal growth factor receptor (EGFR). Cetuximab augments the effect of chemotherapy; however, a significant number of patients show therapy resistance. The mechanism of resistance is yet to be unveiled, although extracellular alterations of the receptor have been reported, and their role in cetuximab failure has been proposed. AIMS: Here, we investigate possible effects of the multi-exon deletion variant (EGFRvIII), and the single nucleotide polymorphism EGFR R521K on cetuximab efficacy. RESULTS: Our results show that in HNSCC patients, the EGFRvIII allele frequency is under 1%; therefore, it cannot lead to common resistance. EGFR R521K, present in 42% of the patients, is investigated in vitro in four HNSCC cell lines (two wild-type and two heterozygous for EGFR R521K). While no direct effect is found to be related to the EGFR status, cells harboring R521K show a reduced sensitivity in ADCC experiments and in vivo xenograft experiments. However, this preclinical difference is not reflected in the progression-free or overall survival of HNSCC patients. Furthermore, NK cell and macrophage presence in tumors is not related to EGFR R521K. DISCUSSION: Our results suggest that EGFR R521K, unlike reported previously, is unable to cause cetuximab resistance in HNSCC patients; therefore, its screening before therapy selection is not justifiable.

Platinum-based chemotherapy plus cetuximab in head and neck cancer.

BACKGROUND: Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. METHODS: We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. RESULTS: Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P=0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths. CONCLUSIONS: As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00122460.)

Clinical importance of retropharyngeal lymph node metastases / A retropharyngealis nyirokcsomóáttétek klinikai jelentosége.

Összefoglaló. A retropharyngealis nyirokcsomóáttétek incidenciája a primer fej-nyaki daganat lokalizációjától függ. Leggyakrabban az elorehaladott vagy recidív nasopharynx-carcinomák esetén fordul elo, de III-IV. stádiumú oro- és hypopharynxtumorok esetén is megjelenhetnek. Non-nasopharyngealis primer tumoroknál a manifesztációjuk kedvezotlen prognosztikai faktornak tekintheto, melynek hátterében a diagnosztikus nehézség miatti késoi detektálás, a kifejezetten nehéz sebészi eltávolíthatóság, valamint az agresszív biológiai viselkedés állhat. Az esetismertetésünkben bemutatásra kerülo, 58 éves betegünknél bal oldali elülso szájfenéki primer tumort diagnosztizáltunk azonos oldali nyaki és retropharyngealis nyirokcsomó-metastasissal, mely a nemzetközi irodalom alapján extrém raritás, incidenciája kevesebb mint 1%. A retropharyngealis nyirokcsomók diagnosztikájában a lokalizáció miatt a képalkotóknak jut hangsúlyosabb szerep. Elhelyezkedésük nemcsak diagnosztikus, hanem sebésztechnikai kihívást is jelentenek az életfontosságú anatómiai képletek közelsége, illetve a szuk feltárási viszonyok miatt. Ilyenformán ezek a mutétek csak intenzív osztályos háttérrel és kello jártassággal rendelkezo centrumokban végezhetok. Az alapvetoen rossz prognózist a korai diagnózis és a multimodális terápia kedvezoen befolyásolja. Esetünkben a komplex kezeléssel (sebészi terápia és posztoperatív radiokemoterápia) sikerült lokoregionális tumormentességet elérni, és ezzel a teljes és a betegségmentes túlélési idot növelni. Orv Hetil. 2021; 162(25): 997-1003. Summary. The incidence of retropharyngeal lymph node metastasis depends on the localization of the primary head and neck cancer. Involved nodes are seen most commonly in cases of advanced or recurrent nasopharyngeal carcinoma, however, they might occur with stage III-IV oro- and hypopharyngeal tumours. The involvement of retropharyngeal lymph nodes has been associated with poor outcome of non-nasopharyngeal primary tumours, which might be explained by the delayed diagnosis, the difficult surgical procedure in the retropharyngeal space, and the aggressive nature of the disease. Here we present the case of a 58-year-old patient with an anterior oral cavity tumour on the left side with ipsilateral cervical lymph node and retropharyngeal lymph node metastases, which has been noted an extreme rarity in the literature with less than 1% incidence. Due to the localization of the retropharyngeal lymph nodes, the detection is based on imaging modalities. It represents a challenge for diagnosis and surgical treatment due to the close proximity of vital anatomical structures. Accordingly, these operations should only be performed in specialist surgical centres with intensive care units. The early diagnosis and the multimodality treatment might have a positive effect on the poor prognosis. In our case, we managed to achieve locoregional disease-free status with the complex treatment (surgical therapy and postoperative radiochemotherapy) and increase the overall and the disease-free survival. Orv Hetil. 2021; 162(25): 997-1003.

