Individualising radiation therapy decisions in breast cancer patients based on tumour infiltrating lymphocytes and genomic biomarkers.

Radiation therapy (RT) has long been fundamental for the curative treatment of breast cancer. While substantial progress has been made in the anatomical and technological precision of RT delivery, and some approaches to de-escalate or omit RT based on clinicopathologic features have been successful, there remain substantial opportunities to refine individualised RT based on tumour biology. A major area of clinical and research interest is to ascertain the individualised risk of loco-regional recurrence to direct treatment decisions regarding escalation and de-escalation of RT. Patient-tailored treatment with RT is considerably lagging behind compared with the massive progress made in the field of personalised medicine that currently mainly applies to decisions on the use of systemic therapy or targeted agents. Herein we review select literature surrounding the use of tumour genomic biomarkers and biomarkers of the immune system, including tumour infiltrating lymphocytes (TILs), within the management of breast cancer, specifically as they relate to progress in moving toward analytically validated and clinically tested biomarkers utilized in RT.

The use of in-vivo dosimetry to identify head and neck cancer patients needing adaptive radiotherapy.

BACKGROUND AND PURPOSE: Head and neck cancer (HNC) patients experiencing anatomical changes during their radiotherapy (RT) course may benefit from adaptive RT (ART). We investigated the sensitivity of an electronic portal imaging device (EPID)-based in-vivo dosimetry (EIVD) system to detect patients that require ART and identified its limitations. MATERIALS AND METHODS: A retrospective study was conducted for 182 HNC patients: laryngeal cancer without elective lymph nodes (group A), postoperative RT (group B) and primary RT including elective lymph nodes (group C). The effect of anatomical changes on the dose distribution and volumetric changes was quantified. The receiver operating characteristic curve was used to obtain the optimal cut-off value for the gamma passing rate (%GP) with a dose difference of 3% and a distance to agreement of 3 mm. RESULTS: Fifty HNC patients receiving ART were analyzed: 1 in group A, 10 in group B and 39 in group C. Failed fractions (FFs) occurred in 1/1, 6/10 and 23/39 cases before ART in group A, B and C respectively. In the four cases in group B without FFs, only minor dosimetric changes were observed. One of the cases in group C without FFs had significant dosimetric changes (false negative). Three cases received ART because of clinical reasons that cannot be detected by EIVD. The optimal cut-off value for the %GP was 95%/95.2% for old/new generation machines respectively. CONCLUSION: EIVD combined with 3D imaging techniques can be synergistic in the detection of anatomical changes in HNC patients who benefit from ART.

Comparing treatment uncertainty for ultra- vs. standard-hypofractionated breast radiation therapy based on in-vivo dosimetry.

Background and purpose: Postoperative ultrahypofractionated radiation therapy (UHFRT) in 5 fractions (fx) for breast cancer patients is as effective and safe as conventionally hypofractionated RT (HFRT) in 15 fx, liberating time for higher-level daily online Image-Guided Radiation Therapy (IGRT) corrections. In this retrospective study, treatment uncertainties occurring in patients treated with 5fx (5fx-group) were evaluated using electronic portal imaging device (EPID)-based in-vivo dosimetry (EIVD) and compared with the results from patients treated with conventionally HFRT (15fx-group) to validate the new technique and to evaluate if the shorter treatment schedule could have a positive effect on the treatment uncertainties. Materials and methods: EPID-based integrated transit dose images were acquired for each treatment fraction in the 5fx-group (203 patients) and on the first 3 days of treatment and weekly thereafter in the 15fx-group (203 patients). A total of 1015 EIVD measurements in the 5fx-group and 1144 in the 15fx-group were acquired. Of the latter group, 755 had been treated with online IGRT correction (i.e., Online-IGRT 15fx-group). Results: In the 15fx-group 12.0% of fractions failed (FFs) compared to 3.8% in the 5fx-group and 6.9% in the online-IGRT 15fx-group. Causes for FFs in the 15fx-group compared with the 5fx-group were patient positioning (7.4% vs. 2.2%), technical issues (3.1% vs. 1.2%) and breast swelling (1.4% vs. 0.5%). In the online-IGRT 15fx-group, 2.5% were attributed to patient positioning, 3.8% to technical issues and 0.5% to breast swelling. Conclusions: EIVD demonstrated that UHFRT for breast cancer results in less FFs compared to standard HFRT. A large proportion of this decrease could be explained by using daily online IGRT.

