Overall Survival After Treatment Failure Among Patients With Rectal Cancer.

Importance: Oncologic outcomes among patients with rectal cancer after developing local recurrence and/or distant metastases remain poorly studied. Objective: To analyze the trend of overall survival after treatment failure for patients with rectal cancer within three consecutive phase 2 or 3 trials of the German Rectal Cancer Study Group. Design, Setting, and Participants: This cohort study is a post hoc analysis of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trials, conducted in Germany) that included 1948 patients with locally advanced rectal adenocarcinoma. The CAO/ARO/AIO-94 trial recruited patients between February 1995 and September 2002, the CAO/ARO/AIO-04 trial recruited patients between July 2006 and February 2010, and the CAO/ARO/AIO-12 trial recruited patients between June 2015 and January 2018. Statistical analysis was conducted between September 2022 and March 2023. Exposures: A total of 119 of 391 patients in the CAO/ARO/AIO-94 trial group A, 295 of 1236 patients in the CAO/ARO/AIO-04 trial, and 69 of 306 in the CAO/ARO/AIO-12 trial experienced treatment failure (R2 resection or local recurrence or distant metastases) and were included in further analyses. Main Outcomes and Measures: Characteristics of treatment failure and overall survival were assessed in all 3 trial cohorts. Results: Of the 1948 patients treated in the 3 trials, 15 were excluded because of missing data. Of the remaining 1933 patients (median age, 62.5 years [range, 19-84 years]; 1363 men [71%] and 570 women [29%]) with locally advanced rectal adenocarcinoma (cT3 or 4 or cN+) treated within 3 consecutive clinical trials, 483 experienced treatment failure and were analyzed. After a median follow-up of 36 months (IQR, 24-51 months) for all patients, overall survival after treatment failure was significantly improved in the CAO/ARO/AIO-04 trial (at 3 years, 44% [IQR, 37%-51%]; hazard ratio [HR], 0.61 [95% CI, 0.47-0.79]) and further improved in the CAO/ARO/AIO-12 trial (at 3 years, 73% [IQR, 60%-87%]; HR, 0.32 [95% CI, 0.18-0.54]) compared with the CAO/ARO/AIO-94 trial (at 3 years, 30% [IQR, 22%-39%]) (both P < .001). Distant metastasis was the main reason for treatment failure throughout a 5-year follow-up (range, 67%-87%), and the relative risk for treatment failure was highest in the first 18 months in all 3 trials. ypTNM stage was significantly associated with the risk and time interval to treatment failure. Improvement in overall survival after treatment failure was independent of sex. Conclusions and Relevance: This cohort study suggests that advancements in salvage strategies during the past decades have likely improved overall survival among patients with rectal cancer who experienced treatment failure.

Advances in molecular targeted therapies to increase efficacy of (chemo)radiation therapy.

Recent advances in understanding the tumor's biology in line with a constantly growing number of innovative technologies have prompted characterization of patients' individual malignancies and may display a prerequisite to treat cancer at its patient individual tumor vulnerability. In recent decades, radiation- induced signaling and tumor promoting local events for radiation sensitization were explored in detail, resulting the development of novel molecular targets. A multitude of pharmacological, genetic, and immunological principles, including small molecule- and antibody-based targeted strategies, have been developed that are suitable for combined concepts with radiation (RT) or chemoradiation therapy (CRT). Despite a plethora of promising experimental and preclinical findings, however, so far, only a very limited number of clinical trials have demonstrated a better outcome and/or patient benefit when RT or CRT are combined with targeted agents. The current review aims to summarize recent progress in molecular therapies targeting oncogenic drivers, DNA damage and cell cycle response, apoptosis signaling pathways, cell adhesion molecules, hypoxia, and the tumor microenvironment to impact therapy refractoriness and to boost radiation response. In addition, we will discuss recent advances in nanotechnology, e.g., RNA technologies and protein-degrading proteolysis-targeting chimeras (PROTACs) that may open new and innovative ways to benefit from molecular-targeted therapy approaches with improved efficacy.

Customized 3D-printed molds for high dose-rate brachytherapy in facial skin cancer: First clinical experience.

