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Purpose: Radiation therapy (RT) causes tissue damage and inflammation. Because cytokines play a key role in such processes, their expression levels can be an indicator of cell and tissue toxicity. This critical review aims to explore whether levels of circulating inflammatory biomarkers in peripheral blood are associated with proton- or photon-based therapy in the pelvic area and how these levels vary over time. Further, we investigated whether these levels can be linked to radiation dose, the incidence of toxicity, and changes in toxicity over time.

Methods and Materials: A literature search was conducted in PubMed to find studies involving comparative cohorts of pelvic irradiated patients with cancer. Studies reporting on the association of markers in peripheral blood with inflammatory processes and/or toxicity were included.

Results: We found evidence of associations between changes in inflammatory cytokine levels and the total cumulative dose-volume together with RT-induced toxicity in patients with cancer treated with pelvic RT. Common patient-reported outcomes demonstrate an association between radiation toxicity (eg, genitourinary toxicity) and circulating inflammatory biomarker levels.

Conclusions: This review highlights that the total cumulative dose and irradiated tissue volume are the primary drivers of RT-induced biomarker expression, influencing both early and late toxicity outcomes. The diversity in RT techniques, total dose, and number of treatment sessions across studies likely contributes to the variation in observed results. Circulating cytokine and biomarker levels in the blood can provide valuable monitoring and predictive insights for patients undergoing proton- or photon-based RT of the pelvis. Biomarker analysis in the context of RT offers clinical value by enabling personalized treatment by helping predict which patients are at higher risk for certain toxicities, guiding clinicians in tailoring treatment, optimizing supportive care, and adjusting RT plans. This approach could improve patient outcomes and quality of life by reducing long-term complications from radiation exposure.

Purpose: The study investigated curative radiation therapy (RT) plus cisplatin versus RT plus cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC).

Methods and Materials: This was a Swedish multicenter randomized phase 3 study. Included patients were randomized 1:1. Patients with T3-T4 tumors underwent a second randomization 1:1 between a final RT dose of 68.0 and 73.1 Gy to the primary tumor. Cisplatin dosage was 40 mg/m2/wk during RT. Cetuximab was administered with a loading dose of 400 mg/m2 1 week before start of RT, followed by weekly doses of 250 mg/m2 during RT. Primary endpoint was overall survival (OS), evaluated by adjusted Cox regression analysis. Secondary endpoints were locoregional control, pattern of failure, morbidity, quality of life (QL), and comparisons between dose-escalated RT and standard-dose RT in T3-T4 tumors.

Results: Following an unplanned interim analysis, patient inclusion was prematurely closed. The intention-to-treat population included 291 patients, 76% of whom had p16-positive oropharyngeal cancer. Median follow-up was 7.5 years for OS and 5.3 years for treatment efficacy. Five-year OS was 82% (95% confidence interval [CI], 76-89) in the RT plus cisplatin group compared with 71% (95% CI, 64-79) in the RT plus cetuximab group (log-rank P = .019). Adjusted hazard ratios for OS, locoregional failure, and distant failure were 1.66 (95% CI, 1.08−2.56; P = .021), 2.24 (95% CI, 1.25-4.02; P = .007), and 1.44 (95% CI, 0.67-3.09; P = .34), respectively, for patients treated with concomitant cetuximab versus cisplatin. Although potentially affected by the early termination of patient inclusion, no improvement in local control was found in patients with T3-T4 tumors receiving RT dose escalation (adjusted HR, 0.63; 95% CI, 0.30-1.34; P = .23). Late morbidity and QL were similar between the treatment groups.

Conclusions: The study showed inferior treatment outcomes for cetuximab compared with cisplatin concurrent with RT. Cisplatin remains standard concomitant treatment for locoregionally advanced HNSCC.

Collecting large amounts of radiotherapy (RT) data from clinical systems is known to be a challenging task. Still, data collections outside the original RT systems are needed to follow-up on the quality of cancer care and to improve RT. This paper aims to describe how RT data is collected nationally in Denmark and Sweden for this purpose and gives an overview of the stored information in both countries' national data sources.

