HYpofractionated, dose-redistributed RAdiotherapy with protons and photons to combat radiation-induced immunosuppression in head and neck squamous cell carcinoma: study protocol of the phase I HYDRA trial.

BACKGROUND: Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient's immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA). METHODS: The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included. DISCUSSION: In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA's expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022).

Disease course after the first recurrence of head and neck squamous cell carcinoma following (chemo)radiation.

PURPOSE: Recurrent head and neck squamous cell carcinoma (HNSCC) after chemoradiation is a challenging clinical problem. Salvage surgery (SS) is often extensive and mutilating. Oncological outcomes of SS are relatively well known, but little is published about the course of disease after the first recurrence, especially in patients without salvage possibilities. The aim of this study was to analyze the course of disease in patients with recurrent HNSCC after chemoradiation. METHODS: We retrospectively analyzed and descriptively reported the disease course in 198 patients with recurrent HNSCC after chemoradiation in the time period after the first recurrence. We scored any type of event, salvage treatment, systemic treatment and overall survival (OS). RESULTS: Of the 198 patients with recurrent HNSCC, salvage surgery was attempted in 104 (53%). SS was more frequently given in patients with recurrent laryngeal cancer, isolated regional failure (p < 0.001) and HPV-positive disease (p = 0.09). The 2-year OS of the whole group was 31% and was significantly different by tumor site, type of failure and SS. HPV-positive disease and salvaged recurrences were significantly predictive for better survival. One third of that salvaged patients was still alive without second recurrence. Median survival in patients that received any palliative systemic treatment without surgery, compared to those were no treatment was given, was 6 and 3 months, respectively (p = 0.006). CONCLUSIONS: Main factors influencing the course of disease in recurrent HNSCC are the possibilities for SS and HPV-status. Therefore, SS should always be considered and discussed. In patients without possibilities for SS, overall survival is 3-6 months.

Salvage surgery for advanced stage head and neck squamous cell carcinoma following radiotherapy or chemoradiation.

PURPOSE: Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma (HNSCC) is known to result in poor prognosis. As there are only small and heterogeneous studies available with wide variety in outcome measures, our purpose was to select and pool literature according to specific criteria. METHODS: Systematic review and meta-analysis of clinical outcome after salvage surgery for recurrent advanced stage HNSCC following primary radiotherapy or chemoradiation. RESULTS: 16 of 3956 screened studies were included for analysis (729 patients). Pooled 5-year OS was 37% (95% CI 30-45%, 12 studies, 17 outcome measurements, 540 patients). Outcome was presented for larynx (6 studies, 397 patients), hypopharynx (2 studies, 47 patients), larynx and hypopharynx combined (3 studies, 69 patients) or separately (1 study, 134 patients), oral cavity (1 study, 11 patients), oropharynx (1 study, 34 patients) and multiple subsites combined (2 studies, 37 patients). There was no significant difference in survival outcome between subsites (pheterogeneity = 0.8116). The pooled tumor-positive resection margin rate was 32% and pooled re-operation rate 17%. Complication rates from the pooled data were: fistulas 33%, wound infections 24% and flap failure 3%. Treatment-related mortality rate was 1% and mean hospital stay was 23 days. CONCLUSIONS: Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma after primary (chemo)radiotherapy is a good last resort curative treatment option, resulting in 37% overall survival at 5 years. As data from advanced stage non-laryngeal tumors were sparse, no solid conclusions can be drawn with regard to outcome differences between tumor subsites.

Clindamycin-rifampin combination therapy for staphylococcal periprosthetic joint infections: a retrospective observational study.

