Blood- and Imaging-Derived Biomarkers for Oncological Outcome Modelling in Oropharyngeal Cancer: Exploring the Low-Hanging Fruit.

AIMS: To assess whether CT-based radiomics and blood-derived biomarkers could improve the prediction of overall survival (OS) and locoregional progression-free survival (LRPFS) in patients with oropharyngeal cancer (OPC) treated with curative-intent RT. METHODS: Consecutive OPC patients with primary tumors treated between 2005 and 2021 were included. Analyzed clinical variables included gender, age, smoking history, staging, subsite, HPV status, and blood parameters (baseline hemoglobin levels, neutrophils, monocytes, and platelets, and derived measurements). Radiomic features were extracted from the gross tumor volumes (GTVs) of the primary tumor using pyradiomics. Outcomes of interest were LRPFS and OS. Following feature selection, a radiomic score (RS) was calculated for each patient. Significant variables, along with age and gender, were included in multivariable analysis, and models were retained if statistically significant. The models' performance was compared by the C-index. RESULTS: One hundred and five patients, predominately male (71%), were included in the analysis. The median age was 59 (IQR: 52-66) years, and stage IVA was the most represented (70%). HPV status was positive in 63 patients, negative in 7, and missing in 35 patients. The median OS follow-up was 6.3 (IQR: 5.5-7.9) years. A statistically significant association between low Hb levels and poorer LRPFS in the HPV-positive subgroup (p = 0.038) was identified. The calculation of the RS successfully stratified patients according to both OS (log-rank p < 0.0001) and LRPFS (log-rank p = 0.0002). The C-index of the clinical and radiomic model resulted in 0.82 [CI: 0.80-0.84] for OS and 0.77 [CI: 0.75-0.79] for LRPFS. CONCLUSIONS: Our results show that radiomics could provide clinically significant informative content in this scenario. The best performances were obtained by combining clinical and quantitative imaging variables, thus suggesting the potential of integrative modeling for outcome predictions in this setting of patients.

The T-N tract involvement as a new prognostic factor for PORT in locally advanced oral cavity tumors.

OBJECTIVE: The space comprised between tumor and neck lymph nodes (T-N tract) is one of the main routes of tumor spread in oral cavity tumors. Aim of the study was to investigate the impact of T-N tract involvement on the postoperative radiotherapy (PORT) outcomes. MATERIALS AND METHODS: Patients (pts) treated between 2000 and 2016 with indication to PORT were retrospectively retrieved. Inclusion criteria were: (a) locally advanced tumors of the oral cavity, (b) who received with indication to PORT (c) with a minimum follow-up of six months. RESULTS: One hundred and fifty-seven pts met the inclusion criteria (136 pts treated with PORT and 21 pts not treated with PORT). In the PORT cohort, the T-N tract involvement had no impact on both OS (p = .09) and LRFS (p = .2). Among the non-PORT cohort, both OS (p = .007) and LRFS (p = .017) were worse for pts with positive T-N tract compared to those with negative T-N tract. PORT improved both OS (p = .008) and LRFS (p = .003) in pts with positive T-N tract but not in those with negative T-N tract (p = .36 and p = .37, respectively). CONCLUSIONS: Our results suggest that involvement of T-N tract should be considered as prognostic factors informing the indication to PORT.

LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer.

BACKGROUND AND PURPOSE: Currently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome. Here, we evaluated the prognostic value of LINE-1 methylation level in OPSCC patients and further addressed the relationship between LINE-1 methylation status and p53 protein expression as well as genome-wide/gene-specific DNA methylation. RESULTS: In this study, DNA was extracted from 163 formalin-fixed paraffin-embedded tissue samples retrospectively collected from stage III-IVB OPSCC patients managed with curative intent with up-front treatment. Quantitative methylation-specific PCR revealed that LINE-1 hypomethylation was directly associated with poor prognosis (5-year overall survival-OS: 28.1% for LINE-1 methylation < 35% vs. 69.1% for ≥ 55%; p < 0.0001). When LINE-1 methylation was dichotomized as < 55% versus ≥ 55%, interaction with HPV16 emerged: compared with hypermethylated HPV16-positive patients, subjects with hypomethylated HPV16-negative OPSCC reported an adjusted higher risk of death (HR 4.83, 95% CI 2.24-10.38) and progression (HR 4.54, 95% CI 2.18-9.48). Tumor protein p53 (TP53) gene is often mutated and overexpressed in HPV-negative OPSCC. Since p53 has been reported to repress LINE-1 promoter, we then analyzed the association between p53 protein expression and LINE-1 methylation levels. Following p53 immunohistochemistry, results indicated that among HPV16-negative patients with p53 ≥ 50%, LINE-1 methylation levels declined and remained stable at approximately 43%; any HPV16-positive patient reported p53 ≥ 50%. Finally, DNA methylation analysis demonstrated that genome-wide average methylation level at cytosine-phosphate-guanine sites was significantly lower in HPV16-negative OPSCC patients who relapsed within two years. The subsequent integrative analysis of gene expression and DNA methylation identified 20 up-regulated/hypomethylated genes in relapsed patients, and most of them contained LINE-1 elements in their promoter sequences. CONCLUSIONS: Evaluation of the methylation level of LINE-1 may help in identifying the subset of OPSCC patients with bad prognosis regardless of their HPV status. Aberrant LINE-1 hypomethylation might occur along with TP53 mutations and lead to altered gene expression in OPSCC.

