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The European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS ≥ 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70–72 Gy (EQD2/α/β = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic’s multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL.Clinical Trial Registrationclinicaltrials.gov, identifier NCT06137378.

IntroductionLarynx organ preservation (LOP) in locoregional-advanced laryngeal and hypopharyngeal squamous cell carcinoma (LA-LHSCC) being only R0-resectable (clear margins > 5 mm) by total laryngectomy (TL) is desirable. Based on tumor-specific survival (TSS) and overall survival (OS) data from the RTOG 91-11 trial and meta-analyses of randomized clinical trials (RCTs), cisplatin-based concurrent radiochemotherapy (CRT) is discussed being superior to cisplatin-based induction chemotherapy followed by radiotherapy (IC+RT) and TL followed by postoperative RT (TL+PORT) or radiochemotherapy (TL+PORCT). Outside of RCTs, T4 LHSCC treated with TL+PORCT demonstrated improved OS and TSS compared to CRT alone; comparisons with docetaxel plus cisplatin (TP)-based IC+RT are unpublished. Head-to-head comparisons in RCTs of these four alternatives are missing.Materials and methodsWe utilized monocentric registry data to compare the outcome in the LOP trial DeLOS-II (NCT00508664) and propensity score (PS)–matched LHSCC patients. DeLOS-II utilized endoscopic tumor staging after one cycle of TP-based IC for selecting TL+R(C)T for non-responders versus IC+RT for responders. Main risk factors for survival (localization hypopharynx, T4, N+, tobacco smoking >30 pack years, alcohol consumption >60 g/day, age, sex) were used to calculate the individual PS for each DeLOS-II patient and 330 LHSCC patients suitable for DeLOS-II according to eligibility criteria in Leipzig by CRT (78), TL+PORT (148), and TL+PORCT (104). We performed PS matching with caliper width 0.2.ResultsThe 52 DeLOS-II patients (whole intent-to-treat cohort) and three PS-matched cohorts (52 LHSCC patients each) had equal distribution regarding risk factors including Charlson comorbidity score (CS; all p > 0.05) but differed in outcome. During 12,498.6 months of follow-up, 162 deaths (36/41/43/42 in DeLOS-II/TL+PORCT/TL+PORT/CRT, p = 0.356) occurred; DeLOS-II patients had superior OS and TSS. Compared to DeLOS-II, the HR (95% CI) observed in TL+PORCT, TL+PORT, and CRT for OS and TSS were 1.49 (0.92–2.43), 1.49 (1.15–3.18), and 1.81 (1.11–2.96) for OS; and 2.07 (0.944–4.58), 3.02 (1.32–6.89), and 3.40 (1.58–7.31) for TSS.ConclusionIn addition potential LOP, LA-LHSCC suitable for LOP according the DeLOS-II protocol may achieve improved survival.

Most of the patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed with locally advanced disease. Standards of care for curative-intent treatment of this patient group are either surgery and adjuvant radio(chemo)therapy (aRCT) or definitive chemoradiation. Despite these treatments, especially pathologically intermediate and high-risk HNSCC often recur. The ADRISK trial investigates in locally advanced HNSCC and intermediate and high risk after up-front surgery if the addition of pembrolizumab to aRCT with cisplatin improves event-free sur-vival compared to aRCT alone. ADRISK is a prospective, randomized controlled investiga-tor-initiated (IIT)-phase II multicenter trial within the German Interdisciplinary Study Group of German Cancer Society (IAG-KHT). Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0

Purpose: Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. The 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% after primary radiochemotherapy (RCT). There is a strong rationale for combining immunotherapy with RCT in patients with ASCC due to its association with human papilloma virus (HPV) infection. Methods/design: RADIANCE is an investigator initiated, prospective, multicenter, randomized phase II trial testing the addition of Durvalumab, a PD-L1 immune checkpoint inhibitor, to standard RCT in 178 patients with locally advanced ASCC (T2 ≥ 4 cm Nany, cT3-4 and/or cN+). In the control arm, patients will be treated with standard mitomycin C (MMC)/5-fluorouracil (5-FU)-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV_A (primary tumor) T1-T2