BACKGROUND AND OBJECTIVE: Radiotherapy of elderly, frail patients with facial skin cancer in proximity to critical organs is challenging. This is the first report on clinical experience with facial skin cancer treated by individualized 3D-printer-based mold high-dose-rate (HDR) brachytherapy (BT). PATIENTS AND METHODS: Fifteen patients not eligible for radical surgery or definitive external beam radiotherapy (EBRT) were treated with 3D-printer-based mold HDR-BT. Patient selection and treatment were in accordance with multidisciplinary tumor board recommendations. Clinical response, toxicity and cosmesis were analyzed. RESULTS: Median age was 77 years. Histology revealed squamous cell carcinoma in seven, basal cell carcinoma in five, melanoma in situ in one, Lentigo maligna in one, and melanoma in one patient, respectively. Median prescription dose was 39 Gy delivered in once-daily fractions of 3 Gy. After a median follow-up of 12.2 months, local recurrence was observed in one patient with melanoma in situ. Apart from one grade 4 cataract, no other > grade 2 late toxicity was documented. CONCLUSIONS: HDR-BT with 3D-printer-based molds for facial skin cancer is a well-tolerated and safe treatment option for elderly, frail patients not eligible for radical surgery or definitive EBRT due to functional inoperability or tumor location.

Clinical outcome after total neoadjuvant treatment (CAO/ARO/AIO-12) versus intensified neoadjuvant and adjuvant treatment (CAO/ARO/AIO-04) a comparison between two multicenter randomized phase II/III trials.

BACKGROUND: Total neoadjuvant therapy (TNT) can enhance local tumor regression, but its survival benefits compared to intensified chemoradiotherapy (CRT) followed by adjuvant chemotherapy (CT) remain unclear. METHODS: This is a secondary comparison between 607 patients treated with intensified 5-FU/Oxaliplatin neoadjuvant CRT and adjuvant CT within the experimental arm of the CAO/ARO/AIO-04 phase III trial, and 306 patients treated with TNT within the CAO/ARO/AIO-12 phase II trial. Comparison between clinical-pathological characteristics, surgical quality, and post-surgical complications were analyzed using the Pearson's Chi-squared or Mann-Whitney U test. Oncological outcome was examined with log-rank, Gray's test, and multivariate cox regression. In addition, further subgroup analyses and propensity score matching were performed to optimize the balance of baseline covariates. FINDINGS: Patients treated with CRT followed by consolidation CT had a significantly higher rate of pathological complete remission (pCR) compared to patients treated within the experimental arm of the CAO/ARO/AIO-04 trial (25.3 % vs 17.3 %, P = 0.04). Post-surgical complications were less common in the CAO/ARO/AIO-12 trial. After a median follow-up of 46 months, clinical outcome did not differ significantly in the overall cohort, in any subgroup or after propensity score matching. In multivariate analysis, disease-free survival (DFS) was similar between the experimental arm of the CAO/ARO/AIO-04 trial and treatments arms of the CAO/ARO/AIO-12 trial (vs arm A: HR 0.92 [95 % CI 0.62-1.37], P = 0.69; vs arm B: HR 1.06 [95 % CI 0.72-1.58], P = 0.76). INTERPRETATION: Notwithstanding the limitations of intertrial comparison, TNT did not improve long term oncological outcome in our study compared to the intensified neoadjuvant CRT and adjuvant CT treatment in the CAO/ARO/AIO-04 trial. Improved response rates after TNT offers an attractive option to explore organ preservation in selective patients with locally advanced rectal cancer.

Acute toxicities of patients with locally advanced rectal cancer treated with intensified chemoradiotherapy within the CAO/ARO/AIO-12 trial: comparing conventional versus VMAT planning at a single center.

In locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is regarded as standard treatment. We assessed acute toxicities in patients receiving conventional 3D-conformal radiotherapy (3D-RT) and correlated them with dosimetric parameters after re-planning with volumetric modulated arc therapy (VMAT). Patients were randomized within the multicenter CAO/ARO/AIO-12 trial and received 50.4 Gy in 28 fractions and simultaneous chemotherapy with fluorouracil and oxaliplatin. Organs at risk (OAR) were contoured in a standardized approach. Acute toxicities and dose volume histogram parameters of 3D-RT plans were compared to retrospectively calculated VMAT plans. From 08/2015 to 01/2018, 35 patients with LARC were treated at one study center. Thirty-four patients were analyzed of whom 1 (3%) was UICC stage II and 33 (97%) patients were UICC stage III. Grade 3 acute toxicities occurred in 5 patients (15%). Patients with acute grade 1 cystitis (n = 9) had significantly higher Dmean values for bladder (29.4 Gy vs. 25.2 Gy, p < 0.01) compared to patients without bladder toxicities. Acute diarrhea was associated with small bowel volume (grade 2: 870.1 ccm vs. grade 0-1: 647.3 ccm; p < 0.01) and with the irradiated volumes V5 to V50. Using VMAT planning, we could reduce mean doses and irradiated volumes for all OAR: Dmean bladder (21.9 Gy vs. 26.3 Gy, p < 0.01), small bowel volumes V5-V45 (p < 0.01), Dmean anal sphincter (34.6 Gy vs. 35.6 Gy, p < 0.01) and Dmean femoral heads (right 11.4 Gy vs. 25.9 Gy, left 12.5 Gy vs. 26.6 Gy, p < 0.01). Acute small bowel and bladder toxicities were dose and volume dependent. Dose and volume sparing for all OAR could be achieved through VMAT planning and might result in less acute toxicities.

Prognostic Impact of Caspase-8, CDK9 and Phospho-CDK9 (Thr 186) Expression in Patients with Uterine Cervical Cancer Treated with Definitive Chemoradiation and Brachytherapy.

Introduction: After primary platinum-based chemoradiation of locally advanced uterine cervical cancer, a substantial proportion of women present with persistent, recurrent or metastatic disease, indicating an unmet need for biomarker development. Methods: We evaluated the clinical records of 69 cervical cancer patients (Federation of Gynecology and Obstetrics, FIGO Stage > IB3) who were subjected to definitive CRT. Immunohistochemical scoring of caspase-8, cyclin dependent kinase 9 (CDK9) and phosphorylated (phospho-)CDK9 (threonine (Thr) 186) was performed on pretreatment samples and correlated with the histopathological and clinical endpoints, including relapse-free survival (RFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS) and overall survival (OS). Results: Lower levels of caspase-8 were more prevalent in patients with a higher T-stage (p = 0.002) and a higher FIGO stage (p = 0.003), and were significantly correlated with CDK9 expression (p = 0.018) and inversely with pCDK9 detection (p = 0.014). Increased caspase-8 levels corresponded to improved RFS (p = 0.005), DMFS (p = 0.038) and CSS (p = 0.017) in the univariate analyses. Low CDK9 expression was associated with worse RFS (p = 0.008), CSS (p = 0.015) and OS (p = 0.007), but not DMFS (p = 0.083), and remained a significant prognosticator for RFS (p = 0.003) and CSS (p = 0.009) in the multivariate analyses. Furthermore, low pCDK9 staining was significantly associated with superior RFS (p = 0.004) and DMFS (p = 0.001), and increased CSS (p = 0.022), and remained significant for these endpoints in the multivariate analyses. Conclusion: Increased caspase-8 and CDK9 levels correlate with improved disease-related outcomes in cervical cancer patients treated with CRT, whereas elevated pCDK9 levels predict worse survival in this patient population.

Development and Validation of a Predictive Model for Toxicity of Neoadjuvant Chemoradiotherapy in Rectal Cancer in the CAO/ARO/AIO-04 Phase III Trial.

Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3−4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3−4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.

Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited.