Local Treatment of Triple-Negative Breast Cancer.

ABSTRACT: Triple-negative breast cancer, compared with other molecular subtypes, poses particular challenges for optimizing the timing and the extent of locoregional treatments. In the past, the combination of increased rates of both locoregional and distant recurrences led to a preference of radical surgery and extensive radiation therapy; however, since the introduction of more effective chemotherapy, a sharp de-escalation in the extent of locoregional treatments followed. Current evidence confirms that less aggressive surgery in combination with tailored radiation therapy offers improved oncological outcomes combined with better quality of life. However, further research is required to optimize locoregional treatments, considering the significant heterogeneity in biological behavior and tumor response to systemic treatments.

Oncological outcome, postoperative complications, and mammographic changes after intraoperative radiotherapy with electrons (IOERT) as a boost in a large single-institution cohort of breast cancer patients.

Advantages of using intraoperative radiotherapy with electrons (IOERT) as a boosting modality in breast-conserving therapy include the direct visualization of the tumor bed, a reduced skin dose, and patient convenience. We report oncological outcome, postoperative complication rate, and mammographic changes on follow-up imaging in women treated at our institution with IOERT as a boost modality in breast-conserving therapy for early-stage breast carcinoma. Between January 2007 and June 2018, 763 consecutive patients were enrolled. During breast-conserving surgery, an IOERT boost of 9 Gy was applied, followed by whole breast irradiation (WBI). At a median follow-up of 62.2 months (range: 0.5-135), 13 in-breast recurrences were observed, yielding a local tumor control rate of 98.4% at 5 years. In multivariable analysis, high tumor grading was predictive for local recurrence (HR = 5.6; 95%CI: 1.19-26.2). A total of 27 (3.5%) patients developed any kind of postoperative complication. None of the tumor characteristics nor any of the IOERT technical parameters were predictive for development of a postoperative complication. On follow-up imaging, 145 patients with mammographic changes BIRADS score ≥3 were found of which 50.3% required a biopsy. Only 17 patients had positive biopsies; none of the IOERT parameters were predictive for false-positive imaging. A 9 Gy IOERT boost combined with postoperative WBI provided outstanding local control rates, was well-tolerated, with limited postoperative complications. However, radiologists must be aware of a presumable higher prevalence of mammographic changes after IORT as a boost.

Microscopic tumor spread beyond (echo)endoscopically determined tumor borders in esophageal cancer.

OBJECTIVE: The microscopic tumor spread (MS) beyond the macroscopic tumor borders of esophageal tumors is crucial for determining the clinical target volume (CTV) in radiotherapy. The question arises whether current voluminous CTV margins of 3-5 cm around the macroscopic gross tumor volume (GTV) to account for MS are still accurate when fiducial markers are used for GTV determination. We aimed to pathologically validate the use of fiducial markers placed on the (echo)endoscopically determined tumor border (EDTB) as a surrogate for macroscopic tumor borders and to analyse the MS beyond EDTBs. METHODS: Thirty-three consecutive esophageal cancer patients treated with neo-adjuvant chemoradiotherapy after (echo)endoscopic fiducial marker implantation at cranial and caudal EDTB were included in this study. Fiducial marker positions were detected in the surgical specimens under CT guidance and demarcated with beads, and subsequently analysed for macroscopic tumor spread and MS beyond the demarcations. A logistic regression analysis was performed to determine predicting factors for MS beyond EDTB. RESULTS: A total of 60 EDTBs were examined in 32 patients. In 50% of patients no or only partial regression of tumor in response to therapy (≥Mandard 3) or higher was seen (i.e., residual tumor group) and included for MS analysis. None had macroscopic tumor spread beyond EDTBs. In the residual tumor group, only 20 and 21% of the cranial and caudal EDTBs were crossed with a maximum of 9 mm and 16 mm MS, respectively. This MS was corrected for each individual determined contraction rate (mean: 93%). Presence of MS beyond EDTB was significantly associated with initial tumor length (p = 0.028). CONCLUSION: Our results validate the use of fiducial markers on EDTB as a surrogate for macroscopic tumor and indicate that CTV margins around the GTV to compensate for MS along the esophageal wall can be limited to 1-1.5 cm, when the GTV is determined with fiducial markers.