BackgroundStandardized staging procedures and presentation of oral squamous cell carcinoma (OSCC) patients in multidisciplinary tumor boards (MDTB) before treatment and utilization of elective neck dissection (ND) are expected to improve the outcome, especially in local advanced LAOSCC (UICC stages III–IVB). As standardized diagnostics but also increased heterogeneity in treatment applied so far have not been demonstrated to improve outcome in LAOSCC, a retrospective study was initiated.MethodsAs MDTB was introduced into clinical routine in 2007, 316 LAOSCC patients treated during 1991-2017 in our hospital were stratified into cohort 1 treated before (n=104) and cohort 2 since 2007 (n=212). Clinical characteristics, diagnostic procedures and treatment modality of patients were compared using Chi-square tests and outcome analyzed applying Kaplan-Meier plots and log-rank tests as well as Cox proportional hazard regression. Propensity scores (PS) were used to elucidate predictors for impaired distant metastasis-free survival (DMFS) in PS-matched patients.ResultsMost patient characteristics and treatment modalities applied showed insignificant alteration. Surgical treatment included significantly more often resection of the primary tumor plus neck dissection, tracheostomy and percutaneous endoscopic gastrostomy tube use. Cisplatin-based chemo-radiotherapy was the most frequent. Only insignificant improved disease- (DFS), progression- (PFS) and event-free (EFS) as well as tumor-specific (TSS) and overall survival (OS) were found after 2006 as local (LC) and loco-regional control (LRC) were significantly improved but DMFS significantly impaired. Cox regression applied to PS-matched patients elucidated N3, belonging to cohort 2 and cisplatin-based chemo-radiotherapy as independent predictors for shortened DMFS. The along chemo-radiotherapy increased dexamethasone use in cohort 2 correlates with increased DM.ConclusionsDespite standardized diagnostic procedures, decision-making considering clear indications and improved therapy algorithms leading to improved LC and LRC, shortened DMFS hypothetically linked to increased dexamethasone use had a detrimental effect on TSS and OS.

BackgroundAbout five to 10% of cancers in the head and neck region are neck squamous cell carcinoma of unknown primary (NSCCUP). Their diagnosis and treatment are challenging given the risk of missing occult tumors and potential relapse. Recently, we described human papillomavirus (HPV)-related NSCCUP-patients (NSCCUP-P) as a subgroup with superior survival. However, standardized diagnostic workup, novel diagnostic procedures, decision-making in the multidisciplinary tumor board (MDTB) and multimodal therapy including surgery and post-operative radio-chemotherapy (PORCT) may also improve survival.MethodsFor assessing the impact of standardized diagnostic processes simultaneously established with the MDTB on outcome, we split our sample of 115 NSCCUP-P into two cohorts treated with curative intent from 1988 to 2006 (cohort 1; n = 53) and 2007 to 2018 (cohort 2; n = 62). We compared diagnostic processes and utilized treatment modalities applying Chi-square tests, and outcome by Kaplan–Meier plots and Cox regression.ResultsIn cohort 2, the standardized processes (regular use of [18F]-FDG-PET-CT imaging followed by examination under anesthesia, EUA, bilateral tonsillectomy and neck dissection, ND, at least of the affected site) improved detection of primaries (P = 0.026) mostly located in the oropharynx (P = 0.001). From 66.0 to 87.1% increased ND frequency (P = 0.007) increased the detection of extracapsular extension of neck nodes (ECE+) forcing risk factor-adapted treatment by increased utilization of cisplatin-based PORCT that improved 5-years progression-free and overall survival from 60.4 and 45.3 to 67.7% (P = 0.411) and 66.1% (P = 0.025).ConclusionsStandardized diagnostic workup followed by ND and risk-factor adapted therapy improves survival of NSCCUP-P.