BACKGROUND: Early efficacy outcome measures in rectal cancer after total neoadjuvant treatment are increasingly investigated. We examined the prognostic role of pathological complete response (pCR), tumor regression grading (TRG) and neoadjuvant rectal (NAR) score for disease-free survival (DFS) in patients with rectal carcinoma treated within the CAO/ARO/AIO-12 randomized phase 2 trial. METHODS: Distribution of pCR, TRG and NAR score was analyzed using the Pearson's chi-squared test. Univariable analyses were performed using the log-rank test, stratified by treatment arm. Discrimination ability of non-pCR for DFS was assessed by analyzing the ROC curve as a function of time. RESULTS: Of the 311 patients enrolled, 306 patients were evaluable (Arm A:156, Arm B:150). After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR, 0.95, 95% CI, 0.63-1.45, p = 0.82). pCR tended to be higher in Arm B (17% vs. 25%, p = 0.086). In both treatment arms, pCR, TRG and NAR were significant prognostic factors for DFS, whereas survival in subgroups defined by pCR, TRG or NAR did not significantly differ between the treatment arms. The discrimination ability of non-pCR for DFS remained constant over time (C-Index 0.58) but was slightly better in Arm B (0.61 vs. 0.56). CONCLUSION: Although pCR, TRG and NAR were strong prognostic factors for DFS in the CAO/ARO/AIO-12 trial, their value in selecting one TNT approach over another could not be confirmed. Hence, the conclusion of a long-term survival benefit of one treatment arm based on early surrogate endpoints should be stated with caution.

Analysis of MRI and CT-based radiomics features for personalized treatment in locally advanced rectal cancer and external validation of published radiomics models.

Radiomics analyses commonly apply imaging features of different complexity for the prediction of the endpoint of interest. However, the prognostic value of each feature class is generally unclear. Furthermore, many radiomics models lack independent external validation that is decisive for their clinical application. Therefore, in this manuscript we present two complementary studies. In our modelling study, we developed and validated different radiomics signatures for outcome prediction after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) based on computed tomography (CT) and T2-weighted (T2w) magnetic resonance (MR) imaging datasets of 4 independent institutions (training: 122, validation 68 patients). We compared different feature classes extracted from the gross tumour volume for the prognosis of tumour response and freedom from distant metastases (FFDM): morphological and first order (MFO) features, second order texture (SOT) features, and Laplacian of Gaussian (LoG) transformed intensity features. Analyses were performed for CT and MRI separately and combined. Model performance was assessed by the area under the curve (AUC) and the concordance index (CI) for tumour response and FFDM, respectively. Overall, intensity features of LoG transformed CT and MR imaging combined with clinical T stage (cT) showed the best performance for tumour response prediction, while SOT features showed good performance for FFDM in independent validation (AUC = 0.70, CI = 0.69). In our external validation study, we aimed to validate previously published radiomics signatures on our multicentre cohort. We identified relevant publications on comparable patient datasets through a literature search and applied the reported radiomics models to our dataset. Only one of the identified studies could be validated, indicating an overall lack of reproducibility and the need of further standardization of radiomics before clinical application.

Image-guided high-dose-rate brachytherapy for rectal cancer: technical note and first clinical experience on an organ-preserving approach.

PURPOSE: As the population ages, the incidence of rectal cancer among elderly patients is rising. Due to the risk of perioperative morbidity and mortality, alternative nonoperative treatment options have been explored in elderly and frail patients who are clinically inoperable or refuse surgery. METHODS: Here we present technical considerations and first clinical experience after treating a cohort of six rectal cancer patients (T1­3, N0­1, M0; UICC stage I-IIIB) with definitive external-beam radiation therapy (EBRT) followed by image-guided, endorectal high-dose-rate brachytherapy (HDR-BT). Patients were treated with 10-13â€¯× 3 Gy EBRT followed by HDR-BT delivering 12-18 Gy in two or three fractions. Tumor response was evaluated using endoscopy and magnetic resonance imaging of the pelvis. RESULTS: Median age was 84 years. All patients completed EBRT and HDR-BT without any high-grade toxicity (> grade 2). One patient experienced rectal bleeding (grade 2) after 10 weeks. Four patients (67%) demonstrated clinical complete response (cCR) or near cCR, there was one partial response, and one residual tumor and hepatic metastasis 8 weeks after HDR-BT. The median follow-up time for all six patients is 42 weeks (range 8-60 weeks). Sustained cCR without evidence of local regrowth has been achieved in all four patients with initial (n)cCR to date. CONCLUSION: Primary EBRT combined with HDR-BT is feasible and well tolerated with promising response rates in elderly and frail rectal cancer patients. The concept could be an integral part of a highly individualized and selective nonoperative treatment offered to patients who are not suitable for or refuse surgery.

ACO/ARO/AIO-21 - Capecitabine-based chemoradiotherapy in combination with the IL-1 receptor antagonist anakinra for rectal cancer Patients: A phase I trial of the German rectal cancer study group.