A Novel Liquid Fiducial Marker in Esophageal Cancer Image Guided Radiation Therapy: Technical Feasibility and Visibility on Imaging.

PURPOSE: To assess the technical feasibility of injection, visibility on imaging modalities, and positional stability of a novel liquid fiducial marker (ie, BioXmark) for radiation therapy in patients with esophageal cancer. METHODS: First, the visibility on imaging of different volumes of the liquid marker was analyzed ex vivo in porcine tissue (ie, on computed tomography [CT], cone beam CT (CBCT), and magnetic resonance imaging [MRI]). Next, for the in vivo part, the liquid fiducial markers were injected under endoscopic (ultrasound) guidance in 10 patients with curable esophageal cancer. The technical feasibility of the injection procedure and the clinical performance (ie, visibility and positional stability on imaging) were evaluated. Planning CT, daily CBCT, and serial MRI images (before, during, and after chemoradiation therapy in a subset of 3 patients) were acquired. RESULTS: Ex vivo, the optimal volume for good visibility without artifacts was 0.1 mL per injected marker. In vivo, a total of 28 markers were injected in 10 patients (range, 0.025-0.1 mL). No adverse effects were identified. The first 2 cases (4 markers) were considered as learning cases. A total of 19 of 24 of the liquid markers (79%) were visible on CT, 3 of 4 (75%) on MRI, and 19 of 24 (79%) on the first CBCT. All markers with an injected volume of >0.05 mL were visible on the different imaging modalities. Positional stability analysis on CBCT identified no time trend during the radiation therapy course. No artifacts could be detected for liquid marker volumes of 0.05 and 0.025 mL in CT or CBCT. CONCLUSIONS: Injection of a liquid fiducial marker for esophageal cancer radiation therapy is technically feasible with no adverse events identified. Volumes of >0.05 mL have an appropriate visibility on CT, CBCT, and MRI, with an excellent positional stability. Liquid fiducial markers are therefore promising for use in image guided radiation therapy.

Reduced inter-observer and intra-observer delineation variation in esophageal cancer radiotherapy by use of fiducial markers.

Objective: Delineation variation of esophageal tumors remains a large source of geometric uncertainty. In the present study, we investigated the inter- and intra-observer variation in esophageal gross tumor volume (GTV) delineation and the impact of endoscopically implanted fiducial markers on these variations. Material/Methods: Ten esophageal cancer patients with at least two markers endoscopically implanted at the cranial and caudal tumor borders and visible on the planning computed tomography (pCT) were included in this study. Five dedicated gastrointestinal radiation oncologists independently delineated GTVs on the pCT without markers and with markers. The GTV was first delineated on pCTs where markers were digitally removed and next on the original pCT with markers. Both delineation series were executed twice to determine intra-observer variation. For both the inter- and intra-observer analyses, the generalized conformity index (CIgen), and the standard deviation (SD) of the distances between delineated surfaces (i.e., overall, longitudinal, and radial SDs) were calculated. Linear mixed-effect models were used to compare the without and with markers series (α = 0.05). Results: Both the inter- and intra-observer CIgen were significantly larger in the series with markers than in the series without markers (p < .001). For the series without markers vs. with markers, the inter-observer overall SD, longitudinal SD, and radial SD was 0.63 cm vs. 0.22 cm, 1.44 cm vs. 0.42 cm, and 0.26 cm vs. 0.18 cm, respectively (p < .05); moreover, the intra-observer overall SD, longitudinal SD, and radial SD was 0.45 cm vs. 0.26 cm, 1.10 cm vs. 0.41 cm, and 0.22 cm vs. 0.15 cm, respectively (p < .05). Conclusion: The presence of markers at the cranial and caudal tumor borders significantly reduced both inter- and intra-observer GTV delineation variation, especially in the longitudinal direction. Our results endorse the use of markers in GTV delineation for esophageal cancer patients.

