Background Head and neck squamous cell carcinoma (HNSCC) presents as locally advanced disease in a majority of patients and is prone to relapse despite aggressive treatment. Since immune checkpoint ...inhibitors (ICI) have shown clinically significant efficacy in patients with recurrent/metastatic HNSCC (R/M HNSCC), a plethora of trials are investigating their role in earlier stages of disease. At the same time, preclinical data showed the synergistic role of concurrently administered radiotherapy and ICIs (immunoradiotherapy) and explained several mechanisms behind it. Therefore, this approach is prospectively tested in a neoadjuvant, definitive, or adjuvant setting in non-R/M HNSCC patients. Due to the intricate relationship between host, immunotherapy, chemotherapy, and radiotherapy, each of these approaches has its advantages and disadvantages. In this narrative review we present the biological background of immunoradiotherapy, as well as a rationale for, and possible flaws of, each treatment approach, and provide readers with a critical summary of completed and ongoing trials. Conclusions While immunotherapy with ICIs has already become a standard part of treatment in patients with R/M HNSCC, its efficacy in a non-R/M HNSCC setting is still the subject of extensive clinical testing. Irradiation can overcome some of the cancer's immune evasive manoeuvres and can lead to a synergistic effect with ICIs, with possible additional benefits of concurrent platinum-based chemotherapy. However, the efficacy of this combination is not robust and details in trial design and treatment delivery seem to be of unprecedented importance.
Purpose
To assess and explain variation in quality of care in breast cancer patients and estimate its impact on disease outcome.
Methods
The Slovenian National Cancer Registry database and clinical ...records of 1053 women with unilateral primarily non-metastatic invasive breast cancer diagnosed in 2013 were reviewed in this retrospective analysis. Quality care was defined as care fully compliant with quality indicators (QI) defined by European Society of Breast Cancer Specialists (EUSOMA). Multivariate logistic regression was used to determine the predictors of receiving quality care. Differences in overall survival (OS) and event-free survival (EFS, relapse, or progression of disease or death considered an event) based on adherence to QI were analyzed using Kaplan–Meier method and Cox models.
Results
Younger age, no comorbidities, and HER2-negative tumor were associated with increased odds ratios for receiving quality care, whereas tumor stage and type of hospital had no significant association. Median follow-up was 54.5 months. Not receiving quality care resulted in an increased risk of dying hazard ratio (HR) 1.68; 95% confidence interval (CI) 1.06–2.66;
p
= 0.026. Difference in EFS between two groups was significant after adjusting for case mix and type of hospital (HR 1.80; 95% CI 1.29–2.52;
p
= 0.001) but disappeared when type of treatment was added into the model (HR 1.30; 95% CI 0.89–1.90;
p
= 0.178).
Conclusion
Observed comorbidity and age bias in delivering quality breast cancer care could be medically justifiable, whereas observed deviations dependent on HER2 status are puzzling. Complete adherence of treatment to quality indicators resulted in better OS.
Immunotherapy with immune checkpoint inhibitors (ICI) has recently become a standard part of the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), although the ...response rates are low. Numerous preclinical and clinical studies have now illuminated several mechanisms by which radiotherapy (RT) enhances the effect of ICI. From RT-induced immunogenic cancer cell death to its effect on the tumor microenvironment and vasculature, the involved mechanisms are diverse and intertwined. Moreover, the research of these interactions is challenging because of the thin line between immunostimulatory and the immunosuppressive effect of RT. In the era of active research of immunoradiotherapy combinations, the significance of treatment and host-related factors that were previously seen as being less important is being revealed. The impact of dose and fractionation of RT is now well established, whereas selection of the number and location of the lesions to be irradiated in a multi-metastatic setting is something that is only now beginning to be understood. In addition to spatial factors, the timing of irradiation is as equally important and is heavily dependent on the type of ICI used. Interestingly, using smaller-than-conventional RT fields or even partial tumor volume RT could be beneficial in this setting. Among host-related factors, the role of the microbiome on immunotherapy efficacy must not be overlooked nor can we neglect the role of gut irradiation in a combined RT and ICI setting. In this review we elaborate on synergistic mechanisms of immunoradiotherapy combinations, in addition to important factors to consider in future immunoradiotherapy trial designs in R/M HNSCC.
