Bone metastases from differentiated thyroid carcinoma: current knowledge and open issues.

Bone represents the second most common site of distant metastases in differentiated thyroid cancer (DTC). The clinical course of DTC patients with bone metastases (BM) is quite heterogeneous, but generally associated with low survival rates. Skeletal-related events might be a serious complication of BM, resulting in high morbidity and impaired quality of life. To achieve disease control and symptoms relief, multimodal treatment is generally required: radioiodine therapy, local procedures-including surgery, radiotherapy and percutaneous techniques-and systemic therapies, such as kinase inhibitors and antiresorptive drugs. The management of DTC with BM is challenging: a careful evaluation and a personalized approach are essential to improve patients' outcomes. To date, prospective studies focusing on the main clinical aspects of DTC with BM are scarce; available analyses mainly include cohorts assembled over multiple decades, small samples sizes and data about BM not always separated from those regarding other distant metastases. The aim of this review is to summarize the most recent evidences and the unsolved questions regarding BM in DTC, analyzing several key issues: pathophysiology, prognostic factors, role of anatomic and functional imaging, and clinical management.

Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer.

Concurrent chemotherapy and radiotherapy (CCRT) followed by durvalumab immune therapy in appropriate patients is considered to be the standard of care in most fit stage III non-small-cell lung cancer (NSCLC) patients. However, CCRT is a toxic treatment that affects all organ systems and may cause acute and permanent side effects, some of which may be lethal. Supportive care is therefore of utmost importance in this clinical setting. A group of experts from the European Society for Therapeutic Radiology and Oncology (ESTRO) and the European Society of Medical Oncology (ESMO) identified the following items of importance for further improvement of supportive care: smoking cessation; nutrition before and during CCRT (including treatment and prevention of anorexia); physical exercise before and during CCRT; prevention and treatment of acute esophagitis and dysphagia; treatment of cough and dyspnea; treatment of skin reactions; treatment of fatigue; prophylaxis of nausea and emesis; prevention, diagnosis, and treatment of cardiac disease and damage; and optimization of radiotherapy techniques and chemotherapy adjustments to reduce toxicity in the era of immune therapy. The resulting recommendations are summarized in this manuscript and knowledge gaps identified, in which future investments are needed to improve supportive care and hence quality of life and survival for our stage III NSCLC patients.

Treatment of classical Hodgkin lymphoma in the era of brentuximab vedotin and immune checkpoint inhibitors.

The majority of Hodgkin lymphoma patients are now cured with conventional first-line therapy; however, 10-15% of early-stage disease and less than 30% of advanced-stage patients are refractory(rare) or relapsed. Salvage second-line therapy combined with high-dose therapy and autologous stem-cell transplantation can cure 40-50% of patients. Recently novel agents (Brentuximab Vedotin and Immune Checkpoint inhibitors) have demonstrated evidence of therapeutic activity and are potential bridge to an allogeneic stem-cell transplantation. The review is aimed to present not only salvage strategies; indeed, the paper contains paragraphs about therapy and new treatment options at diagnosis.

Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG).

BACKGROUND: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. PATIENTS AND METHODS: In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. RESULTS: Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. CONCLUSION: Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

Could machine learning improve the prediction of pelvic nodal status of prostate cancer patients? Preliminary results of a pilot study.

We tested and compared performances of Roach formula, Partin tables and of three Machine Learning (ML) based algorithms based on decision trees in identifying N+ prostate cancer (PC). 1,555 cN0 and 50 cN+ PC were analyzed. Results were also verified on an independent population of 204 operated cN0 patients, with a known pN status (187 pN0, 17 pN1 patients). ML performed better, also when tested on the surgical population, with accuracy, specificity, and sensitivity ranging between 48-86%, 35-91%, and 17-79%, respectively. ML potentially allows better prediction of the nodal status of PC, potentially allowing a better tailoring of pelvic irradiation.

GH replacement therapy and second neoplasms in adult survivors of childhood cancer: a retrospective study from a single institution.