Although both countries have clinical national quality registries with broad coverage and completeness for many cancer diagnoses, some were initiated already in the seventies, and less than one in ten includes quantitative information on RT to a level of detail useful for more than basic descriptive statistics. Detailed RT data can, however, be found in Denmark's DICOM Collaboration (DcmCollab) database, initiated in 2009 and in Sweden's quality registry for RT launched in 2023 (SKvaRT). Denmark has collected raw DICOM data for all patients enrolled in clinical trials, with files being directly and automatically transferred to DcmCollab from the original data sources at each RT centre. Sweden collects aggregated RT data into SKvaRT for all patients undergoing RT in Sweden, with DICOM files being transferred and selected alpha-numeric variables forwarded via a local intermediate storage database (MIQA) at each hospital. In designing their respective solutions, both countries have faced similar challenges regarding which RT variables to collect and how to technically link clinical systems to their data repositories. General lessons about how flexibility currently is balanced with storage requirements and data standards are presented here together with future plans to harvest real-world RT data.

ImportanceThe management of complications following oral cavity squamous cell carcinoma (OCSCC) surgery can be challenging. Previous studies show conflicting results on complication risks after preoperative radiotherapy (RT), necessitating a randomized controlled trial (RCT).ObjectiveTo compare early complications during hospitalization for OCSCC surgery between patients receiving preoperative accelerated fractionated RT and those planned for but not yet exposed to RT.DesignA part of the ARTSCAN 2 RCT comparing preoperative accelerated RT with postoperative conventionally fractionated RT for OCSCC.SettingA multicentre trial in 6 tertiary care hospitals in Sweden.ParticipantsUntreated and resectable OCSCC patients of all stages recommended combination treatment by the local multidisciplinary board.InterventionPreoperative accelerated RT was administered twice daily to a total dose of 68 Gy, completed 4 to 6 weeks before surgery.Main Outcome MeasuresComplications during hospitalization included wound infection, neck flap necrosis, chyle leakage, oro/pharyngocutaneous fistula, free flap necrosis, tracheostomy, revision surgery, and medical complications. Length of surgery, perioperative blood loss, and transfusions were also monitored.ResultsTwo hundred and twenty-one patients were eligible for analysis: 103 in the preoperative RT group and 118 not yet exposed to RT. Complication rates were low, with no statistically significant differences between groups. Patients receiving preoperative RT had similar wound infection rates (12/103; 11.7%) to those not exposed (9/118; 7.6%) (P = .31). Among free flap patients, 1/40 (2.5%) in the preoperative RT group and 3/52 (5.8%) in the unirradiated group had free flap necrosis (P = .63). No differences were found in oro/pharyngocutaneous fistula frequency (3/103; 2.9% vs 3/118; 2.5%) (P = 1.00).Conclusion and RelevancePreoperative accelerated RT at 68 Gy, administered 4 to 6 weeks before surgery, does not increase early complications. Although survival rates, morbidities, quality of life, and societal costs need consideration in the ARTSCAN 2 assessment, our findings show that early postoperative complication risks remain unchanged by preoperative RT.Trial RegistrationISRCTN, ISRCTN00608410, Registered 20 March 2008-Retrospectively registered, https://www.isrctn.com/ISRCTN00608410.

BACKGROUND AND PURPOSE: The study aims to evaluate dosimetric properties of hypofractionated treatment plans integrating focal boost, using registered whole-mount histopathology (WMHP) as reference standard.

METHODS: Fifteen men from the PAMP trial (EudraCT: 2015-005046-55) were included. Participants had ≥ 1 ISUP Grade group ≥ 4 lesion and underwent [⁶⁸Ga]prostate-specific membrane antigen (PSMA) positron emission tomography/multiparametric magnetic resonance imaging (PET/mpMRI) and [¹¹C]Acetate-PET/computed tomography before radical prostatectomy. Four radiation oncologists delineated gross tumor volumes (GTVs) on PSMA-PET/mpMRI. Sixty treatment plans were optimized, one per GTV and patient. Prostate planning target volumes were prescribed 42.7 Gy in seven fractions, with a simultaneous GTV boost up to 49.0 Gy, prioritizing organs at risk (OARs). Digital WMHP provided Gleason grading and was co-registered with in-vivo imaging. Target coverage for GTVs and voxels sharing Gleason patterns (GPs) was assessed via dose-volume histogram (DVH) analysis. Interobserver agreement in GTV-delineations was quantified with Fleiss' kappa.