Xerostomia is a common side effect of radiotherapy in patients with head and neck tumors that negatively affects quality of life. There is no known effective standard treatment for xerostomia. Here, ...we present the study protocol used to evaluate the safety and preliminary efficacy of allogeneic mesenchymal stromal stem cells (MSCs) derived from umbilical cord tissue.
Ten oropharyngeal cancer patients with post-radiation xerostomia and no evidence of disease recurrence 2 or more years after (chemo)irradiation (intervention group) and 10 healthy volunteers (control group) will be enrolled in this nonrandomized, open-label, phase I exploratory study. MSCs from umbilical cord tissue will be inserted under ultrasound guidance into both parotid glands and both submandibular glands of the patients. Toxicity of the procedure will be assessed according to CTCAE v5.0 criteria at days 0, 1, 5, 28, and 120. Efficacy will be assessed by measuring salivary flow and analyzing its composition, scintigraphic evaluation of MSC grafting, retention, and migration, and questionnaires measuring subjective xerostomia and quality of life. In addition, the radiological, functional, and morphological characteristics of the salivary tissue will be assessed before, at 4 weeks, and at 4 months after the procedure. In the control group subjects, only salivary flow rate and salivary composition will be determined.
The use of allogeneic MSCs from umbilical cord tissue represents an innovative approach for the treatment of xerostomia after radiation. Due to the noninvasive collection procedure, flexibility of cryobanking, and biological advantages, xerostomia therapy using allogeneic MSCs from umbilical cord tissue may have an advantage over other similar therapies.
Objectives
Bilateral parotid gland aplasia is a rare congenital anomaly that almost consistently leads to xerostomia and caries. It is often associated with other congenital craniofacial ...abnormalities. The objective was to describe a case with asymptomatic bilateral parotid gland aplasia and to review previously reported cases.
Methods
Panoramic radiograph, computed tomography and magnetic resonance imaging were obtained and an in-depth assessment of patient’s dental status and sequence analysis of
FGF10, FGFR2
and
FGFR3
genes were performed. Previous reports of bilateral parotid gland aplasia were assessed.
Results
In a 64-year-old woman with extensive basal cell carcinoma of nasal skin an incidental bilateral parotid gland aplasia was noted during radiotherapy treatment planning. Dental status revealed surprisingly numerous (
n
= 15) teeth without active caries lesions. No other craniofacial abnormalities were identified. To rule out most probable syndromes associated with parotid gland aplasia, sequence analysis of
FGF10
,
FGFR2
and
FGFR3
genes was performed showing no pathogenic variants. With a literature review, we identified 148 cases of salivary gland aplasia in which median age at diagnosis was 21 years and one third were asymptomatic. In only 10 of these cases, the patients presented with bilateral aplasia of parotid glands without other craniofacial abnormalities.
Conclusions
Absence of salivary glands can have a debilitating effect on oral health and is often accompanied by other craniofacial abnormalities. However, relatively frequent asymptomatic course suggests that this rare malformation is probably underdiagnosed. Therefore, we propose systematic reporting of salivary gland aplasia to assess its true prevalence in general population.
In the current study, we sought to compare survival outcomes after breast-conserving therapy (BCT) or mastectomy alone in patients with stage I-IIA breast cancer, whose tumors are typically suitable ...for both locoregional treatments. The study cohort consisted of 1360 patients with stage I-IIA (T1–2N0 or T0–1N1) breast cancer diagnosed between 2001 and 2013 and treated with either BCT (n = 1021, 75.1%) or mastectomy alone (n = 339, 24.9%). Median follow-ups for disease-free survival (DFS) and overall survival (OS) were 6.9 years (range, 0.3–15.9) and 7.5 years (range, 0.2–25.9), respectively. Fifteen (1.1%), 14 (1.0%) and 48 (3.5%) patients experienced local, regional, and distant relapse, respectively. For the whole cohort of patients, the estimated 5-year DFS and OS were 96% and 97%, respectively. After stratification based on the type of local treatment, the estimated 5-year DFS for BCT was 97%, while it was 91% (p < 0.001) for mastectomy-only treatment. Inverse probability of treatment weighting matching based on confounding confirmed that mastectomy was associated with worse DFS (HR 2.839, 95% CI 1.760–4.579, p < 0.0001), but not with OS (HR 1.455, 95% CI 0.844–2.511, p = 0.177). In our study, BCT was shown to have improved disease-specific outcomes compared to mastectomy alone, emphasizing the important role of adjuvant treatments, including postoperative radiation therapy, in patients with early-stage breast cancer at diagnosis.