In the locoregional advanced group of larynx and hypopharyngeal squamous cell carcinomas (LHSCC), there are two kinds of patients: those who are candidates for functional larynx organ preservation (LP) by avoiding ablative surgery and those who are not. Currently, the distinction between them is depending on the patient's needs and desires, the experience and recommendation of the surgeon, the philosophy of the institution and others. The milestone VA trial established non-surgical LP in advanced LHSCC utilizing induction-chemotherapy (IC) with PF (cisplatin, P plus 5-fluorouracil, F) followed by irradiation (IC+RT) as appropriate alternative treatment to total laryngectomy (TL) already in the 1990s. Even thou the VA trial's findings were verified by the EORTC 24891 trial we have an ongoing debate about the best protocol balancing survival and laryngectomy-free survival (LFS) with acceptable late toxicity and good functional outcome. In advanced LHSCC without surgical options preserving the larynx, only IC+RT and primary concurrent chemo-radiotherapy (CRT) are accepted treatment options aiming to preserve a functional larynx. In the US, cisplatin-based CRT is still recommended as best protocol to achieve cure of the disease and LP. But current views on long term survival with functional organ preservation and still high failure rates are addressing the need of better selection of patients which will be discussed as follows taking the current debate in literature and in particular the recently published data of the DeLOS-II trial in consideration.

Background/purpose: To evaluate whether radiation damage to dental hard tissues depends on patient-related factors in addition to irradiation dose on the spared parotid gland. Materials and methods: Seventy curatively irradiated patients with head and neck cancer underwent dental treatment prior to, during, and after radiotherapy. During a follow-up period of 24 months, damages to dental hard tissues were classified. Mean doses (Dmean) during spared parotid gland radiotherapy, patients' oral hygiene practice, and socioeconomic status were determined. Results: No carious lesions were observed in 30 patients (Group A), while sporadic and general carious lesions were noticed in 18 patients (Group B) and 22 patients (Group C), respectively. The Dmean of Group A (21.2 ± 11.00 Gy) was significantly lower than that of Group C (33.9 ± 9.9 Gy; P

Background and Purpose:  Transurethral resection of bladder tumor (TUR-BT) and radiochemotherapy with cisplatin achieve high rates of bladder preservation and survival figures identical to radical cystectomy in muscle-invasive bladder cancers. The authors have investigated the potential use of paclitaxel in a radiochemotherapy protocol for patients with inoperable bladder carcinomas and mainly contraindications to cisplatin. Patients and Methods:  Between October 1997 to August 2004, 42 patients (median age 71 years) suffering from muscle-invasive (n = 32) or recurrent (n = 10) bladder cancers were treated with a paclitaxel-containing radiochemotherapy (paclitaxel 25–35 mg/m2 twice weekly) after TUR-BT (R0/1/2/x in n = 18/4/14/3) or cystectomy with residual tumor (n = 3). Five patients received additional cisplatin. Radiation treatment was administered to a total dose of 45–60 Gy. Results:  76.2% completed the planned regimen. Adaptations of treatment were mainly required due to diarrhea. Grade 3/4 toxicities occurred in 15/1 patients. Severe renal toxicities did not occur. 28 patients underwent restaging TUR-BT 6 weeks after radiochemotherapy (complete remission/partial remission/progressive disease: n = 24/3/1). Three patients developed a local recurrence and four distant metastases. Seven patients died from tumor, six of other reasons. Conclusion:  Radiochemotherapy with paclitaxel was feasible and this bladder approach needs further investigation to evaluate whether paclitaxel could become a substitute for cisplatin. [ABSTRACT FROM AUTHOR]