Purpose: Recent advances in the treatment algorithm of locally advanced rectal cancer (LARC) have significantly improved complete response (CR) rates and disease-free survival (DFS), but therapy resistance, with its substantial impact on outcomes and survival, remains a major challenge. Our group has recently unraveled a critical role of interleukin-1α (IL-1α) signaling in activating inflammatory cancer-associated fibroblasts (iCAFs) and mediating radiation-induced senescence, extracellular matrix (ECM) accumulation, and ultimately therapy resistance. We here summarize the recently initiated ACO/ARO/AIO-21 phase I trial, testing the IL-1 receptor antagonist (IL-1 RA) anakinra in combination with fluoropyrimidine-based chemoradiotherapy (CRT) for advanced rectal cancer. Methods/Design: The ACO/ARO/AIO-21 is an investigator-driven, prospective, open-labeled phase I drug-repurposing trial assessing the maximum tolerated dose (MTD) of capecitabine administered concurrently to standard preoperative radiotherapy (45 Gy in 25 fractions followed by 9 Gy boost in 5 fractions) in combination with fixed doses of the IL1-RA anakinra (100 mg, days -10 to 30). Capecitabine will be administered using a 3 + 3 dose-escalation design (500 mg/m2 bid; 650 mg/m2 bid; 825 mg/m2 bid, respectively) from day 1 to day 30. Response assessment including digital rectal examination (DRE), endoscopy and pelvic magnetic resonance imaging (MRI) is scheduled 10 weeks after completion of CRT. For patients achieving clinical complete response (cCR), primary non-operative management is provided. In case of non-cCR immediate total mesorectal excision (TME) will be performed. Primary endpoint of this phase I trial is the MTD of capecitabine. Discussion: Based on extensive preclinical research, the ACO/ARO/AIO-21 phase I trial will assess whether the IL-1RA anakinra can be safely combined with fluoropyrimidine-based CRT in rectal cancer. It will further explore the potential of IL-1 inhibition to overcome therapy resistance and improve response rates. A comprehensive translational research program will expand our understanding from a clinical perspective and may help translate the results into a randomized phase II trial.

Effects of iodinated contrast agent on HU-based dose calculation and dose delivered in iridium-192 high-dose-rate brachytherapy.

PURPOSE: This study compares the effect of iodinated contrast agent on Hounsfield unit (HU)-based TG-186 dose calculation vs. delivered dose for high-dose-rate (HDR) iridium-192 brachytherapy using a phantom model. MATERIAL AND METHODS: A reservoir filled with a diluted contrast agent was placed inside a water phantom. A single steel needle applicator was centrally positioned inside the reservoir. Computed tomography (CT) datasets of five different contrast agent dilutions (25 to 300 mg/ml iodine concentration) were acquired, and dose calculations were performed with TG-186 ACE dose calculation formalism of Oncentra®Brachy (Elekta). The dose was measured with a PinPoint® ionization chamber (PTW) inside the contrast agent. ACE calculated and measured data were compared. RESULTS: For the different contrast agent dilutions, averaged Hounsfield units from 453 ±21 to 2623 ±221 were obtained. Electron densities derived from CT data were significantly higher than corresponding electron densities calculated from chemical compositions. Consequently, the measured dose was higher than corresponding HU-based calculated dose. Relative deviation ranged from 2.5% to 7% per 10 mm penetration depth, depending on contrast agent concentration. CONCLUSIONS: The application of HU-based TG-186 dose formalisms in the presence of high-Z contrast agent bulks overestimates electron densities. Consequently, HU-based dose calculations result in a higher delivered dose than expected from the treatment planning system.

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer.

Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.

Impact of body-mass index on treatment and outcome in locally advanced rectal cancer: A secondary, post-hoc analysis of the CAO/ARO/AIO-04 randomized phase III trial.