Prognostic factor analysis and long-term results of the TAX 323 (EORTC 24971) study in unresectable head and neck cancer patients.

BACKGROUND: In the TAX 323 (EORTC 24971) phase III trial enrolling patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), the addition of docetaxel (T) to cisplatin and 5-fluorouracil (PF)-based induction chemotherapy prior to definite radiotherapy significantly improved progression-free survival (PFS) and overall survival (OS). METHODS: The data were updated for PFS, OS and treatment-related long-term side-effects. Baseline clinical and laboratory data of 17 variables were collected and subjected to univariate and multivariate prognostic factor analyses for OS. RESULTS: All 358 patients randomised between 1999 and 2002 were included in the long-term analysis with a median follow-up of 8.6 years. The primary end-point of PFS remained significantly improved with TPF compared with PF (adjusted hazard ratio [HR], 0.70; 95% CI, 0.56-0.88, p = 0.002), translating into a persisting benefit in OS (adjusted HR, 0.75; 95% CI, 0.60-0.95, p = 0.015). Long-term side-effects in the TPF/PF arms comprised tracheostomy (7%/5%), feeding tube dependency (3%/6%) and gastrostomy (11%/11%). Second malignancy occurred in 8%/3%, respectively. Out of 177 patients randomised to the TPF arm, 160 were included in the multivariate analysis. Grade 2 or more dysphagia (p = 0.002) and grade 2 or more pain (p = 0.004) at baseline were identified as independent negative prognostic factors. In addition, OS differed across primary tumour sites (p = 0.027) and was worse in patients with a higher N-stage (p = 0.025). CONCLUSIONS: In LA-SCCHN patients treated with sequential chemoradiotherapy, TPF induction chemotherapy demonstrated long-lasting efficacy, superior to the PF regimen. Higher-grade dysphagia and pain are unfavourable prognosticators.

[Consequences of extracellular alterations of EGFR on cetuximab therapy in HNSCC]. / Az EGFR extracelluláris módosulásainak hatása fej-nyaki daganatok cetuximabterápiájára.

Head and neck squamous cell carcinomas (HNSCC) take many lifes worldwide. Patients with recurrent/metastatic disease receive combination chemotherapy containing anti-EGFR antibody cetuximab. However, resistance often hurdles therapy. The mechanism is yet to unveil, although EGFR extracellular alterations and activity of c-Met signaling were accused. We investigated the effects of EGFR-vIII and EGFR-R521K on cetuximab efficacy in HNSCC in cellular, xenograft, and clinical setup. Furthermore, we investigated the efficacy of c-Met inhibition in HNSCC in vitro and in vivo. We showed that EGFR-vIII is very rare in HNSCC, while the common R521K polymorphism abolishes antibody-dependent cellular cytotoxicity and in vivo antitumor effect of cetuximab. This selectivity was not reflected in immunophenotype or survival data of HNSCC patients, suggesting a more complex mechanism behind. Interestingly, c-Met inhibitor SU11274 was more effective in cetuximab-resistant, EGFR R521K heterozygous cells and xenografts, raising the possible importance of simultaneous targeting of the two receptors.

Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.

BACKGROUND: Phase 2 studies suggest that the standard regimen of cisplatin and fluorouracil (PF) plus docetaxel (TPF) improves outcomes in squamous-cell carcinoma of the head and neck. We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced, unresectable disease. METHODS: We randomly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF (docetaxel and cisplatin, day 1; fluorouracil by continuous infusion, days 1 to 5) or PF every 3 weeks for four cycles. Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy. The primary end point was progression-free survival. RESULTS: A total of 358 patients underwent randomization, with 177 assigned to the TPF group and 181 to the PF group. At a median follow-up of 32.5 months, the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group (hazard ratio for disease progression or death in the TPF group, 0.72; P=0.007). Treatment with TPF resulted in a reduction in the risk of death of 27% (P=0.02), with a median overall survival of 18.8 months, as compared with 14.5 months in the PF group. There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia, nausea, vomiting, stomatitis, and hearing loss in the PF group. The rates of death from toxic effects were 2.3% in the TPF group and 5.5% in the PF group. CONCLUSIONS: As compared with the standard regimen of cisplatin and fluorouracil, induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00003888 [ClinicalTrials.gov].).