Tissue and circulating PD-L2: moving from health and immune-mediated diseases to head and neck oncology.

Amongst the chief targets of immune-checkpoint inhibitors (ICIs), namely the Programmed cell death protein 1 (PD-1)/PD-Ligands (Ls) axis, most research has focused on PD-L1, while to date PD-L2 is still under-investigated. However, emerging data support PD-L2 relevant expression in malignancies of the head and neck area, mostly in head and neck squamous cell carcinoma (HNSCC) and salivary gland cancers (SGCs). In this context, ICIs have achieved highly heterogeneous outcomes, emphasizing an urgent need for the identification of predictive biomarkers. With the present review, we aimed at describing PD-L2 biological significance by focusing on its tissue expression, its binding to PD-1 and RGMb receptors, and its impact on physiological and anti-cancer immune response. Specifically, we reported PD-L2 expression rates and significant clinical correlates among different head and neck cancer histotypes. Finally, we described the biology of soluble PD-L2 form and its potential application as a prognostic and/or predictive circulating biomarker.

Stereotactic radiotherapy (SRT) for differentiated thyroid cancer (DTC) oligometastases: an AIRO (Italian association of radiotherapy and clinical oncology) systematic review.

PURPOSE: The aim of this systematic review was to examine efficacy of stereotactic radiotherapy (SRT) in patients with oligometastatic thyroid cancer. MATERIALS AND METHODS: A systematic search was conducted by means of PubMed, Scopus, and Cochrane library. CLINICALTRIALS: gov was searched for ongoing or recently completed trials, and PROSPERO was searched for ongoing or recently completed systematic reviews. We analyzed only clinical studies as full text carried out on patients with oligometastatic thyroid cancer treated with SRT. Conference papers, surveys, letters, editorials, book chapters, and reviews were excluded. Time of publication was restricted to the years 1990-2021. RESULTS: The number of evaluated patients was 146 (267 lesions), and the median age was 58 years. The median 1-year local control (LC) was 82% (range 67.0%-97.1%); the median disease-free survival (DFS) was 12 months (range 4-53); the median 1-year overall survival was 72% (range 66.6%-85.0%); the 3-year cancer-specific survival was 75.0%; and the 4-year cancer-specific survival was 37.5%. No grade 3-5 acute toxicity was reported. No late effects were recorded. CONCLUSIONS: SRT for oligometastases from thyroid cancer as salvage therapy is well tolerated and yields high rates of LC and prolonged DFS.

Indication to post-operative radiotherapy for oral cavity squamous cell carcinoma: what's new in the depth of infiltration (DOI) era?

OBJECTIVE: The last edition of the American Joint Committee on Cancer (AJCC eighth) has introduced the depth of infiltration (DOI) as a new prognostic parameter in oral cavity squamous cell carcinomas (OCSCCs). The aim of this study is to analyze the impact of stage migration on the indication to post-operative radiotherapy (PORT). METHODS: OCSCCs treated at two institutions between 2014 and 2019 were retrieved. As per the AJCC eighth, only pT3 primarily OCSCCs were considered; availability of the pathologic specimen was a further inclusion criterion. Risk factors considered for PORT were: pT3-pT4, nodal involvement, positive/close surgical margins, perineural and lymph vascular invasion. RESULTS: 149 patients staged as pT3 AJCC eighth were included. A four-fold increase in the number of patients staged as pT3 from the seventh to the eighth AJCC was found. Stage migration to pT3 was equally due to the downstaging from former pT4 (38%) and upstaging of former pT1-pT2 (35%). Considering the former pT1-pT2 53 patients, 13 (25%) had no risk factors for PORT other than DOI. Among 25 cases with former pT1-pT2 and negative lymph nodes, no additional risk factors were found in 11 (44%). CONCLUSION: 90% of patients had at least one risk factor besides DOI and would have received PORT also according to the AJCC seventh; notably, of former pT1-pT2N0, half of them have been upstaged to pT3 in the current TNM classification. The role of PORT in this cohort of patients has not been clarified yet. ADVANCES IN KNOWLEDGE: Other-than-DOI risk factors leading to PORT indication are highly prevalent in OCSSC patients classified as pT3 per the latest AJCC TNM staging system and should therefore be considered for a comprehensive oncological assessment.