The Efficacy and Safety of (Neo)Adjuvant Therapy for Gastric Cancer: A Network Meta-analysis.

Background: Alternatives in treatment-strategies exist for resectable gastric cancer. Our aims were: (1) to assess the benefit of perioperative, neoadjuvant and adjuvant treatment-strategies and (2) to determine the optimal adjuvant regimen for gastric cancer treated with curative intent. Methods: PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to August 2017 for randomized-controlled-trials on the curative treatment of resectable gastric cancer. We performed two network-meta-analyses (NMA). NMA-1 compared perioperative, neoadjuvant and adjuvant strategies only if there was a direct comparison. NMA-2 compared different adjuvant chemo(radio)therapy regimens, after curative resection. Overall-survival (OS) and disease-free-survival (DFS) were analyzed using random-effects NMA on the hazard ratio (HR)-scale and calculated as combined HRs and 95% credible intervals (95% CrIs). Results: NMA-1 consisted of 9 direct comparisons between strategies for OS (14 studies, n = 4187 patients). NMA-2 consisted of 16 direct comparisons between adjuvant chemotherapy/chemoradiotherapy regimens for OS (37 studies, n = 10,761) and 14 for DFS (30 studies, n = 9714 patients). Compared to taxane-based-perioperative-chemotherapy, surgery-alone (HR = 0.58, 95% CrI = 0.38⁻0.91) and perioperative-chemotherapy regimens without a taxane (HR = 0.79, 95% CrI = 0.58⁻1.15) were inferior in OS. After curative-resection, the doublet oxaliplatin-fluoropyrimidine (for one-year) was the most efficacious adjuvant regimen in OS (HR = 0.47, 95% CrI = 0.28⁻0.80). Conclusions: For resectable gastric cancer, (1) taxane-based perioperative-chemotherapy was the most promising treatment strategy; and (2) adjuvant oxaliplatin-fluoropyrimidine was the most promising regimen after curative resection. More research is warranted to confirm or reproach these findings.

Dosimetric Benefits of Midposition Compared With Internal Target Volume Strategy for Esophageal Cancer Radiation Therapy.

PURPOSE: Both midposition (MidP) and internal target volume (ITV) strategies can take the respiration-induced target motion into account. This study aimed to compare these 2 strategies in terms of clinical target volume (CTV) coverage and dose to organs at risk (OARs) for esophageal cancer radiation therapy (RT). METHODS AND MATERIALS: Fifteen patients with esophageal cancer were included retrospectively for neoadjuvant RT planning. Per patient, a 10-phase, 4-dimensional (4D) computed tomography (CT) scan (4D-CT) was acquired with CTV and OARs delineated on the 20% phase. The MidP-CT scan was reconstructed based on deformable image registration between the 20% phase and the other 9 phases; thereby, the CTV and OARs delineations were propagated and an ITV was constructed. Both MidP and ITV strategies were used for treatment planning, yielding the planned dose. Next, these plans were applied to the 10-phase 4D-CT to calculate the dose distribution for each phase of the 4D-CT. On the basis of the deformable image registration, these calculated dose distributions were warped and averaged to yield the accumulated 4D dose. Subsequently, we compared, in terms of CTV coverage and dose to OARs, the planned dose with the accumulated 4D dose and the MidP strategy with the ITV strategy. RESULTS: The differences between the planned dose and the accumulated 4D dose were limited and clinically irrelevant. In 14 patients, both MidP and ITV strategies showed V95% > 98% for the CTV. Compared with the ITV strategy, the MidP strategy showed a significant reduction of approximately 10% in the dose-volume histogram parameters for the lungs, heart, and liver (P < .001, Wilcoxon signed-rank test). CONCLUSIONS: Compared with the ITV strategy, the MidP strategy in treatment planning can lead to a reduction of approximately 10% in the dose to OARs, with an adequate CTV coverage for esophageal cancer RT.

Comparison of carina-based versus bony anatomy-based registration for setup verification in esophageal cancer radiotherapy.