PURPOSE: Growth hormone deficiency (GHD) is the most common endocrine late effect observed in childhood cancer survivors (CCS) previously submitted to cranial irradiation. Radiation therapy can also increase the risk of second neoplasms (SNs). Since in previous studies GH replacement therapy was associated with increased incidence of neoplasia, we explored the association between SNs and GH replacement therapy in a cohort of CCS with GHD. METHODS: Within the clinical cohort of CCS referred to the Transition Unit for Childhood Cancer Survivors of Turin between November 2001 and December 2012, we considered all patients who developed GHD as a consequence of cancer therapies. GHD was always diagnosed in childhood. To evaluate the quality of data, our cohort was linked to the Childhood Cancer Registry of Piedmont. RESULTS: GHD was diagnosed in 49 out of 310 CCS included in our clinical cohort. At least one SN was diagnosed in 14 patients, meningioma and basal cell carcinoma being the most common SNs. The cumulative incidence of SNs was similar in GH-treated and -untreated patients (8 SNs out of 26 GH-treated and 6 out of 23 GH-untreated patients; p = 0.331). Age, sex and paediatric cancer type had no impact on SNs development. CONCLUSIONS: In our CCS, GH replacement therapy does not seem to increase the risk of SNs. Anyway, independently from replacement therapy, in these patients we observed an elevated risk of SNs, possibly related to previous radiation therapy, which suggests the need of a close long-term follow-up.

ESTRO clinical practice guideline: Stereotactic body radiotherapy for spine metastases.

BACKGROUND AND PURPOSE: Recent progress in diagnostics and treatment of metastatic cancer patients have improved survival substantially. These developments also affect local therapies, with treatment aims shifting from short-term palliation to long-term symptom or disease control. There is consequently a need to better define the value of stereotactic body radiotherapy (SBRT) for the treatment of spinal metastases. METHODS: This ESTRO clinical practice guideline is based on a systematic literature review conducted according to PRISMA standards, which formed the basis for answering four key questions about the indication and practice of SBRT for spine metastases. RESULTS: The analysis of the key questions based on current evidence yielded 22 recommendations and 5 statements with varying levels of endorsement, all achieving a consensus among experts of at least 75%. In the majority, the level of evidence supporting the recommendations and statements was moderate or expert opinion, only, indicating that spine SBRT is still an evolving field of clinical research. Recommendations were established concerning the selection of appropriate patients with painful spine metastases and oligometastatic disease. Recommendations about the practice of spinal SBRT covered technical planning aspects including dose and fractionation, patient positioning, immobilization and image-guided SBRT delivery. Finally, recommendations were developed regarding quality assurance protocols, including description of potential SBRT-related toxicity and risk mitigation strategies. CONCLUSIONS: This ESTRO clinical practice guideline provides evidence-based recommendations and statements regarding the selection of patients with spinal metastases for SBRT and its safe implementation and practice. Enrollment of patients into well-designed prospective clinical trials addressing clinically relevant questions is considered important.

Efficacy and safety of SBRT for spine metastases: A systematic review and meta-analysis for preparation of an ESTRO practice guideline.

BACKGROUND AND PURPOSE: Advances in characterizing cancer biology and the growing availability of novel targeted agents and immune therapeutics have significantly changed the prognosis of many patients with metastatic disease. Palliative radiotherapy needs to adapt to these developments. In this study, we summarize the available evidence for stereotactic body radiotherapy (SBRT) in the treatment of spinal metastases. MATERIALS AND METHODS: A systematic review and meta-analysis was performed using PRISMA methodology, including publications from January 2005 to September 2021, with the exception of the randomized phase III trial RTOG-0631 which was added in April 2023. Re-irradiation was excluded. For meta-analysis, a random-effects model was used to pool the data. Heterogeneity was assessed with the I2-test, assuming substantial and considerable as I2 > 50 % and I2 > 75 %, respectively. A p-value < 0.05 was considered statistically significant. RESULTS: A total of 69 studies assessing the outcomes of 7236 metastases in 5736 patients were analyzed. SBRT for spine metastases showed high efficacy, with a pooled overall pain response rate of 83 % (95 % confidence interval [CI] 68 %-94 %), pooled complete pain response of 36 % (95 % CI: 20 %-53 %), and 1-year local control rate of 94 % (95 % CI: 86 %-99 %), although with high levels of heterogeneity among studies (I2 = 93 %, I2 = 86 %, and 86 %, respectively). Furthermore, SBRT was safe, with a pooled vertebral fracture rate of 9 % (95 % CI: 4 %-16 %), pooled radiation induced myelopathy rate of 0 % (95 % CI 0-2 %), and pooled pain flare rate of 6 % (95 % CI: 3 %-17 %), although with mixed levels of heterogeneity among the studies (I2 = 92 %, I2 = 0 %, and 95 %, respectively). Only 1.7 % of vertebral fractures required surgical stabilization. CONCLUSION: Spine SBRT is characterized by a favorable efficacy and safety profile, providing durable results for pain control and disease control, which is particularly relevant for oligometastatic patients.