Background. Simultaneous radiochemotherapy (RCT) is the treatment of choice for locally advanced headand neck cancers. In order to evaluate the toxicity and the survival rates, we investigated the use of a veryaggressive combination protocol that included cisplatinum and paclitaxel combined with hyperfractionatedacceleratedradiotherapy. The final results of the phase II study are listed below.Methods. For the phase II trial 32 patients (29 male, 3 female) with histologically diagnosed locallyadvanced non-metastatic squamous cell carcinoma of the head and neck in stage III/IV were treated from 1999to 2003. Radiotherapy was administered as hyperfractionated-accelerated to a total dose of 70.6 Gy. Thechemotherapy regime included administering cisplatinum on d 1-5 and on d 29-33 at doses of 20 mg/m2 andduring the entire course of treatment paclitaxel was administered twice a week at doses of 25 mg/m2.Results. The 5-yr overall and disease-free survival rates were 48% and 43%. Twenty-two (69%) patientsreached a clinically complete response and 8 (25%) a partial response (for two of the patients the response rateis not known). Two (6%) patients died during the treatment. Seven (22%) patients developed local recurrencesand six of these patients have in the meantime died. With regards to the four (12%) patients who developeddistant metastases, three of them have in the meantime died and two (6%) patients have died as a result of secondarymalignancies.Seven out of 25 (28%) patients developed grade 3 erythema and 22 out of 31 (71%) patients developedgrade 3 mucositis. No cases of grade 4 mucositis were observed; however, one patient out of 25 (4%) was classifiedwith grade 4 dermatitis. One out of 24 (4%) patients developed grade 2 liver toxicity and 1 out of 22patients (5%) developed grade 3 thrombopenia. Seven out of 25 patients (28%) developed a grade 3 leukopenia,and 2 out of 25 patients (8%) experienced a grade 4 eutropenic infection. Dysphagia was a significant latetoxicity. Out of 24 patients, 4 (17%) developed a grade 3 dysphagia and 1 (4%) patient developed a grade 3xerostomia. An osteoradionecrosis was seen in 2 out of 24 (8%) patients.Conclusion. This very aggressive radiochemotherapy protocol yielded excellent response and overall survivalrates; however it is associated with a very high rate of acute toxicity. Therefore, in such cases whereacute toxicity resulted, extensive supportive care is required. [ABSTRACT FROM AUTHOR]

Background: Simultaneous radiochemotherapy (sRCT) is the treatment of first choice in locally advanced head and neck cancers. We have tested a very aggressive combination protocol with cisplatin and escalated paclitaxel in combination with accelerated hyperfractionated radiotherapy to assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), overall toxicity, and response rate. Patients and Methods: The trial recruited 24 patients (21 males, three females, mean age 57 years) treated at our department from 1998 through 2001. Irradiation was administered in daily doses of 2 Gy up to 30 Gy followed by 1.4 Gy twice daily up to 70.6 Gy to the primary tumor and involved nodes and 51 Gy to the clinically negative regional nodes. The chemotherapy schedule included cisplatin in a fixed dose of 20 mg/m 2 on days 1?5 and 29?33 and paclitaxel at increasing dose levels of 20, 25, 30 mg/m 2 twice weekly over the whole treatment time. Patients were recruited in cohorts of three to six, and the MTD was reached if two out of six patients in one cohort developed DLT. DLT was defined as any grade 4 toxicity or any grade 3 toxicity requiring treatment interruption or unplanned hospitalization or any grade 3 neurotoxicity. We recruited mainly patients with large tumors for this protocol; all patients were stage IV, and the mean tumor volume (primary + metastases) amounted to 72 ± 61 cm 3. The mean follow-up was 30 months (range 4?39 months). Results: One early death (peritonitis and sepsis at day 10) occurred, and 23 patients were evaluable for acute toxicity and response. The MTD of paclitaxel was reached at the third dose level (30 mg/m 2 paclitaxel twice weekly). The DLT was severe mucositis grade 3 (n = 1) and skin erythema grade 4 (n = 2). After determining the MTD, another 14 patients were treated at the recommended dose level of paclitaxel with 25 mg/m 2 twice weekly. In summary, 13/23 patients (57%) developed grade 3 and 10/23 (43%) grade 2 mucositis. Two patients (9%) had grade 4, five (22%) grade 3, and 16 (69%) grade 2 dermatitis. One patient died at day 30 of neutropenic infection. In one patient, a grade 2 nephrotoxicity appeared requiring cessation of cisplatin chemotherapy. 18/23 patients (78%) required blood transfusion (1?3 units) and 16/23 (70%) i.v. antibiotics. 14 patients (61%) achieved a complete and nine (39%) a partial remission, yielding an overall response rate of 100%. In summary, six patients died of local tumor progression (n = 2), distant metastases (n = 2), or therapy-related complications (n = 2) during follow-up. The 3-year overall survival was 71%. Tumor volume was not a risk factor for failure in this protocol (mean tumor volume in relapse-free vs. progressive patients 71 ± 65 cm 3 vs. 64 ± 38 cm 3). All patients have, so far, developed only slight late effects (fibrosis, lymphedema) with no grade 3?4 late sequelae. Conclusions: This very aggressive sRCT protocol yielded excellent response and survival figures but was associated with a very high rate of acute toxicity (8% therapy-related deaths). A maximal supportive treatment is therefore required. [ABSTRACT FROM AUTHOR]