Three weekly versus weekly concurrent cisplatin: safety propensity score analysis on 166 head and neck cancer patients.

BACKGROUND: Radio-chemotherapy with CDDP is the standard for H&N squamous cell cancer. CDDP 100 mg/m2/q3 is the standard; alternative schedules are used to reduce toxicity, mostly 40 mg/m2/q1. METHODS: Patients were treated from 1/2010 to 1/2017 in two Radiation Oncology Centres. Propensity score analysis (PS) was retrospectively used to compare these two schedules. RESULTS: Patients analyzed were 166. Most (114/166) had 1w-CDDP while 52 had 3w-CDDP. In the 3w-CDDP group, patients were younger, with better performance status, smaller disease extent and a more common nodal involvement than in the 1w-CDDP. Acute toxicity was similar in the groups. Treatment compliance was lower in the w-CCDP. Overall survival before PS was better for female, for oropharyngeal disease and for 3w-CDDP group. After PS, survival was not related to the CDDP schedule. CONCLUSIONS: 3w-CDDP remains the standard for fit patients, weekly schedule could be safely used in selected patients.

The Impact of Post-Operative Radiotherapy in Early Stage (pT1-pT2N0M0) Oral Tongue Squamous Cell Carcinoma in Era of DOI.

Background: This study investigated the role of depth of infiltration (DOI) as an independent prognosticator in early stage (T1-T2N0M0) oral cavity tumors and to evaluate the need of postoperative radiotherapy in the case of patients upstaged to pT3 for DOI > 10 mm in the absence of other risk factors. Methods: We performed a retrospective analysis on patients treated with surgery and re-staged according to the 8th edition of malignant tumors classification (TNM). The role of DOI as well as other clinical/pathological features was investigated at both univariable and multivariable analyses on overall survival (OS), disease free survival (DFS), relapse free survival (RFS), and local RFS. Results: Among the 94 included patients, 23 would have been upstaged to pT3 based on DOI. Multivariable analysis showed that DOI was not an independent prognostic factor for any of the considered outcomes. The presence of perineural invasion was associated with a significant worse RFS (p = 0.02) and LRFS (p = 0.04). PORT was found to be significantly associated with DFS (p = 0.04) and RFS (p = 0.06). Conclusions: The increasing DOI alone was not sufficient to impact the prognosis, and therefore, should not be sufficient to dictate PORT indications in early-stage patients upstaged on the sole basis of DOI.

Carotid blowout syndrome after reirradiation for head and neck malignancies: a comprehensive systematic review for a pragmatic multidisciplinary approach.

AIM: To provide a literature review on risk factors and strategies to prevent acute carotid blowout (CBO) syndrome in patients who underwent reirradiation (reRT) for recurrent head and neck (HN) malignancies. PATIENTS AND METHODS: Inclusion criteria were: 1) CBO following reRT in the HN region, 2) description on patient-, tumor- or treatment-related risk factors, 3) clinical or radiological signs of threatened or impending CBO, and 4) CBO prevention strategies. RESULTS: Thirty-five studies were selected for the analysis from five hundred seventy-seven records. Results provided indications on clinical, radiological and dosimetric parameters possibly associated with higher risk of CBO. Endovascular procedures (artery occlusion and stenting) to prevent acute massive hemorrhage in high risk patients were discussed. CONCLUSION: Literature data are still scarce with a low level of evidence. Nevertheless, the present work provides a comprehensive review useful for clinicians as a multidisciplinary pragmatic tool in their clinical practice.

Head and neck cancer radiotherapy amid COVID-19 pandemic: Report from Milan, Italy.