RESULTS: The median GTV dose per plan (D50) ranged from 48.3 to 49.1 Gy. For voxels with the highest GP, D₅₀ was 42.9-49.2 Gy, exceeding 47.2 Gy in all except one plan. In lowest pattern voxels, D₅₀ was 42.5-49.3 Gy, and below 43.4 Gy in over half the plans. Significant positive correlations between Fleiss' kappa and DVH parameters appeared only for GP 5 regions, specifically for Fleiss' kappa and D₅₀ for two observers and the average D₅₀ across observers.

INTERPRETATION: The histologically confirmed tumor was only partially boosted. Regions with more aggressive disease received better coverage. These findings provide a rational for prioritizing OARs in treatment planning.

BACKGROUND: The delineation of intraprostatic lesions is vital for correct delivery of focal radiotherapy boost in patients with prostate cancer (PC). Errors in the delineation could translate into reduced tumour control and potentially increase the side effects. The purpose of this study is to compare PET-based delineation methods with histopathology.

MATERIALS AND METHODS: The study population consisted of 15 patients with confirmed high-risk PC intended for prostatectomy. [68Ga]-PSMA-PET/MR was performed prior to surgery. Prostate lesions identified in histopathology were transferred to the in vivo [68Ga]-PSMA-PET/MR coordinate system. Four radiation oncologists manually delineated intraprostatic lesions based on PET data. Various semi-automatic segmentation methods were employed, including absolute and relative thresholds, adaptive threshold, and multi-level Otsu threshold.

RESULTS: The gross tumour volumes (GTVs) delineated by the oncologists showed a moderate level of interobserver agreement with Dice similarity coefficient (DSC) of 0.68. In comparison with histopathology, manual delineations exhibited the highest median DSC and the lowest false discovery rate (FDR) among all approaches. Among semi-automatic approaches, GTVs generated using standardized uptake value (SUV) thresholds above 4 (SUV > 4) demonstrated the highest median DSC (0.41), with 0.51 median lesion coverage ratio, FDR of 0.66 and the 95th percentile of the Hausdorff distance (HD95%) of 8.22 mm.

INTERPRETATION: Manual delineations showed a moderate level of interobserver agreement. Compared to histopathology, manual delineations and SUV > 4 exhibited the highest DSC and the lowest HD95% values. The methods that resulted in a high lesion coverage were associated with a large overestimation of the size of the lesions.

Background and purpose: Dose escalation in external radiotherapy of prostate cancer shows promising results in terms of biochemical disease-free survival. Boost volume delineation guidelines are sparse which may cause high interobserver variability. The aim of this research was to characterize gross tumor volume (GTV) delineations based on multiparametric magnetic resonance imaging (mpMRI) and prostate specific membrane antigen-positron emission tomography (PSMA-PET) in relation to histopathology-validated Gleason grade 4 and 5 regions.

Material and methods: The study participants were examined with [68Ga]PSMA-PET/mpMRI prior to radical prostatectomy. Four radiation oncologists delineated GTVs in 15 study participants, on four different image types; T2-weighted (T2w), diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) and PSMA-PET scans separately. The simultaneous truth and performance level estimation (STAPLE) algorithm was used to generate combined GTVs. GTVs were subsequently compared to histopathology. We analysed how Dice similarity coefficient (DSC) and lesion coverage are affected by using single versus multiple image types as well as by adding a clinical target volume (CTV) margin.

Results: Median DSC (STAPLE) for different GTVs varied between 0.33 and 0.52. GTVPSMA-PET/mpMRI generated the highest median lesion coverage at 0.66. Combining different image types achieved similar lesion coverage as adding a CTV margin to contours from a single image type, while reducing non-malignant tissue inclusion within the target volume.

Conclusion: The combined use of mpMRI or PSMA-PET/mpMRI shows promise, achieving higher DSC and lesion coverage while minimizing non-malignant tissue inclusion, in comparison to the use of a single image type with an added CTV margin.

Background: To date, anal cancer patients are treated with radiotherapy to similar volumes despite a marked difference in risk profile based on tumor location and stage. A more individualized approach to delineation of the elective clinical target volume (CTVe) could potentially provide better oncological outcomes as well as improved quality of life. The aim of the present work was to establish Nordic Anal Cancer (NOAC) group guidelines for delineation of the CTVe in anal cancer.