Multi-centre real-world validation of automated treatment planning for breast radiotherapy.

PURPOSE: To present the results of the first multi-centre real-world validation of autoplanning for whole breast irradiation after breast-sparing surgery, encompassing high complexity cases (e.g. with a boost or regional lymph nodes) and a wide range of clinical practices. METHODS: The 24 participating centers each included 10 IMRT/VMAT/Tomotherapy patients, previously treated with a manually generated plan ('manplan'). There were no restrictions regarding case complexity, planning aims, plan evaluation parameters and criteria, fractionation, treatment planning system or treatment machine/technique. In addition to dosimetric comparisons of autoplans with manplans, blinded plan scoring/ranking was conducted by a clinician from the treating center. Autoplanning was performed using a single configuration for all patients in all centres. Deliverability was verified through measurements at delivery units. RESULTS: Target dosimetry showed comparability, while reductions in OAR dose parameters were 21.4 % for heart Dmean, 16.7 % for ipsilateral lung Dmean, and 101.9 %, 45.5 %, and 35.7 % for contralateral breast D0.03cc, D5% and Dmean, respectively (all p < 0.001). Among the 240 patients included, the clinicians preferred the autoplan for 119 patients, with manplans preferred for 96 cases (p = 0.01). Per centre there were on average 5.0 ± 2.9 (1SD) patients with a preferred autoplan (range [0-10]), compared to 4.0 ± 2.7 with a preferred manplan ([0,9]). No differences were observed regarding deliverability. CONCLUSION: The automation significantly reduced the hands-on planning workload compared to manual planning, while also achieving an overall superiority. However, fine-tuning of the autoplanning configuration prior to clinical implementation may be necessary in some centres to enhance clinicians' satisfaction with the generated autoplans.

Value of staging squamous cell carcinoma of the anal margin and canal using the sentinel lymph node procedure: an update of the series and a review of the literature.

BACKGROUND: Inguinal metastases in patients affected by anal cancer are an independent prognostic factor for local failure and overall mortality. Since 2001, sentinel lymph node biopsy was applied in these patients. This original study reports an update of personal and previous published series, which were compared with Literature to value the incidence of inguinal metastases T-stage related and the overall incidence of false negative inguinal metastases at sentinel node. METHODS: In all, 63 patients diagnosed with anal cancer submitted to inguinal sentinel node. Furthermore a research in the Pub Med database was performed to find papers regarding this technique. RESULTS: In our series, detection rate was 98.4%. Inguinal metastases were evidentiated in 13 patients (20.6%). Our median follow-up was 35 months. In our series, no false negative nodes were observed. CONCLUSION: Sentinel node technique in the detection of inguinal metastases in patients affected by anal cancer should be considered as a standard of care. It is indicated for all T stages in order to select patients to be submitted to inguinal radiotherapy, avoiding related morbidity in negative ones. An overall 3.7% rate of false negative must be considered acceptable.

A novel biomarker-based analysis reliably predicts nodal metastases in anal carcinoma: preliminary evidence of therapeutic impact.

AIM: Routine prophylactic inguinal irradiation in anal cancer may cause significant toxicity associated with overtreatment bias. The aim of this study was to determine the risk of regional node metastases in anal carcinoma by identifying predictive molecular biomarkers. METHOD: Clinicohistopathological data from 50 pretreatment anal carcinoma biopsies were collected. Immunohistochemical analyses with antibodies against Ki67, p53, epidermal growth factor receptor (EGFR) and YKL-40 were performed. Statistical correlations between biomarkers and clinicopathological features and outcomes were studied. Sentinel lymph node biopsy was performed in a subset of 36 patients. RESULTS: All patients had undergone synchronous radiochemotherapy; tumour recurrence had developed in 26%, and 16% had died. YKL-40 tumour expression correlated with lymph node metastasis, whereas no inguinal node metastases were found in any of the (14%) patients presenting with a YKL-40/EGFR-negative tumour. YKL-40 expression and node metastasis were both significantly associated with shorter overall and disease-free survival. Tumour grade significantly correlated with disease-free survival only. HIV, tumour histological type, Ki67, p53 and EGFR were not associated with outcome. CONCLUSION: YKL-40 expression in anal carcinoma is correlated with a poor outcome and can predict lymph node metastases. The combined absence of YKL-40 and EGFR expression in a first biopsy of anal carcinoma reliably selects a subset of patients without inguinal metastases. Such patients could be spared sentinel lymph node biopsy and/or inguinal radiotherapy.