BACKGROUND: Staphylococcal species account for more than 50% of periprosthetic joint infections (PJI) and antimicrobial therapy with rifampin-based combination regimens has been shown effective. The present study evaluates the safety and efficacy of clindamycin in combination with rifampin for the management of staphylococcal PJI. METHODS: In this retrospective cohort study, patients were included who received clindamycin-rifampin combination therapy to treat a periprosthetic hip or knee infection by Staphylococcus aureus or coagulase-negative staphylococci. Patients were treated according to a standardized treatment algorithm and followed for a median of 54 months. Of the 36 patients with periprosthetic staphylococcal infections, 31 had an infection of the hip, and five had an infection of the knee. Eighteen patients underwent debridement and retention of the implant (DAIR) for an early infection, the other 18 patients underwent revision of loose components in presumed aseptic loosening with unexpected positive cultures. RESULTS: In this study, we report a success rate of 86%, with five recurrent/persistent PJI in 36 treated patients. Cure rate was 78% (14/18) in the DAIR patients and 94% (17/18) in the revision group. Five patients (14%) discontinued clindamycin-rifampin due to side effects. Of the 31 patients completing the clindamycin-rifampin regimen 29 patients (94%) were cured. CONCLUSION: Combined therapy with clindamycin and rifampin is a safe, well tolerated and effective regimen for the treatment of staphylococcal periprosthetic infection.

Dual Immune Checkpoint Blockade Induces Analogous Alterations in the Dysfunctional CD8+ T-cell and Activated Treg Compartment.

To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in treatment-naive head and neck squamous cell carcinoma, we analyzed primary tumor immune infiltrates from responding and nonresponding patients. At baseline, a higher ratio between active (4-1BB/OX40+) and inactive regulatory CD4+ T cells was associated with immunotherapy response. Furthermore, upon therapy, this active regulatory T-cell (Treg) population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells displayed decreased expression of activity and dysfunction-related genes in responding patients, whereas in clinical nonresponders, natural killer cells showed an increased cytotoxic profile early upon treatment. These data reveal immunologic changes in response to dual PD-1/CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive Treg and CD8+ T-cell compartments in responding patients, and indicate that the presence of activated Tregs at baseline may be associated with response. SIGNIFICANCE: In head and neck squamous cell carcinoma, neoadjuvant PD-1/CTLA4 blockade has shown substantial response rates (20%-35%). As recognition of tumor antigens by T cells appears to be a critical driver of therapy response, a better understanding of alterations in T-cell state that are associated with response and resistance is of importance. This article is featured in Selected Articles from This Issue, p. 2109.

Defining oligometastatic non-small cell lung cancer: concept versus biology, a literature review.

OBJECTIVE: In this review, the concept of (synchronous) oligometastatic disease in patients with non-oncogene-driven non-small cell lung cancer (NSCLC) will be placed in the context of tumor biology and metastatic growth patterns. We will also provide considerations for clinical practice and future perspectives, which will ultimately lead to better patient selection and oligometastatic disease outcome. BACKGROUND: The treatment landscape of metastasized NSCLC has moved from "one-size fits all" to a personalized approach. Prognosis has traditionally been poor but new treatment options, such as immunotherapy and targeted therapy, brighten future perspectives. Another emerging development is the recognition of patients with so-called "oligometastatic" state of disease. Oligometastatic disease has been recognized as a distinct clinical presentation in which the tumor is stated to be early in its evolution of metastatic potential. It is suggested that this stage of disease has an indolent course, comes with a better prognosis and therefore could be considered for radical multimodality treatment. METHODS: Narrative overview of the literature synthesizing the findings of literature retrieved from searches of computerized databases, hand searches, and authoritative texts. CONCLUSIONS: Oligometastatic NSCLC is a broad spectrum disease, with a variable prognosis. Although the biology and behavior of "intermediate state" of metastatic disease are not fully understood, there is evidence that a subgroup of patients can benefit from local radical treatment when integrated into a multimodality regime. The consensus definition of oligometastatic NSCLC, including accurate staging, may help to uniform future trials. The preferable treatment strategy seems to sequential systemic treatment with subsequent local radical treatment in patients with a partial response or stable disease. Prognostic factors such as N-stage, number and site of distant metastases, tumor volume, performance status, age, and tumor type should be considered. The local radical treatment strategy has to be discussed in a multidisciplinary team meeting, taking into account patient characteristics and invasiveness of the procedure. However, many aspects remain to be explored and learned about the cancer biology and characteristics of intermediate state tumors.

Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma.

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.

Immuno-radiotherapy with cetuximab and avelumab for advanced stage head and neck squamous cell carcinoma: Results from a phase-I trial.

BACKGROUND AND PURPOSE: Radiotherapy (RT) with cetuximab is an alternative for advanced-stage head and neck squamous cell carcinoma (HNSCC) patients who are unfit for cisplatin treatment. As 5-year overall survival is below 50%, it is of interest to test PD-L1 immune checkpoint blockade (avelumab) with cetuximab-RT in the curative setting. MATERIALS AND METHODS: Phase-I feasibility trial (planned n = 10, NCT02938273) of conventional cetuximab-RT with avelumab (concurrent 10 mg/kg Q2W + 4 months maintenance) for advanced-stage HNSCC patients unfit for cisplatin treatment. RESULTS: One of ten included patients experienced grade 2 cetuximab-related infusion reaction and withdrew from the study before avelumab was administered. One patient discontinued treatment after 2 courses of avelumab and 12×2Gy RT for personal reasons. In 2/8 remaining patients, avelumab was stopped after 4 and 8 courses because of toxicity and tumor progression, respectively. There was no grade 4-5 toxicity. Grade 3 immune-related toxicity was manageable and occurred in 4 patients. One patient was treated with topical steroids for grade 3 maculopapular rash and 3 patients received high-dose prednisone for grade 3 elevated liver enzymes (n = 1) and pneumonitis (n = 2). Seven patients experienced grade 3 RT-related toxicity with no severe specific cetuximab-related toxicity. Tumor recurrence occurred in 4/8 patients (50%) after a median of 12 (8-26) months follow-up. CONCLUSION: Cetuximab-RT plus avelumab is feasible in patients with advanced-stage HNSCC who are unfit for cisplatin treatment. Immune-related toxicity was transient and manageable and radiotherapy-related toxicity was in accordance with standard of care. This pilot study provides grounds for larger efficacy trials.

HLA class II expression on tumor cells and low numbers of tumor-associated macrophages predict clinical outcome in oropharyngeal cancer.

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is a highly immunogenic tumor and differences in tumor microenvironment might contribute to the improved survival of HPV-positive OPSCC patient. METHODS: A comprehensive multivariate analysis with clinical and immune variables (human leukocyte antigen [HLA] I/II, programmed death ligand 1 (PD-L1), programmed death receptor 1 (PD1), T cells, and macrophages) was performed in 142 OPSCC patients. RESULTS: We found an inverse correlation between the expression of HLA class II molecules on tumor cells and CD68+ CD163+ tumor-associated macrophages (TAMs). High HLA-DP/DQ/DR expression and low number of TAMs were associated with longer disease-specific survival and disease-free survival (DFS). Furthermore, a new population of CD8+ FoxP3+ T cells was correlated with shorter DFS in multivariate analysis. CONCLUSIONS: \We identified new prognostic markers for patients with oropharyngeal cancer, which can be used for selecting patients that can benefit from immunotherapy.

Salvage Surgery for Recurrence after Radiotherapy for Squamous Cell Carcinoma of the Head and Neck.