Methods: First, 12 radiation oncologists reviewed the literature in one of the following four areas: (1) previous delineation guidelines; (2) patterns of recurrence; (3) anatomical studies; (4) common iliac and para-aortic recurrences and delineation guidelines. Second, areas of controversy were identified and discussed with the aim of reaching consensus.

Results: We present consensus-based recommendations for CTVe delineation in anal cancer regarding (a) which regions to include, and (b) how the regions should be delineated. Some of our recommendations deviate from current international guidelines. For instance, the posterolateral part of the inguinal region is excluded, decreasing the volume of irradiated normal tissue. For the external iliac region and the cranial border of the CTVe, we agreed on specifying two different recommendations, both considered acceptable. One of these recommendations is novel and risk-adapted; the external iliac region is omitted for low-risk patients, and several different cranial borders are used depending on the individual level of risk.

Conclusion: We present NOAC consensus guidelines for delineation of the CTVe in anal cancer, including a risk-adapted strategy.

Background: The prescribed radiation dose to patients with oropharyngeal squamous cell carcinoma (OPSCC) is standardized, even if the prognosis for individual patients may differ. Easy-at-hand pre-treatment risk stratification methods are valuable to individualize therapy. In the current study we assessed the prognostic impact of primary tumor volume for p16-positive and p16-negative tumors and in relationship to other prognostic factors for outcome in patients with OPSCC treated with primary radiation therapy (RT). Methods: Five hundred twenty-three OPSCC patients with p16-status treated with primary RT (68.0 Gy to 73.1 Gy in 7 weeks, or 68.0 Gy in 4.5 weeks), with or without concurrent chemotherapy, within three prospective trials were included in the study. Local failure (LF), progression free survival (PFS) and overall survival (OS) in relationship to the size of the primary gross tumor volume (GTV-T) and other prognostic factors were investigated. Efficiency of intensified RT (RT with total dose 73.1 Gy or given within 4.5 weeks) was analyzed in relationship to tumor volume. Results: The volume of GTV-T and p16-status were found to be the strongest prognostic markers for LF, PFS and OS. For p16-positive tumors, an increase in tumor volume had a significantly higher negative prognostic impact compared with p16-negative tumors. Within a T-classification, patients with a smaller tumor, compared with a larger tumor, had a better prognosis. The importance of tumor volume remained after adjusting for nodal status, age, performance status, smoking status, sex, and hemoglobin-level. The adjusted hazard ratio for OS per cm3 increase in tumor volume was 2.3% (95% CI 0–4.9) for p16-positive and 1.3% (95% 0.3–2.2) for p16-negative. Exploratory analyses suggested that intensified RT could mitigate the negative impact of a large tumor volume. Conclusions: Outcome for patients with OPSCC treated with RT is largely determined by tumor volume, even when adjusting for other established prognostic factors. Tumor volume is significantly more influential for patients with p16-positive tumors. Patients with large tumor volumes might benefit by intensified RT to improve survival.

Background and purpose: An earlier prospective randomised multicentre study (ARTSCAN) in head and neck cancer patients that compared conventionally fractionated radiotherapy (CF) with accelerated radiotherapy (AF) was inconclusive. In the subgroup of oral cavity squamous cell cancer (OCSCC) a large absolute, but not statistically significant, difference in local control was seen in favour of AF. This difference was more pronounced in resectable tumours. The finding raised the hypothesis that AF could be beneficial for OCSCC patients. In addition, the longstanding controversy on pre- or postoperative radiotherapy was addressed.

Materials and methods: Patients with OCSCC, judged to withstand and likely benefit from combined therapy, were recruited. Subjects were randomised to either preoperative AF with 43 fractions given as a concomitant boost with two fractions/day to the tumour bearing volume to a total dose of 68 Gy in 4.5 weeks followed by surgery, or primary surgery with postoperative CF, total dose 60 or 66 Gy in 6–7 weeks. For patients whose tumours had high-risk features, 66 Gy and concomitant cisplatin was prescribed.

Results: 250 patients were randomised. Median follow-up was 5 years for locoregional control (LRC) and 9 years for overall survival (OS). There were no statistically significant differences between the two treatment arms regarding LRC and OS. LRC at five years was 73% (95% CI, 65–82) in preoperative AF and 78% (95% CI, 70–85) in postoperative CF. Toxicity was more pronounced in preoperative AF.

Conclusion: This study does not support that AF prior to surgery improves outcome in oral cavity cancer compared with postoperative CF.