Active bone marrow segmentation based on computed tomography imaging in anal cancer patients: A machine-learning-based proof of concept.

PURPOSE: Different methods are available to identify haematopoietically active bone marrow (ActBM). However, their use can be challenging for radiotherapy routine treatments, since they require specific equipment and dedicated time. A machine learning (ML) approach, based on radiomic features as inputs to three different classifiers, was applied to computed tomography (CT) images to identify haematopoietically active bone marrow in anal cancer patients. METHODS: A total of 40 patients was assigned to the construction set (training set + test set). Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET) images were used to detect the active part of the pelvic bone marrow (ActPBM) and stored as ground-truth for three subregions: iliac, lower pelvis and lumbosacral bone marrow (ActIBM, ActLPBM, ActLSBM). Three parameters were used for the correspondence analyses between 18FDG-PET and ML classifiers: DICE index, Precision and Recall. RESULTS: For the 40-patient cohort, median values [min; max] of the Dice index were 0.69 [0.20; 0.84], 0.76 [0.25; 0.89], and 0.36 [0.15; 0.67] for ActIBM, ActLSBM, and ActLPBM, respectively. The Precision/Recall (P/R) ratio median value for the ActLPBM structure was 0.59 [0.20; 1.84] (over segmentation), while for the other two subregions the P/R ratio median has values of 1.249 [0.43; 4.15] for ActIBM and 1.093 [0.24; 1.91] for ActLSBM (under segmentation). CONCLUSION: A satisfactory degree of overlap compared to 18FDG-PET was found for 2 out of the 3 subregions within pelvic bones. Further optimization and generalization of the process is required before clinical implementation.

Technical note: patient-specific quality assurance methods for TomoDirect(TM) whole breast treatment delivery.

PURPOSE: To investigate the feasibility of implementing a novel approach for patient-specific QA of TomoDirect(TM) whole breast treatment. METHODS: The most currently used TomoTherapy DQA method, consisting in the verification of the 2D dose distribution in a coronal or sagittal plane of the Cheese Phantom by means of gafchromic films, was compared with an alternative approach based on the use of two commercially available diode arrays, MapCHECK2(TM) and ArcCHECK(TM). The TomoDirect(TM) plans of twenty patients with a primary unilateral breast cancer were applied to a CT scan of the Cheese Phantom and a MVCT dataset of the diode arrays. Then measurements of 2D dose distribution were performed and compared with the calculated ones using the gamma analysis method with different sets of DTA and DD criteria (3%-3 mm, 3%-2 mm). The sensitivity of the diode arrays to detect delivery and setup errors was also investigated. RESULTS: The measured dose distributions showed excellent agreement with the TPS calculations for each detector, with averaged fractions of passed Γ values greater than 95%. The percentage of points satisfying the constraint Γ < 1 was significantly higher for MapCHECK2(TM) than for ArcCHECK(TM) and gafchromic films using both the 3%-3 mm and 3%-2 mm gamma criteria. Both the diode arrays show a good sensitivity to delivery and setup errors using a 3%-2 mm gamma criteria. CONCLUSIONS: MapCHECK2™ and ArcCHECK(TM) may fulfill the demands of an adequate system for TomoDirect(TM) patient-specific QA.

Target registration errors with surface imaging system in conformal radiotherapy for prostate cancer: study on 19 patients.

PURPOSE: Accurate patient setup is a prerequisite for conformal radiotherapy (3D-CRT) and is based on various methods, including surface imaging systems. To evaluate the validity of a surface imaging system (AlignRT), we analysed setup reproducibility of a cohort of patients. MATERIALS AND METHODS: Nineteen patients affected by prostate adenocarcinoma were enrolled in this study. We acquired 653 surface images and 99 digital portal images (DPI). Setup errors were found by matching surface images with computed tomography (CT) and DPI images. RESULTS: The setup errors from the threshold of 5 mm detected by AlignRT along the Y, Z and X axes occurred in 47.4%, 42.1% and 5.3% of patients, respectively. For the threshold of 3 mm, shifts along the Y, Z and X axes were observed in 68%, 69% and 10%, respectively. Comparing AlignRT and DPI, we found a statistically significant difference in the detection of shifts along the Y and Z axes. For a threshold ≥ 5 mm, the two systems provided corresponding setup errors along the Y and Z axes, whereas along the X axis, the threshold was not necessary. CONCLUSIONS: AlignRT is an accurate technique for setup in 3D-CRT prostate cancer patients, especially along the lateral direction.