[Cytogenetic and hormonal changes in head and neck squamous cell cancer patients: potential biomarkers for functional approaches in surgical oncology]. / Citogenetikai és hormonális változások fej-nyaki laphámrákos betegekben: potenciális biomarkerek a funkciómegtartó onkológiai sebészet számára.

Squamous cell cancer of the head and neck (SCCHN) is the third most common cause of death from cancer among Hungarian males. This cancer is caused in most of the cases by chronic toxic effects of the environment, especially by tobacco smoking and regular alcohol consumption. SCCHNs similar for the first sight, might have different clinical course, mainly because of their different responses to anticancer therapies. In this study, potential biomarkers were examined that were thought to develop as biologic responses to the known environmental toxicities, therefore, their testing is supposed to help answer the most important questions of clinical oncology: understanding tumor development, early detection of cancer and individually tailored therapy planning based on the biological nature of a particular cancer. Elevated rate of spontaneous chromosome aberrations proved to be a reliable marker of the SCCHN phenotype. However, increased mutagen sensitivity by the bleomycin-test, unlike in the US or in Western Europe, was not suitable to detect the individual cancer risk in this country, because of the high mutagen sensitivity of more than half of the healthy Hungarian population examined. In the light of the high cancer incidence and mortality statistics of Hungary, the frequency of elevated mutagen sensitivity even among healthy people is a meaningful finding, and requires further clarification. Our studies on the hormonal status of male SCCHN patients revealed some pathological changes in the sex steroid and pituitary hormone serum levels, which most probably accompanied chronic alcoholic liver disease. The elevated prolactin and decreased total and free testosterone levels predicted poor prognosis of the disease. The importance of the potential relationship between hormones and SCCHN is underscored by our further finding of functioning estrogen and progesterone receptors in SCCHN tissue of our patients.

Patritumab or placebo, with cetuximab plus platinum therapy in recurrent or metastatic squamous cell carcinoma of the head and neck: A randomised phase II study.

BACKGROUND: The fully human monoclonal antibody patritumab blocks HER3 activation, a resistance mechanism to cetuximab, induced by heregulin (HRG). A phase Ib study in recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) demonstrated tolerability and tumour response of patritumab + cetuximab + platinum. METHODS: This was a randomised, double-blind, phase II study of patritumab + cetuximab with platinum-based therapy for first-line treatment of R/M SCCHN (Clinicaltrials.gov identifier: NCT02633800). Patients aged ≥18 years received patritumab or placebo, both combined with cetuximab + cisplatin or carboplatin. Co-primary end-points were progression-free survival (PFS) in the intent-to-treat (ITT) and the high-expression HRG (HRG high) populations. RESULTS: Eighty-seven patients (n = 43 in the patritumab group; n = 44 in placebo group) enrolled. A median (range) of 6.5 (1-24) patritumab cycles were completed. Median PFS was similar between the patritumab group and placebo group in the ITT population (5.6 versus 5.5 months; hazard ratio [HR] 0.99 [95% confidence interval [CI], 0.6-1.7]; P = 0.96) and HRG-high subgroup (n = 51; 5.6 versus 5.6 months; HR 0.93 [95% CI, 0.5-1.8]; P = 0.82). Median overall survival in the ITT population was also similar (10.0 versus 12.7 months; HR 1.3 [95% CI, 0.69-2.29]; P = 0.46). All patients experienced ≥1 treatment-emergent adverse event (TEAE). Grade ≥III TEAEs were more frequent in the patritumab than the placebo group (84.1% versus 60.5%). The most common grade ≥III patritumab-related TEAE in the patritumab group (20.5% overall) was rash (6.8%). CONCLUSION: Patritumab + cetuximab + platinum was tolerable but not superior to cetuximab + platinum.

Local immune parameters as potential predictive markers in head and neck squamous cell carcinoma patients receiving induction chemotherapy and cetuximab.