BACKGROUND: To investigate the feasibility and geometric accuracy of carina-based registration for CBCT-guided setup verification in esophageal cancer IGRT, compared with current practice bony anatomy-based registration. METHODS: Included were 24 esophageal cancer patients with 65 implanted fiducial markers, visible on planning CTs and follow-up CBCTs. All available CBCT scans (n = 236) were rigidly registered to the planning CT with respect to the bony anatomy and the carina. Target coverage was visually inspected and marker position variation was quantified relative to both registration approaches; the variation of systematic (Σ) and random errors (σ) was estimated. RESULTS: Automatic carina-based registration was feasible in 94.9% of the CBCT scans, with an adequate target coverage in 91.1% compared to 100% after bony anatomy-based registration. Overall, Σ (σ) in the LR/CC/AP direction was 2.9(2.4)/4.1(2.4)/2.2(1.8) mm using the bony anatomy registration compared to 3.3(3.0)/3.6(2.6)/3.9(3.1) mm for the carina. Mid-thoracic placed markers showed a non-significant but smaller Σ in CC and AP direction when using the carina-based registration. CONCLUSIONS: Compared with a bony anatomy-based registration, carina-based registration for esophageal cancer IGRT results in inadequate target coverage in 8.9% of cases. Furthermore, large Σ and σ, requiring larger anisotropic margins, were seen after carina-based registration. Only for tumors entirely confined to the mid-thoracic region the carina-based registration might be slightly favorable.

Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: A literature-based critical review.

BACKGROUND: The head and neck region has rich regional lymphatic network, with a theoretical risk on contralateral metastasis from oropharyngeal cancer (OPC). There is a long-standing convention to irradiate the great majority of these tumors electively to both sides of the neck to reduce the risk of contralateral regional failure (cRF), but this can induce significant toxicity. We aimed to identify patient groups where elective contralateral irradiation may safely be omitted. METHODS: PubMed and EMBASE were searched for original full-text articles in English with a combination of search terms related to the end points: cRF in OPC primarily treated by radiotherapy only to the ipsilateral neck and identifying predictive factors for increased incidence of cRF. The data from the identified studies were pooled, the incidence of cRF was calculated and the correlation with different predictive factors was investigated. RESULTS: Eleven full-text articles met the inclusion criteria. In these studies, 1116 patients were treated to the ipsilateral neck alone. The mean incidence of cRF was 2.42% (range 0-5.9%, 95% CI 1.6-3.5%). The incidence of cRF correlated only with T-stage (p=0.008), and involvement of midline (p=0.001). However, the significant correlation with T-stage can be explained by the very low incidence of cRF among T1 (0.77%), and disappeared when the incidence of cRF was compared between T2, T3,and T4 (p=0.344). CONCLUSION: The incidence of cRF in patients with OPC is very low, with involvement of midline providing the most significant prognosticator. These results call for trials on unilateral elective irradiation in selected groups.

Distribution of lymph node metastases on FDG-PET/CT in inoperable or unresectable oesophageal cancer patients and the impact on target volume definition in radiation therapy.

INTRODUCTION: Definitive chemoradiotherapy (dCRT) is standard care for localised inoperable/unresectable oesophageal tumours. Many surgical series have reported on distribution of lymph node metastases (LNM) in resected patients. However, no data is available on the distribution of at-risk LN regions in this more unfavourable patient group. This study aimed to determine the spread of LNM using FDG-PET/CT, to compare it with the distribution in surgical series and to define its impact on the definition of elective LN irradiation (ENI). METHODS: FDG-PET/CT images of patients with oesophageal cancer treated with dCRT (from 2003 to 2013) were reviewed to identify the anatomic distribution of FDG-avid LNs. Tumours were divided according to proximal, mid-thoracic or distal localisation. RESULTS: About 105 consecutive patients entered analysis. The highest numbers of FDG-avid LNs in proximal tumours were at LN station 101R (45%) and 106recL (35%). For mid-thoracic tumours at 104R (30%) and 105 (30%). For tumours located in the distal oesophagus, the most common sites were along the lesser curvature of the stomach (21%) and the left gastric artery (21%). Except for the supraclavicular and pretracheal nodes, there were no positive locoregional LNM found outside the standard surgical resection area. CONCLUSION: Our results show a good correlation between the distribution of nodal volumes at risk in surgical series and on FDG-PET/CT. The results can be used to determine target definition in dCRT for oesophageal cancer. For mid-thoracic tumours, the current target delineation guidelines may be extended based on the risk of node involvement, but more clinical studies are needed to determine if the potential harm of expanding the CTV outweighs the potential benefit.