Tracking target position variability using intraprostatic fiducial markers and electronic portal imaging in prostate cancer radiotherapy.

PURPOSE: Modern radiotherapy has achieved substantial improvement in tumour control and toxicity rates by escalating the total dose to the target volume while sparing surrounding normal tissues. It has therefore become necessary to precisely track tumour position in order to minimise geometrical uncertainties due to setup errors and organ motion. We conducted this prospective evaluation of prostate cancer patients treated with image-guided conformal radiation therapy at our institution. We implanted three fiducial markers (gold seeds) within the prostatic gland in order to quantify daily target displacements and to generate specific margins around the clinical target volume (CTV) to create an appropriate planned target volume (PTV). MATERIALS AND METHODS: Between April and December 2009, ten patients affected with localised prostate cancer were transrectally implanted with three radio-opaque markers. Each patient underwent a computed tomography (CT) scan for planning purposes following proper bladder and rectum preparation. During treatment two orthogonal images were acquired daily and compared with previously generated digitally reconstructed radiographs. After manual localisation, comparison between the position of the gold seeds on the portal and reference images was carried out, and a set of extrapolated lateral-lateral (LL), anterior-posterior (AP) and cranial-caudal (CC) shift corrections was calculated and recorded. Couch corrections were applied with a threshold of 3 mm displacement. RESULTS: Systematic and random errors for each direction were calculated either as measured according to displacement of the gold seeds prior to any couch movement and after couch position correction according to the radio-opaque markers. For skin marks, mean systematic and random errors were 0.12+2.94 mm for LL, 1.04+3.37 mm for AP, -1.14+2.71 mm for CC, whereas for seed markers, mean and systematic errors were 0.6+1.5 mm for LL, 0.51+2.45 mm for AP and -0.25+2.51 mm for CC. A scatter plot generated on all measurements after couch repositioning according to gold-seed displacement suggested a confidence range of shift distributions within 5 mm for LL, 8 mm for CC, and 7 mm for AP. The total systematic and random components were then used to calculate proper PTV in patients receiving conventional treatment (7 mm for LL and 9 mm for both AP and CC). CONCLUSIONS: Prostate positional variability during a course of radiation treatment is strongly influenced by setup and organ motion. Organ tracking through fiducial markers and electronic portal imaging is able to reduce the spread of displacements, significantly contributing to improve the ballistic precision of radiation delivery.

Outcomes and toxicities in oligometastatic patients treated with stereotactic body radiotherapy for adrenal gland metastases: A multi-institutional retrospective study.

BACKGROUND: Studies reporting SBRT outcomes in oligometastatic patients with adrenal gland metastases (AGM) are limited. Herein, we present a multi-institutional analysis of oligometastatic patients treated with SBRT for AGM. MATERIAL/METHODS: The Consortium for Oligometastases Research (CORE) is among the largest retrospective series of patients with oligometastases. Among CORE patients, those treated with SBRT for AGM were included. Clinical and dosimetric data were collected. Adrenal metastatic burden (AMB) was defined as the sum of all adrenal GTV if more than one oligometastases is present.Competing risk analysis was used to estimate actuarial cumulative local recurrence (LR) and widespread progression (WP). Kaplan-Meier method was used to report overall survival (OS), local recurrence-free survival (LRFS), and progression-free survival (PFS). Treatment related toxicities were also reported. RESULTS: The analysis included 47 patients with 57 adrenal lesions. Median follow-up was 18.2 months. Median LRFS, PFS, and OS were 15.3, 5.3, and 19.1 months, respectively. A minimum PTV dose BED10 > 46 Gy was associated with an improved OS and LRFS. A prescribed BED10 > 70 Gy was an independent predictor of a lower LR probability. AMB>10 cc was an independent predictor of a lower risk for WP. Only one patient developed an acute Grade 3 toxicity consisting of abdominal pain. CONCLUSION: SBRT to AGM achieved a satisfactory local control and OS in oligometastatic patients. High minimum PTV dose and BED10 prescription doses were predictive of improved LR and OS, respectively. Prospective studies are needed to determine comprehensive criteria for patients SBRT eligibility and dosimetric planning.