BACKGROUND: Management of head and neck cancers (HNC) in radiation oncology in the coronavirus disease 2019 (COVID-19) era is challenging. Aim of our work is to report organization strategies at a radiation therapy (RT) department in the first European area experiencing the COVID-19 pandemic. METHODS: We focused on (a) dedicated procedures for HNC, (b) RT scheduling, and (c) health care professionals' protection applied during the COVID-19 breakdown (from March 1, 2020 to April 30, 2020). RESULTS: Applied procedures are reported and discussed. Forty-three patients were treated. Image-guided, intensity modulated RT was performed in all cases. Median overall treatment time was 50 (interquartile range: 47-54.25) days. RT was interrupted/delayed in seven patients (16%) for suspected COVID-19 infection. Two health professionals managing HNC patients were proven as COVID-19 positive. CONCLUSION: Adequate and well-timed organization allowed for the optimization of HNC patients balancing at the best of our possibilities patients' care and personnel's safety.

Whole breast external beam radiotherapy in elderly patients affected by left-sided early breast cancer: a dosimetric comparison between two simple free-breathing techniques.

BACKGROUND: Elderly breast cancer patients are frequently affected by significant comorbidities that make sophisticated radiotherapy treatments particularly challenging. AIMS: We dosimetrically analyzed two different simple free-breathing external beam radiotherapy (EBRT) techniques for the hypofractionated treatment of the left breast in elderly patients with a low compliance, to compare target coverage, and heart and left anterior descending coronary artery (LADCA) sparing. METHODS: We developed radiation plans for 24 elderly patients using 3D conformal (3DCRT) field-in-field tangential technique and intensity-modulated (IMRT) tangential beam technique. Dose-Volume-Histograms (DVHs) were used to provide a quantitative comparison between plans. RESULTS: The median breast volume was 645 cm3. IMRT and 3DCRT plans comparison demonstrated no significant differences in terms of organ sparing for the heart. Regarding LADCA, mean dose (10.3 ± 9.5 Gy vs 11.9 ± 9.6 Gy, p = 0.0003), maximum dose (26.1 ± 16.1 Gy vs 29.1 ± 16.1 Gy, p = 0.004) and V17 Gy (21.5% ± 26.9% vs 25.0% ± 27.2%, p = 0.002) significantly decreased using IMRT compared with 3DCRT. IMRT plans showed a better target coverage compared with 3DCRT (0.91 ± 0.05 vs 0.93 ± 0.04, p = 0.05). DISCUSSION: Comparing the two different EBRT techniques, we demonstrated few, although substantial, dosimetric differences in terms of doses to the organs at risk characterized by a statistically significant dose reduction of LADCA in the IMRT plans. CONCLUSIONS: Elderly patients with a low compliance to treatment might benefit from 3DCRT with field-in-field tangential arrangement or from a simple IMRT approach. IMRT should be preferred.

Rectum Dose Constraints for Carbon Ion Therapy: Relative Biological Effectiveness Model Dependence in Relation to Clinical Outcomes.

The clinical application of different relative biological effectiveness (RBE) models for carbon ion RBE-weighted dose calculation hinders a global consensus in defining normal tissue constraints. This work aims to update the local effect model (LEM)-based constraints for the rectum using microdosimetric kinetic model (mMKM)-defined values, relying on RBE translation and the analysis of long-term clinical outcomes. LEM-optimized plans of treated patients, having suffered from prostate adenocarcinoma (n = 22) and sacral chordoma (n = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (DLEM|v and DMKM|v) was fitted to translate new LEM-based constraints. Normal tissue complication probability (NTCP) values, predicting late rectal toxicity, were obtained by applying published parameters. No late rectal toxicity events were reported within the patient cohort. The rectal toxicity outcome was confirmed using dosimetric analysis: DMKMVHs lay largely below original constraints; the translated DLEM|v values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal DMKM|v of the rectum volume, v-1%, 5%, 10% and 20%. The average NTCP value ranged from 5% for the prostate adenocarcinoma, to 0% for the sacral chordoma group. The redefined constraints, to be confirmed prospectively with clinical data, are DLEM|5cc ≤ 61 Gy(RBE) and DLEM|1cc ≤ 66 Gy(RBE).

Oligometastatic cancer in elderly patients: the "blitzkrieg" radiotherapy approach : SBRT in oligometastatic elderly patients.