Neuroendocrine carcinomas (NECs) of the head and neck are rare and the experience scanty. The Cancer Registry of Slovenia database was used to identify cases of laryngeal and pharyngeal NECs ...diagnosed between 1995–2020. Biopsies were analyzed for the expression of standard neuroendocrine markers (synaptophysin, chromogranin, CD56), INSM1, Ki-67, p16, and PD-L1 (using the combined positive score, CPS). In situ hybridization for human papillomavirus (HPV) and Epstein–Barr virus (EBV) was performed. Twenty patients (larynx, 12; pharynx, 8) were identified. One tumor was well differentiated (WD), five were moderately differentiated (MD), and 14 were poorly differentiated (PD). Disease control was achieved solely by surgery in 4/4 MD/PD T1-2N0-1 tumors. Eight patients died of the disease, seven of which were due to distant metastases. All three traditional markers were positive in 11/17 NECs and the INSM1 marker in all 20 tumors. Two of fourteen p16-positive tumors were HPV-positive, but all three nasopharyngeal NECs were EBV-negative. Three tumors had CPSs ≥ 1. In conclusion, INSM1 was confirmed to be a reliable marker of neuroendocrine differentiation. Except in WD and early-stage MD/PD tumors, aggressive multimodal therapy is needed; the optimal systemic therapy remains to be determined. p16, HPV, and EBV seem to bear no prognostic information.
•Hippocampal (HC) sparing RT for nasopharyngeal cancer (NPC) is feasible and safe.•Lower HC dose translates to significantly lower probability of memory decline.•The cognitive well-being in NPC ...patients should be paramount in RT planning.
Radiation-induced damage to the hippocampi can cause cognitive decline. International recommendations for nasopharyngeal cancer (NPC) radiotherapy (RT) lack specific guidelines for protecting the hippocampi. Our study evaluates if hippocampi-sparing (HS) RT in NPC ensures target coverage and meets recommended dose limits for other at-risk organs.
In a systematic literature review, we compared hippocampal D40% in conventional and HS RT plans. In an in silico dosimetric study, conventional and HS-VMAT plans were created for each patient, following international recommendations for OAR delineation, dose prioritization and acceptance criteria. We assessed the impact on neurocognitive function using a previously published normal tissue complication probability (NTCP) model.
In four previous studies (n = 79), researchers reduced D40% hippocampal radiation doses in HS plans compared to conventional RT on average from 24.9 Gy to 12.6 Gy.
Among 12 NPC patients included in this in silico study, statistically significant differences between HS and conventional VMAT plans were observed in hippocampal EQD2 Dmax (23.8 vs. 46.4 Gy), Dmin (3.8 vs. 4.6 Gy), Dmean (8.1 vs. 15.1 Gy), and D40% (8.3 vs. 15.8 Gy). PTV coverage and OAR doses were similar, with less homogeneous PTV coverage in HS plans (p = 0.038). This translated to a lower probability of memory decline in HS plans (interquartile range 15.8–29.6 %) compared to conventional plans (33.8–81.1 %) based on the NTCP model (p = 0.002).
Sparing the hippocampus in NPC RT is safe and feasible. Given the life expectancy of many NPC patients, their cognitive well-being must be paramount in radiotherapy planning.
Stereotactic body radiotherapy (SBRT) is characterized by a high dose per fraction, well-defined small targets, superior dose conformity, and a steep off-target dose gradient. A literature search was ...conducted to examine the experience with SBRT as a curative treatment for newly diagnosed mucosal carcinoma of the head and neck (MCHN). Four retrospective case series and one prospective phase I clinical trial published between 2012 and 2020 described 124 patients. SBRT was mainly performed in older patients with different tumor sites. The median size of the planning target volumes ranged from 5.3 to 41 cm3. Different approaches were used to create margins. In two studies, limited elective nodal irradiation was performed. The equivalent doses used were 60–83.33 Gy delivered in five fractions. Considerable heterogeneity was observed in the radiation dose specification. The incidence of grade ≥3 late toxicity was 0–8.3%, with local and regional control ranging from 73% to 100%. Improved or stable quality of life after SBRT was reported in two studies. Curative-intent SBRT for de novo MCHN appears to be an effective and relatively safe treatment for small tumor targets, preferably without concomitant elective tissue irradiation. Standardization of SBRT practice and well-designed prospective clinical trials are needed to better define the role of SBRT in this setting.
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