Background: The prognostic impact of tumor volume and hypoxia is well established. We have investigated a possible prognostic impact of the hypoxic tumor volume which can be calculated as the product of tumor volume and hypoxia. Patients and Methods:125 patients with squamous cell cancer of the head and neck were investigated. All had locoregionally confined disease. The total tumor volume was calculated from pretreatment CT scans as the sum of all visible macroscopic tumor lesions (e.g., primary tumor plus neck nodes), and all patients underwent measurement of tumor oxygenation by pO 2 histography. The hypoxic tumor volume was calculated as the product of the total tumor volume and the relative frequency of pO 2 readings < 5 mmHg. The nonhypoxic volume was the difference between total tumor volume and hypoxic volume. Results: The total tumor volume ranged from 2 to 283 cm3 (mean 47 ? 53 cm 3), the hypoxic volume from 0 to 199 cm3 (mean 18 ? 30 cm 3), and the nonhypoxic volume from 1 to 237 cm 3 (mean 29 ? 34 cm 3), and there was a strong correlation between the three parameters. 84 patients died and 41 survived in the observation period with a median survival of 12.5 months. Tumor volume and tumor oxygenation had a significant impact on survival. The tumor volume was significantly different in patients who had died as compared to surviving patients (mean 54 vs. 34 cm 3; p = 0.017). The hypoxic volume was also different (11 vs. 22 cm 3; p = 0.009), whereas the nonhypoxic volume was not significantly different (24 vs. 32 cm 3; p = 0.2). If the impact of large versus small tumor volumes (total volume, hypoxic volume, and nonhypoxic volume, subdivison according to each median) on survival was analyzed, a significant impact of total tumor volume (median survival 298 vs. 485 days; p = 0.03) and a marginal impact of the hypoxic volume (342 vs. 404 days; p = 0.08), but no impact of the nonhypoxic volume were found (383 vs. 374 days; p = 0.6). In a multivariate Cox regression model, the hypoxic tumor volume was a strong and independent prognostic factor for survival (p = 0.001) and more important than the total tumor volume (p = 0.02) whereas the nonhypoxic volume had no impact on prognosis (p = 0.33). Conclusion: The total tumor volume is a major prognostic factor, but its impact mainly results from the hypoxic volume and can be explained by the strong correlation between total tumor volume and hypoxic volume. The nonhypoxic volume had no impact on survival. As a consequence, methods to measure and localize the hypoxic volume should be further developed. [ABSTRACT FROM AUTHOR]