BACKGROUND: A better understanding of the impact of body-mass index (BMI) on the course of multimodal therapy and oncologic outcome in locally advanced rectal cancer could provide new insights for optimization of treatment and supportive strategies. PATIENTS AND METHODS: Correlations of BMI with pretreatment clinical, surgical, and pathological characteristics, toxicity and treatment adherence using the Pearson's Chi-squared test or logistic regression were analyzed in the CAO/ARO/AIO-04 III trial cohort (n = 1236). One-way ANOVA or Welch test were used to analyze correlations of baseline blood-parameters and BMI. The prognostic role of BMI was examined with log-rank test and multivariate cox regression. RESULTS: Obese had a better ECOG performance status (P = 0.027) but were less likely to undergo sphincter preserving surgery (P = 0.01). Post-surgical complications did not differ significantly between BMI classes, whereas underweight was associated with increased neutrophil (P = 0.025) and platelet counts (P < 0.001), poorer TME quality (P = 0.007) and increased incidence of acute organ toxicity (P < 0.001). After a median follow-up of 50 months, underweight [HR 1.896, P = 0.014] and overweight [HR 1.392, P = 0.042] were associated with worse DFS. Obese patients had an increased risk of death [HR 1.653, P = 0.032]. Normalweight men showed superior OS compared to underweight [HR 4.070, P = 0.002], overweight [HR 2.077, P = 0.010], severe overweight [HR 1.886, P = 0.026] and obese [HR 2.046, P = 0.015] men. Adding oxaliplatin to standard CRT significantly improved DFS in obese patients (P = 0.034). CONCLUSION: In our study, underweight and overweight correlated with inferior DFS, underweight experienced more organ toxicity and obesity was associated with an increased risk of abdominoperineal resection and poorer overall survival.

Individualized mould-based high-dose-rate brachytherapy for perinasal skin tumors: technique evaluation from a dosimetric point of view.

PURPOSE: Dosimetric treatment planning evaluations concerning patient-adapted moulds for iridium-192 high-dose-rate brachytherapy are presented in this report. MATERIAL AND METHODS: Six patients with perinasal skin tumors were treated with individual moulds made of biocompatible epithetic materials with embedded plastic applicators. Treatment plans were optimized with regard to clinical requirements, and dose was calculated using standard water-based TG-43 formalism. In addition, retrospective material-dependent collapsed cone calculations according to TG-186 protocol were evaluated to quantify the limitations of TG-43 protocol for this superficial brachytherapy technique. RESULTS: The dose-volume parameters D90, V100, and V150 of the planning target volumes (PTVs) for TG-43 dose calculations yielded 92.2% to 102.5%, 75.1% to 93.1%, and 7.4% to 41.7% of the prescribed dose, respectively. The max- imum overall dose to the ipsilateral eyeball as the most affected organ at risk (OAR) varied between 8.9 and 36.4 Gy. TG-186 calculations with Hounsfield unit-based density allocation resulted in down by -6.4%, -16.7%, and -30.0% lower average D90, V100, and V150 of the PTVs, with respect to the TG-43 data. The corresponding calculated OAR doses were also lower. The model-based TG-186 dose calculations have considered reduced backscattering due to environmental air as well as the dose-to-medium influenced by the mould materials and tissue composition. The median PTV dose was robust within 0.5% for simulated variations of mould material densities in the range of 1.0 g/cm3 to 1.26 g/cm3 up to 7 mm total mould thickness. CONCLUSIONS: HDR contact BT with individual moulds is a safe modality for routine treatment of perinasal skin tumors. The technique provides good target coverage and OARs' protection, while being robust against small variances in mould material density. Model-based dose calculations (TG-186) should complement TG-43 dose calculations for verification purpose and quality improvement.

HDR brachytherapy with individual epithetic molds for facial skin cancer: techniques and first clinical experience.

BACKGROUND: Facial skin cancer lesions in close proximity to critical organs require further development of radiotherapeutic techniques for highly conformal treatment, especially when treating elderly frail patients. We report on our treatment technique and first clinical experience for patients with perinasal/periorbital skin cancer treated with individualized epithetic mold high-dose-rate brachytherapy (BRT). METHODS: From January 2019, patients with complex shaped or unfavorably located skin cancer not eligible for surgery or external beam radiotherapy (RT) were screened for mold-based BRT. Six patients were identified. Toxicity and clinical response were documented during therapy and posttreatment follow-up. RESULTS: Median patient age was 80 years (74-92 years). Median prescription dose was 42 Gy (range, 33-44 Gy) delivered in once-daily fractions of 3 or 4 Gy. Two patients had treatment interruptions caused by acute conjunctivitis grade 2 and a nontreatment-related cardiac event, respectively. At a median follow-up of 335 days (96-628 days), no ≥ grade 2 late toxicity was documented with all patients showing complete clinical response. CONCLUSIONS: High-dose-rate BRT with individualized epithetic molds for perinasal/periorbital skin cancer is a well-tolerated and safe treatment option for patients not eligible for primary surgery or definitive external beam RT because of comorbidities or tumor location.