BACKGROUND: The aim of this study was to determine whether tumor-associated immune cells may predict response to therapy and disease outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving induction chemotherapy and cetuximab. METHODS: Paraffin-embedded pretreatment biopsy samples from 45 patients with stage III-IV resectable HNSCC were investigated retrospectively by immunohistochemistry for density of different immune cell types based on expression of CD8, FOXP3, CD134, CD137, PD-1, CD20, NKp46, dendritic cell lysosomal-associated membrane protein (DC-LAMP), CD16, CD68, and myeloperoxidase. Results were analyzed for possible correlations with clinicopathologic parameters, response to therapy, and survival. RESULTS: Of the immune cell types studied, we found significant association with response to induction chemotherapy only in the case of DC-LAMP+ mature dendritic cells and PD-1+ lymphocytes; density of DC-LAMP+ cells also correlated with progression-free survival. CONCLUSION: DC-LAMP+ mature dendritic cells and PD-1+ cells may be implicated in response to induction chemotherapy and cetuximab in HNSCC patients.

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial.

Importance: Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. Objective: To assess safety and objective response rate of durvalumab combined with tremelimumab. Design, Setting, and Participants: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. Interventions: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. Main Outcomes and Measures: Safety and tolerability and efficacy measured by objective response rate. Results: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. Conclusions and Relevance: In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way. Trial Registration: clinicaltrials.gov Identifier: NCT02319044.

Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy.

BACKGROUND: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. PATIENTS AND METHODS: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS). RESULTS: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. CONCLUSION: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.

[Phoniatrics in the rehabilitation for head and neck cancer]. / A foniátria feladatai az onkológiai betegek rehabilitálásában.

The aim of treating head and neck cancer is to eliminate the tumor and save functions as much as possible. Despite all efforts the vital (swallowing) and communicative (phonation, articulation) functions can be injured. The treatment of dysphagia is the most important in the rehabilitation, because it can lead to fatal complications: aspiration pneumonia (for example aspiration of saliva), dehydration, malnutrition. According to the localization of the lesion we distinguish oropharyngeal and esophageal dysphagia. The aspiration may be pre-, intra- and post-deglutition. The aspiration without coughing is called silent aspiration which is mainly seen in neurogenic dysphagia, but can also happen in head and neck cancer patients. There are different possibilities to compensate the failing functions in the phoniatric rehabilitation. The swallowing therapy includes causal, compensatory and dietary strategies. In addition to the swallowing therapy the treatment of communicative dysfunctions with articulation exercises will also improve the quality of life of the patients.

[Laser surgery of head and neck lesions at the National Institute of Oncology, Budapest]. / Lézermutétek az Országos Onkológiai Intézetben.

In spite of the continued expansion of non-surgical therapeutic modalities surgery still plays an important role in the treatment of head and neck cancer. Parallel with the use of conventional approaches, more sophisticated surgical approaches, like the use of laser in oncologic surgery, appeared with a more favorable outcome. Laser is a precise surgical tool, particularly when coupled to an operating microscope (with a variable spot size micromanipulator), allowing microprecision and hemostatic ability. The benefits of the use of laser are: bloodless operation field, high hit probability, "no touch" technique, ablasticity, support of tissue repair, and the lack of edema and scar formation. Between 1981 and 2008, 7934 surgical procedures were performed at the Department of Head and Neck Surgery, National Institute of Oncology, Budapest, Hungary. The aim is to present our results and experience with laser surgery of cutaneous lesions of the head and neck, oral, pharyngeal and laryngeal pathologies including cases of laryngotracheal stenosis.

[Applicable methods of reconstruction for the replacement of soft tissue after the radical resection of oral tumors]. / Lágyrészhiányok pótlására alkalmazható rekonstrukciós módszerek szájüregi daganatok radikális eltávolítása után.

In Hungary the number of oral and pharyngeal cancers is alarmingly high. While the mortality rate in 1955 was 282, by 2005 it rose to 1567. However, in the last 1-2 years stagnation can be observed. Nevertheless, even now significant proportions of men and women are involved. Alcohol consumption and smoking are invariably the leading causes, but one cannot disregard the shortcomings of oral cancer screenings, either. Unfortunately, drastic changes in this field are not likely to occur in the near future. Numerous solutions have been developed for the replacement of soft tissue. In our article, we describe and evaluate four of them. When using these techniques, we were often successful in replacing soft tissue deficiencies.