Marker-based quantification of interfractional tumor position variation and the use of markers for setup verification in radiation therapy for esophageal cancer.

PURPOSE: The aim of this study was to quantify interfractional esophageal tumor position variation using markers and investigate the use of markers for setup verification. MATERIALS AND METHODS: Sixty-five markers placed in the tumor volumes of 24 esophageal cancer patients were identified in computed tomography (CT) and follow-up cone-beam CT. For each patient we calculated pairwise distances between markers over time to evaluate geometric tumor volume variation. We then quantified marker displacements relative to bony anatomy and estimated the variation of systematic (Σ) and random errors (σ). During bony anatomy-based setup verification, we visually inspected whether the markers were inside the planning target volume (PTV) and attempted marker-based registration. RESULTS: Minor time trends with substantial fluctuations in pairwise distances implied tissue deformation. Overall, Σ(σ) in the left-right/cranial-caudal/anterior-posterior direction was 2.9(2.4)/4.1(2.4)/2.2(1.8) mm; for the proximal stomach, it was 5.4(4.3)/4.9(3.2)/1.9(2.4) mm. After bony anatomy-based setup correction, all markers were inside the PTV. However, due to large tissue deformation, marker-based registration was not feasible. CONCLUSIONS: Generally, the interfractional position variation of esophageal tumors is more pronounced in the cranial-caudal direction and in the proximal stomach. Currently, marker-based setup verification is not feasible for clinical routine use, but markers can facilitate the setup verification by inspecting whether the PTV covers the tumor volume adequately.

Endoscopy/EUS-guided fiducial marker placement in patients with esophageal cancer: a comparative analysis of 3 types of markers.

BACKGROUND: Markers placed at the borders of esophageal tumors are potentially useful to facilitate radiotherapy (RT) target delineation, which offers the possibility of image-guided RT. OBJECTIVE: To evaluate and compare the feasibility and technical benefit of endoscopy/EUS-guided marker placement of 3 different types of markers in patients with esophageal cancer referred for RT. DESIGN: Prospective, single-center, feasibility and comparative study. SETTING: Tertiary-care medical center. PATIENTS: Thirty patients with esophageal cancer who were referred for RT. INTERVENTIONS: Patients underwent endoscopy/EUS-guided implantation of 1 type of marker. A solid gold marker (SM) with fixed dimensions, a flexible coil-shaped gold marker (FM) with hand-cut length (2-10 mm), and a radiopaque hydrogel marker (HG) were used. Technical feasibility and adverse events were registered. CT scans and cone-beam CT scans (CBCT) acquired during RT were analyzed to determine and compare the visibility and continuous clear visibility of the implanted markers. MAIN OUTCOME MEASUREMENTS: Technical feasibility, technical benefit, and adverse events of 3 types of markers. RESULTS: A total of 101 markers were placed in 30 patients. Implantation was technically feasible in all patients without grade 3 to 4 adverse events. Two patients with asymptomatic mediastinitis and one with asymptomatic pneumothorax were seen. Visibility on CT scan of all 3 types of implanted markers was adequate for target delineation. Eighty percent of FMs remained continuously visible over the treatment period on CBCT, significantly better than SMs (63%) and HGs (11%) (P = .015). When we selected FMs ≥5 mm, 90.5% remained visible on CBCT between implantation and the end of RT. LIMITATIONS: Single-center, nonrandomized design. CONCLUSION: Endoscopy/EUS-guided fiducial marker placement for esophageal cancer is both safe and feasible and can be used for target volume delineation purposes on CT. Our results imply a significant advantage of FMs over SMs and HGs, regarding visibility and continuous clear visibility over the treatment period. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR4724.).