AIMS: To retrospectively evaluate the outcome of stereotactic body radiation therapy (SBRT) in the treatment of elderly patients affected by isolated body metastasis from different primitive tumors. METHODS: 70 patients with isolated body metastasis were treated. Median age at diagnosis was 75 years (IQR 69-80). The most common SBRT fractionation scheme was 5 × 7 Gy (total dose 35 Gy). The primary endpoints were Local Control (LC) and Toxicity. Secondary endpoints were Overall Survival (OS) and Disease-Specific Survival (DSS). Response to radiotherapy was assessed according to RECIST criteria v1.1. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. We performed survival analysis with the Kaplan-Meier method. The correlation between time actuarial incidence and clinical parameters was studied. RESULTS: Median follow-up was 26.5 months. 44 patients (62.8%) were alive at the time of analysis, while 22 (31.4%) died because of the disease. Local control at 2 and 3 years was 87%. The 2-year OS and DSS were 84 and 71%, respectively, while the 3-year values were 57 and 62%. PFS at 2 and 3 years was 41 and 25%, respectively. On univariate analysis, KPS ≥ 90 is statistically correlated with improved OS and DSS (p < 0.05). Acute toxicity of grade ≥ 2 occurred in 4 (5.7%) patients, while late toxicity ≥ 2 was recorded in 6 (8.6%) patients. CONCLUSIONS: Ablative Radiotherapy represents a safe, effective, and minimally invasive treatment modality for elderly oligometastatic patients who are judged unfit for systemic therapy.

Volumetric image-guided conformal radiotherapy for localized prostate cancer: Analysis of dosimetric and clinical factors affecting acute and late toxicity.

AIM: To identify factors influencing toxicity in patients affected by localized prostate cancer treated with conformal image-guided radiotherapy. BACKGROUND: Image guidance in combination with conformal techniques is the standard of care in localized prostate cancer, but factors affecting toxicity are still under investigation. MATERIALS AND METHODS: 294 patients were analyzed. Median age at diagnosis was 71 year. 76 Gy (38 × 2 Gy) were delivered to the target volume. We used the χ2 test to analyse associations between toxicity and dosimetric and clinical parameters. Multivariate analysis was performed using binary logistic regression. Kaplan-Meier method was used for survival analysis. RESULTS: Median follow-up was 62.9 months. Acute grade ≥2 gastro-intestinal toxicity (GI) was 12.1%. Acute genito-urinary (GU) toxicity of grade ≥2 was 33.9%. Actuarial 4 and 5 years late grade ≥2 GI was 3% and 4%, respectively. Four and 5-year late grade ≥2 GU toxicity was 6% and 10%. At multivariate analysis for acute toxicity rectal V70 was correlated with GI toxicity (p = 0.01, HR 2.73 CI 1.19-6.26), and smoking habit with GU toxicity (p < 0.01, HR 2.50 CI 1.51-4.14). For late toxicity, rectal V70 was correlated with gastro-intestinal toxicity (p = 0.04, HR 4.76 CI 1.07-21.13), and pre-radiotherapy urinary symptoms with genito-urinary toxicity (p = 0.01, HR 2.84 CI 1.29-6.22). DISCUSSION: Conformal image-guided radiotherapy shows low rates of toxicity. Smoking should be avoided during radiotherapy. Besides the evaluation of high doses received by the organs at risk, individual factors, such as co-morbidities and lifestyle choices, have an impact on normal-tissue complication risk.

Oligometastatic cancer: stereotactic ablative radiotherapy for patients affected by isolated body metastasis.

BACKGROUND: To evaluate the outcome of patients affected by a single isolated body metastasis treated with stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: Seven-eight patients were treated with SBRT for isolated body metastasis. The most frequent primary tumor was prostate cancer (28.2%), followed by colorectal cancer (23.1%) and lung cancer (20.5%). Median age at diagnosis of oligometastatic disease was 70 years (range 47-88). Median Karnofsky Performance Status (KPS) was 90 (range 70-100). The most common SBRT fractionation scheme was 5 × 7 Gy (total dose 35 Gy). Response to radiotherapy was determined according to RECIST criteria v1.1. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The survival analysis was performed with the Kaplan-Meier method. The correlation between time actuarial incidence and clinical parameters was studied, and the Kaplan-Meier method of log-rank test was applied. RESULTS: With a median follow-up of 22.68 months, local control was achieved in 89.7% of the cases. The two-year overall survival (OS) and progression-free survival (PFS) were 68% and 42%, respectively. On univariate analysis, KPS ≥80 is predictive for improved OS (p = .001) and PFS (p = .001). Acute toxicity of grade ≥2 occurred in eight (10.2%) patients and late grade ≥2 toxicity in five (6.4%) patients. CONCLUSIONS: Ablative radiotherapy in 'early oligometastatic state' is a safe, effective and minimally invasive treatment modality. A good performance status (KPS ≥80) seems to influence the clinical outcome.