OBJECTIVE: Most studies that report on salvage surgery after primary radiotherapy for head and neck squamous cell carcinoma (HNSCC) are small and heterogeneous. Subsequently, some relevant questions remain unanswered. We specifically focused on (1) difference in prognosis per tumor subsite, corrected for disease stage, and (2) differences in prognosis after salvage surgery for local, regional, and locoregional recurrences. STUDY DESIGN: Retrospective analysis. SETTING: Single-center study (2000-2016). SUBJECTS AND METHODS: Patients treated with salvage surgery for HNSCC recurrence after (chemo)radiotherapy. RESULTS: In total, 189 patients were included. Five-year overall survival (OS) was 33%, and median OS was 18 (95% confidence interval [CI], 11-26) months. Treatment-related mortality was 2%. Larynx carcinoma was associated with more favorable local (adjusted hazard ratio [HR] = 4.02; 95% CI, 1.46-11.10; P = .007) and locoregional control (adjusted HR = 5.34; 95% CI, 1.83-15.61; P = .002) than pharyngeal carcinoma. American Society of Anesthesiologists (ASA) score (≥3 vs 1-2: adjusted HR = 3.04; 95% CI, 1.17-7.91; P = .023), pT stage (3-4 vs 1-2: adjusted HR = 4.41; 95% CI, 1.65-11.82; P = .003), and salvage surgery for locoregional recurrences (locoregional vs local: adjusted HR = 3.81; 95% CI, 1.13-11.82; P = .021) were independent predictors for disease-free survival (DFS). CONCLUSION: Salvage surgery for larynx carcinoma, regardless of disease stage and other prognostic factors, results in more favorable loco(regional) control but not favorable DFS than pharyngeal carcinoma. The observed difference in DFS between salvage surgery for local and regional recurrences was not significant after correction for confounders. However, survival following salvage surgery for locoregional disease is significantly worse. For this subgroup, we propose to consider T status and comorbidity for clinical decision making, as high pT stage and ASA score are independent predictors for worse DFS.

Definitive (chemo)radiotherapy is a curative alternative for standard of care in advanced stage squamous cell carcinoma of the oral cavity.

OBJECTIVE: To compare outcome after definitive (chemo)radiotherapy (CRT group) with standard of care (surgery group) for advanced stage oral cavity carcinoma (OCC). Although definitive (chemo)radiotherapy is assumed to be inferior to surgery with regard to disease control, data on outcome of this approach are scarce. METHODS: Retrospective analysis by chart review (2000-2013). Endpoints were locoregional control (LRC), disease-free survival (DFS), disease specific survival (DSS) and overall survival (OS). RESULTS: Between the CRT-group (n = 100) and Surgery-group (n = 109), baseline characteristics were equally distributed except stage and local tumor diameter (all p ≤ .001). In the CRT group, at 5 years the LRC rate was 49%, DFS 22%, DSS 39% and OS 22%. In the surgery group, at 5 years the LRC rate was 77%, DFS 45%, DSS 64% and OS 45%. The survival curves of the two groups significantly differed for LRC (p < .001), DFS and DSS (p = .001) and OS (p = .002). After adjusting for confounders and prognostic factors, we found a significant difference between the treatment groups in LRC (adjusted HR = 2.88, 95%CI 1.35-6.16, p = .006). Within 100 days, 5 patients (5%) died from treatment-related toxicity in CRT group and 1 patient after surgery (p = .21). CONCLUSIONS: Although surgery with adjuvant radiotherapy for advanced stage OCC results in favorable locoregional control, definitive (chemo)radiotherapy is a curative alternative in patients often considered beyond cure and should be considered when surgery is not feasible.

Antibiotic mixing through impacted bone grafts does not seem indicated in two-stage cemented hip revisions for septic loosening.

Impaction bone grafts (IBG) in two-stage revision for prosthetic hip infection (PHI) might be more susceptible for infection, therefore antibiotic mixing through these grafts has been suggested. However, outcomes have not been compared with IBG without antibiotics and no long-term results are available. Therefore, we evaluated long-term infection-free outcome after the use of IBG without antibiotic supplement in two-stage revision for PHI. Patients were divided into positive (group 1, n = 8) and negative (group 2, n = 28) cultures at re-implantation and followed up to 18 years after re-implantation. Five of 36 patients died from non-orthopaedic causes (median 37, range 24-149 months). Five patients had a re-operation not related to infection (median 39, range 7-140 months). These were censored in the Kaplan-Meier estimator at the last outpatient evaluation. We found an overall re-infection rate of 2.8% within two years, which matches comparative studies in which antibiotic impregnated bone grafts had been used. In group 1, there was one re-infection after 44 months. In group 2, all three infections occurred within 56 months with an estimated infection-free percentage at 10 years of 87% (95% CI 66-96). Follow-up should be extended beyond two years and randomised clinical trials are needed for further comparison with IBG impregnated with antibiotics.