Association of Treatment Adherence With Oncologic Outcomes for Patients With Rectal Cancer: A Post Hoc Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial.

Importance: Despite numerous published phase 3 trials, the association of treatment adherence with outcomes for patients with rectal cancer remains largely unexplored. Objective: To analyze the association of treatment adherence with disease-free survival (DFS) among patients with rectal cancer in the CAO/ARO/AIO-04 trial. Design, Setting, and Participants: This post hoc analysis of a phase 3 randomized clinical trial was conducted from July 25, 2006, to February 26, 2010, among 1232 patients from 80 centers with T3 to T4 or node-positive rectal adenocarcinoma. Statistical analysis was performed from May 5, 2019, to February 2, 2020. Interventions: A total of 625 patients received neoadjuvant fluorouracil-based chemoradiotherapy (nCRT), and a total of 607 patients received fluorouracil-based nCRT with addition of oxaliplatin. Of the 1126 patients who underwent curative surgery, 439 started fluorouracil-based adjuvant chemotherapy and 419 started fluorouracil-based adjuvant chemotherapy with oxaliplatin. Main Outcomes and Measures: The association of adherence with nCRT and adjuvant chemotherapy with DFS was assessed in both groups in the as-treated population. Results: Among the 625 patients (442 men; mean age, 63.0 years) who received fluorouracil nCRT and the 607 patients (430 men; mean age, 63.0 years) who received fluorouracil-based nCRT with addition of oxaliplatin, after a median follow-up of 50 months (interquartile range, 38-61 months), 3-year DFS in the as-treated population was 71.1% in the fluorouracil group and 75.8% in the fluorouracil-oxaliplatin group (hazard ratio [HR], 0.803; 95% CI, 0.651-0.990; P = .04). Overall, 419 patients in the fluorouracil nCRT group (67.0%) and 434 patients in the fluorouracil-oxaliplatin nCRT group (71.5%) received full doses of preoperative nCRT. Likewise, 253 of 439 patients in the fluorouracil group (57.6%) and 134 of 419 patients in the fluorouracil-oxaliplatin group (32.0%) received full doses of adjuvant chemotherapy. Adherence to nCRT was associated with 3-year DFS in both the fluorouracil group (complete vs near complete: HR, 1.325; 95% CI, 0.959-1.832; P = .09; complete vs reduced: HR, 1.877; 95% CI, 1.147-3.072; P = .01) and the fluorouracil-oxaliplatin group (complete vs near complete: HR, 1.501; 95% CI, 0.980-2.299; P = .06; complete vs reduced: HR, 1.724; 95% CI, 1.144-2.596; P = .009) in multivariable analyses. In contrast, adjuvant chemotherapy was not associated with DFS in both the fluorouracil group (complete vs near complete: HR, 0.900; 95% CI, 0.559-1.448; P = .66; complete vs incomplete: HR, 1.057; 95% CI, 0.807-1.386; P = .69) and the fluorouracil-oxaliplatin group (complete vs near complete: HR, 1.155; 95% CI, 0.716-1.866; P = .56; complete vs incomplete: HR, 1.073; 95% CI, 0.790-1,457; P = .65). Conclusions and Relevance: To our knowledge, this is the first analysis of a phase 3 trial to assess the association of treatment adherence with some clinical outcomes for patients with rectal cancer. The findings emphasize the need for appropriate trial design with optimized nCRT dose and schedule and supportive strategies to facilitate good adherence and precision delivery, especially for intensified nCRT. Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.

Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials.

BACKGROUND: The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS. METHODS: Using ClinicalTrials.gov, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes. RESULTS: A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045). CONCLUSIONS: A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval.