Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Intermuscular extremity myxoid liposarcoma can be managed by marginal resection following neoadjuvant radiotherapy.

BACKGROUND: Compared with other soft tissue sarcomas, myxoid liposarcoma (MLS) occurs in younger patients, has a propensity for intermuscular locations and is highly radiosensitive. With pre-operative radiotherapy, intermuscular MLS demonstrates substantial volume reduction and can be easily separated from surrounding tissues during resection. However, it is unclear whether marginal excision of MLS is oncologically safe. This study aimed to assess the association between margins and survival in irradiated, intermuscular MLS. METHODS: The study identified 198 patients from seven sarcoma centres with a first presentation of localized, extremity, intermuscular MLS that received pre-operative radiotherapy and was diagnosed between 1990 and 2017. Patient and treatment characteristics, radiological and histological responses to neoadjuvant treatment and clinical surveillance were recorded. RESULTS: Margins were microscopically positive in 11% (n = 22), <1.0 mm in 15% (n = 29) and ≥1.0 mm in 72% (n = 143). There was no association between margin status and local recurrence-free, metastasis-free or overall survival. This finding held true even in patients at higher risk of worse overall survival based on multivariable analysis (% round cell≥5%, percentage ellipsoid tumour volume change ≤ -60.1%). CONCLUSION: Irradiated, extremity, intermuscular myxoid liposarcoma can safely undergo marginal resection without compromising oncologic control.

Releasing chemical energy in spatiallyprogrammed ferroelectrics.

Chemical energy ferroelectrics are generally solid macromolecules showing spontaneous polarization and chemical bonding energy. These materials still suffer drawbacks, including the limited control of energy release rate, and thermal decomposition energy well below total chemical energy. To overcome these drawbacks, we report the integrated molecular ferroelectric and energetic material from machine learning-directed additive manufacturing coupled with the ice-templating assembly. The resultant aligned porous architecture shows a low density of 0.35 g cm-3, polarization-controlled energy release, and an anisotropic thermal conductivity ratio of 15. Thermal analysis suggests that the chlorine radicals react with macromolecules enabling a large exothermic enthalpy of reaction (6180 kJ kg-1). In addition, the estimated detonation velocity of molecular ferroelectrics can be tuned from 6.69 ± 0.21 to 7.79 ± 0.25 km s-1 by switching the polarization state. These results provide a pathway toward spatially programmed energetic ferroelectrics for controlled energy release rates.

Control charts for evaluation of quality of low-dose-rate brachytherapy for prostate cancer.

Purpose: Variations in dosimetric outcomes among patients treated with low-dose-rate brachytherapy for prostate cancer exist, even when implants are within dose constraints. Here, we used control charts to investigate reasons for intra-patient dosimetric variability. Material and methods: Univariate and multivariate control charts for prostate V100 (percentage of prostate volume that received 100% of prescribed radiation dose), D90 (radiation dose to 90% of prostate volume), and RV100 (rectal wall volume that received 100% of prescribed radiation dose) were generated for 212 consecutive prostate cancer patients implanted with iodine-125 (125I) radioactive seeds at the Princess Margaret Cancer Centre. Control limits were calculated based on the first fifty implants. Data points that were out of control were identified, and their pre-treatment and post-treatment dosimetric and clinical parameters were compared to data points that were in-control, using Student's t-test. Results: All implants were clinically acceptable. Twelve data points exceeded multivariate control limits. Ten of those points fell below the lower control limit of V100 control chart. Average prostate edema in the 10 out-of-control patients on both multivariate and V100 charts was 8.3%, as compared to 0.4% for in-control patients (p < 0.04). Two patients were observed to be out-of-control on multivariate control chart, but not on V100 control chart, and were found to have a reduction in prostate volume of 19.1% and 20.1% at one month after seed implant, compared to prostate volumes of pre-implantation evaluations. Conclusions: Control charts helped in identifying cases with out-of-control variability in post-plan prostate dosimetry. Post-treatment prostatic edema and contraction are important factors predicting variability in patients treated with 125I permanent seed brachytherapy.

Extended Results and Independent Validation of a Phase 2 Trial of Metastasis-Directed Therapy for Molecularly Defined Oligometastatic Prostate Cancer.

PURPOSE: The role of metastasis-directed therapy (MDT) in molecularly defined oligorecurrent prostate cancer (PCa) remains irresolute. We present extended follow-up and an independent validation cohort of a prospective trial. METHODS AND MATERIALS: This study consists of 2 sequential single-arm phase-2 trials of patients with biochemical recurrence (prostate specific antigen [PSA] 0.4-3.0 ng/mL) and negative conventional imaging after radical prostatectomy and postoperative radiation therapy. All patients underwent [18F]DCFPyL positron emission tomography/computed tomography. Patients with molecularly defined oligorecurrent prostate cancer underwent MDT with stereotactic body radiation therapy or surgery, without androgen deprivation therapy (ADT). The primary end point was biochemical response (≥50% PSA decline from baseline). Secondary end points included PSA progression-free survival and ADT-free survival. The sample size of 37 MDT patients was determined based on a Simon's 2-stage design with biochemical response rate >20%, and this design was also applied for the subsequent independent validation cohort. RESULTS: Seventy-four patients underwent MDT: 37 each in the initial and validation cohorts. Both cohorts met the prespecified biochemical response rate and completed the planned 2-stages of accrual. For the pooled cohort, the median number of prostate specific membrane antigen positron emission tomography avid lesions was 2 and most (87%) recurrences were nodal. Sixty-four (87%) had stereotactic body radiation therapy and 10 (13%) had surgery. Median follow-up (interquartile range [IQR]) for the initial, validation and combined cohorts were 41 (35-46) months, 14 months (7-21), and 24 months (14-41), respectively. The biochemical response rates for the initial, validation and combined cohorts were 59%, 43%, and 51%, respectively. For the combined cohort, median biochemical progression-free survival was 21 months (95% confidence interval, 13-not reached), and median ADT-free survival was 45 months (95% confidence interval, 31-not reached). CONCLUSIONS: Half of patients treated with MDT for molecularly defined-only oligorecurrent prostate cancer exhibited a biochemical response. This study provides necessary and validated evidence to support randomized trials aiming to determine whether MDT (alone or with systemic therapy) can affect clinically meaningful end points.

Critical impact of radiotherapy protocol compliance and quality in the treatment of retroperitoneal sarcomas: Results from the EORTC 62092-22092 STRASS trial.

BACKGROUND: The European Organization for Research and Treatment of Cancer 22092-62092 STRASS trial failed to demonstrate the superiority of neoadjuvant radiotherapy (RT) over surgery alone in patients with retroperitoneal sarcoma. Therefore, an RT quality-assurance program was added to the study protocol to detect and correct RT deviations. The authors report results from the trial RT quality-assurance program and its potential effect on patient outcomes. METHODS: To evaluate the effect of RT compliance on survival outcomes, a composite end point was created. It combined the information related to planning target volume coverage, target delineation, total dose received, and overall treatment time into 2 groups: non-RT-compliant (NRC) for patients who had unacceptable deviation(s) in any of the previous categories and RT-compliant (RC) otherwise. Abdominal recurrence-free survival (ARFS) and overall survival were compared between the 2 groups using a Cox proportional hazard model adjusted for known prognostic factors. RESULTS: Thirty-six of 125 patients (28.8%) were classified as NRC, and the remaining 89 patients (71.2%) were classified as RC. The 3-year ARFS rate was 66.8% (95% confidence interval [CI], 55.8%-75.7%) and 49.8% (95% CI, 32.7%-64.8%) for the RC and NRC groups, respectively (adjusted hazard ratio, 2.32; 95% CI, 1.25-4.32; P = .008). Local recurrence after macroscopic complete resection occurred in 13 of 89 patients (14.6%) versus 2 of 36 patients (5.6%) in the RC and NRC groups, respectively. CONCLUSIONS: The current analysis suggests a significant benefit in terms of ARFS in favor of the RC group. This association did not translate into less local relapses after complete resection in the RC group. Multidisciplinary collaboration and review of cases are critical to avoid geographic misses, especially for rare tumors like retroperitoneal sarcoma.

Selective Phonon Stimulation Mechanism to Tune Thermal Transport.

In this paper, we determine the degree to which changes can be induced in the equilibrium thermal diffusivity and conductivity of a material via a selective nonequilibrium infrared stimulation mechanism for phonons. Using the molecular crystal RDX, we use detailed momentum-dependent coupling information across the entire Brillouin zone and the phonon gas model to show that stimulating selected modes in the spectrum of a target material can induce substantial changes in the overall thermal transport properties. Specifically in the case of RDX, stimulating modes at ∼22.74 cm-1 over a linewidth of 1 cm-1 can lead to enhanced scattering rates that reduce the overall thermal diffusivity and conductivity by 15.58 and 12.46%, respectively, from their equilibrium values. Due to the rich spectral content in the materials, however, stimulating modes near ∼1140.67 cm-1 over a similar bandwidth can produce an increase in the thermal diffusivity and conductivity by 55.73 and 144.07%, respectively. The large changes suggest a mechanism to evoke substantially modulated thermal transport properties through light-matter interaction.

Radiological progression of extremity soft tissue sarcoma following pre-operative radiotherapy predicts for poor survival.

OBJECTIVES: To determine if radiological response to pre-operative radiotherapy is related to oncologic outcome in patients with extremity soft tissue sarcomas (STSs). METHODS: 309 patients with extremity STS who underwent pre-operative radiation and wide resection were identified from a prospective database. Pre- and post-radiation MRI scans were retrospectively reviewed. Radiological response was defined by the modified Response Evaluation Criteria in Solid Tumours. Local recurrence-free, metastasis-free (MFS) and overall survival (OS) were compared across response groups. RESULTS: Tumour volume decreased in 106 patients (34.3%; PR - partial responders), remained stable in 97 (31.4%; SD - stable disease), increased in 106 (34.3%; PD - progressive disease). The PD group were older (p = 0.007), had more upper extremity (p = 0.03) and high-grade tumours (p < 0.001). 81% of myxoid liposarcomas showed substantial decrease in size. There was no difference in initial tumour diameter (p = 0.5), type of surgery (p = 0.5), margin status (p = 0.4), or complications (p = 0.8) between the three groups. There were 10 (3.2%) local recurrences with no differences between the three response groups (p = 0.06). 5-year MFS was 52.1% for the PD group vs 73.8 and 78.5% for the PR and SD groups, respectively (p < 0.001). OS was similar (p < 0.001). Following multivariable analysis, worse MFS and OS were associated with higher grade, larger tumour size at diagnosis and tumour growth following pre-operative radiation. Older age was also associated with worse OS. CONCLUSION: STS that enlarge according to Response Evaluation Criteria in Solid Tumour criteria following pre-operative radiotherapy identify a high risk group of patients with worse systemic outcomes but equivalent local control. ADVANCES IN KNOWLEDGE: Post-radiation therapy, STS enlargement may identify patients with potential for worse systemic outcomes but equivalent local control. Therefore, adjunct therapeutic approaches could be considered in these patients.

Chemically driven energetic molecular ferroelectrics.

Chemically driven thermal wave triggers high energy release rate in covalently-bonded molecular energetic materials. Molecular ferroelectrics bridge thermal wave and electrical energy by pyroelectric associated with heating frequency, thermal mass and heat transfer. Herein we design energetic molecular ferroelectrics consisting of imidazolium cations (energetic ion) and perchlorate anions (oxidizer), and describe its thermal wave energy conversion with a specific power of 1.8 kW kg-1. Such a molecular ferroelectric crystal shows an estimated detonation velocity of 7.20 ± 0.27 km s-1 comparable to trinitrotoluene and hexanitrostilbene. A polarization-dependent heat transfer and specific power suggests the role of electron-phonon interaction in tuning energy density of energetic molecular ferroelectrics. These findings represent a class of molecular ferroelectric energetic compounds for emerging energy applications demanding high power density.

3-Phonon Scattering Pathways for Vibrational Energy Transfer in Crystalline RDX.

A long-held belief is that shock energy induces initiation of an energetic material through an energy up-pumping mechanism involving phonon scattering through doorway modes. In this paper, a Fermi's golden rule-based 3-phonon theoretical analysis of energy up-pumping in RDX is presented that considers possible doorway pathways through which energy transfer occurs. On average, modes with frequencies up to 102 cm-1 scatter quickly and transfer over 99% of the vibrational energy to other low-frequency modes up to 102 cm-1 within 0.16 ps. These low-frequency modes scatter less than 0.5% of the vibrational energy directly to modes with significant nitrogen-nitrogen (NN) activity. The midfrequency modes from 102 to 1331 cm-1 further up-pump the energy to these modes within 5.6 ps. The highest-frequency modes scatter and redistribute a small fraction of the vibrational energy to all other modes, which last over 2000 ps. The midfrequency modes between 457 and 462 cm-1 and between 831 and 1331 cm-1 are the most critical for vibrational heating of the NN modes and phenomena, leading to initiation in energetics. In contrast, modes stimulated by the shock with frequencies up to 102 cm-1 dominate vibrational cooling of the NN modes.

Locally Optimizable Joint Embedding Framework to Design Nitrogen-rich Molecules that are Similar but Improved.

Deep learning has shown great potential for generating molecules with desired properties. But the cost and time required to obtain relevant property data have limited study to only a few classes of materials for which extensive data have already been collected. We develop a deep learning method that combines a generative model with a property prediction model to fuse small data of one class of molecules with larger data in another class. Common low-level physicochemical properties are jointly embedded into a latent space that can be used to design molecules in the smaller class. The chemical space around the molecules in the training set is explored through local gradient ascent optimization. Based on nine molecules from the original training set, nine new molecules are found to have improved properties while remaining structurally similar to the training molecules thereby easing requirements for entirely new synthesis routes. Validation is performed using an equilibrium thermochemistry code to verify the molecules and target properties. A specific example targeting the Chapman-Jouguet velocity and small data for nitrogen-rich molecules is shown. Despite the relative lack of nitrogen-rich molecule data, the results demonstrate that fusing and joint embedding with plentiful low nitrogen molecular data can produce higher generative performance than using the scarce data alone.

Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.

BACKGROUND: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches. OBJECTIVE: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT). DESIGN/SETTING/PARTICIPANTS: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible. INTERVENTIONS: All patients underwent [18F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT. OUTCOME MEASUREMENTS/STATISTICAL ANALYSIS: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and ß of 0.1. RESULTS: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed. CONCLUSIONS: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa. PATIENT SUMMARY: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.

Radiation Oncology Fellowship: a Value-Based Assessment Among Graduates of a Mature Program.

The University of Toronto - Department of Radiation Oncology (UTDRO) has had a well-established Fellowship Program for over 20 years. An assessment of its graduates was conducted to evaluate training experience and perceived impact on professional development. Graduates of the UTDRO Fellowship Program between 1991 and 2015 were the focus of our review. Current employment status was collected using online tools. A study-specific web-based questionnaire was distributed to 263/293 graduates for whom active e-mails were identified; questions focused on training experience, and impact on career progression and academic productivity. As a surrogate measure for the impact of UTDRO Fellowship training, a comparison of current employment and scholarly activities of individuals who obtained their Fellow of the Royal College of Physicians of Canada (FRCPC) designation in Radiation Oncology between 2000 and 2012, with (n = 57) or without (n = 230) UTDRO Fellowship training, was conducted. Almost all UTDRO Fellowship graduates were employed as staff radiation oncologists (291/293), and most of those employed were associated with additional academic (130/293), research (53/293), or leadership (68/293) appointments. Thirty-eight percent (101/263) of alumni responded to the online survey. The top two reasons for completing the Fellowship were to gain specific clinical expertise and exposure to research opportunities. Respondents were very satisfied with their training experience, and the vast majority (99%) would recommend the program to others. Most (96%) felt that completing the Fellowship was beneficial to their career development. University of Toronto, Department of Radiation Oncology Fellowship alumni were more likely to hold university, research, and leadership appointments, and author significantly more publications than those with FRCPC designation without fellowship training from UTDRO. The UTDRO Fellowship Program has been successful since its inception, with the majority of graduates reporting positive training experiences, benefits to scholarly output, and professional development for their post-fellowship careers. Key features that would optimize the fellowship experience and its long-term impact on trainees were also identified.

Curability of patients with lymph node metastases from extremity soft-tissue sarcoma.

BACKGROUND: Lymph node metastases (LNM) rarely occur in adult extremity soft-tissue sarcoma (STS), affecting approximately 5% of patients. To the authors' knowledge, few studies to date have evaluated the prognosis and survival of patients with LNM. METHODS: A retrospective review was performed of a single-center, prospectively collected STS database. Demographic, treatment, and oncologic data for patients with STS of the extremity with LNM were obtained from clinical and radiographic records. RESULTS: Of 2689 patients with extremity STS, a total of 120 patients (4.5%) were diagnosed with LNM. LNM occurred most frequently among patients diagnosed with clear cell sarcoma (27.6%), epithelioid sarcoma (21.9%), rhabdomyosarcoma (17.3%), angiosarcoma (14.0%), and extraskeletal myxoid chondrosarcoma (9.3%). A total of 98 patients (81.7%) underwent LNM surgical resection. Patients with isolated LNM had a greater 5-year overall survival (57.3%) compared with patients with American Joint Committee on Cancer (AJCC) eighth edition stage IV STS with only systemic metastases (14.6%) or both LNM and systemic disease (0%; P < .0001). Patients with isolated LNM had an overall survival rate (52.9%) similar to that of patients with localized AJCC stage III tumors (ie, large, high-grade tumors) (49.3%) (P = .8). Patients with late, isolated, metachronous LNM had a 5-year overall survival rate (61.2%) that was similar to that of patients with isolated synchronous LNM at the time of presentation (53.6%) (P = .4). CONCLUSIONS: Many different types of STS develop LNM. Patients with extremity STS with isolated LNM should not be considered as having stage IV disease as they are according to the current AJCC eighth edition classification because they have significantly better survival than those with systemic metastases. Patients with isolated, late, metachronous LNM have a survival similar to that of patients with isolated synchronous LNM at the time of presentation. LAY SUMMARY: The results of the current study demonstrated that patients diagnosed with isolated lymph node metastases have a prognosis similar to that of patients diagnosed with localized American Joint Committee on Cancer stage III soft-tissue sarcomas, which also equates to a significantly better overall survival compared with patients with systemic metastases. Therefore, the authors recommend modifications to the most recent eighth edition of the American Joint Committee on Cancer staging system to clearly distinguish patients with isolated lymph node metastases to acknowledge their better prognosis compared with those with systemic metastases.

[18F]DCFPyL PET-MRI/CT for unveiling a molecularly defined oligorecurrent prostate cancer state amenable for curative-intent ablative therapy: study protocol for a phase II trial.

INTRODUCTION: The oligometastatic (OM) disease hypothesis of an intermediate metastatic state with limited distant disease deposits amenable for curative therapies remains debatable. Over a third of prostate cancer (PCa) patients treated with radical prostatectomy and postoperative radiotherapy experience disease recurrence; these patients are considered incurable by current standards. Often the recurrence cannot be localised by conventional imaging (CT and bone scan). Combined anatomical imaging with CT and/or MR with positron emission tomography (PET) using a novel second-generation prostate-specific membrane antigen (PSMA) probe, [18F]DCFPyL, is a promising imaging modality to unveil disease deposits in these patients. A new and earlier molecularly defined oligorecurrent (OR) state may be amenable to focal-targeted ablative curative-intent therapies, such as stereotactic ablative radiotherapy (SABR) or surgery, thereby significantly delaying or completely avoiding the need for palliative therapies in men with recurrent PCa after maximal local treatments. METHODS AND ANALYSIS: This ongoing single-institution phase II study will enrol up to 75 patients total, to include up to 37 patients with response-evaluable disease, who have rising prostate-specific antigen (range 0.4-3.0 ng/mL) following maximal local therapies with no evidence of disease on conventional imaging. These patients will undergo [18F]DCFPyL PET-MR/CT imaging to detect disease deposits, which will then be treated with SABR or surgery. The primary endpoints are performance of [18F]DCFPyL PET-MR/CT, and treatment response rates following SABR or surgery. Demographics and disease characteristics will be summarised and analysed descriptively. Response rates will be described with waterfall plots and proportions. ETHICS AND DISSEMINATION: Ethics approval was obtained from the institutional Research Ethics Board. All patients will provide written informed consent. [18F]DCFPyL has approval from Health Canada. The results of the study will be disseminated by the principal investigator. Patients will not be identifiable as individuals in any publication or presentation of this study. TRIAL REGISTRATION NUMBERS: NCT03160794.

Designing a Rational Follow-Up Schedule for Patients with Extremity Soft Tissue Sarcoma.

PURPOSE: The risk of tumor recurrence after resection of soft tissue sarcoma (STS) necessitates surveillance in follow-up. The objective of this study was to determine the frequency/timing of metastasis and local recurrence following treatment for soft tissue sarcoma, and to use these data to justify an evidence-based follow-up schedule. METHODS: Utilizing a prospective database, a retrospective single center review was performed of all patients with minimum 2-year follow-up after resection of a localized extremity STS. Kaplan-Meier estimates were used to calculate the incidence of local recurrence and metastases on an annual basis for 10 years. RESULTS: We identified a total of 230 low-grade, 626 intermediate-grade and 940 high-grade extremity STS and a total of 721 events, 150 local recurrences and 571 metastases. Based on tumor size and grade, follow-up cohorts were developed that had similar metastatic risk. Using pre-determined thresholds for metastatic event, a follow-up schedule was established for each cohort. CONCLUSION: Based on our results we recommend that patients with small low-grade tumors undergo annual follow-up for 5 years following definitive local treatment. Patients with large low-grade tumors, small intermediate-grade and small high-grade tumors should have follow-up every 6 months for the first 2 years, then yearly to 10 years. Only patients with large intermediate- or high-grade tumors require follow-up every 3 months for the first 2 years, then every 6 months for years 3-5, followed by annually until 10 years.

The role of chemotherapy and radiotherapy in localized extraskeletal osteosarcoma.

PURPOSE: The role of chemotherapy (CT) and radiotherapy (RT) for management of extraskeletal osteosarcoma (ESOS) remains controversial. We examined disease outcomes for ESOS patients and investigated the association between CT/RT with recurrence and survival. PATIENTS AND METHODS: Retrospective review at 25 international sarcoma centers identified patients ≥18 years old treated for ESOS from 1971 to 2016. Patient/tumour characteristics, treatment, local/systemic recurrence, and survival data were collected. Kaplan-Meier survival and Cox proportional-hazards regression and cumulative incidence competing risks analysis were performed. RESULTS: 370 patients with localized ESOS treated definitively with surgery presented with mainly deep tumours (n = 294, 80%). 122 patients underwent surgical resection alone, 96 (26%) also received CT, 70 (19%) RT and 82 (22%) both adjuvants. Five-year survival for patients with localized ESOS was 56% (95% CI 51%-62%). Almost half of patients (n = 173, 47%) developed recurrence: local 9% (35/370), distant 28% (102/370) or both 10% (36/370). Considering death as a competing event, there was no significant difference in cumulative incidence of local or systemic recurrence between patients who received CT, RT, both or neither (local p = 0.50, systemic p = 0.69). Multiple regression Cox analysis showed a significant association between RT and decreased local recurrence (HR 0.46 [95% CI 0.26-0.80], p = 0.01). CONCLUSION: Although the use of RT significantly decreased local recurrences, CT did not decrease the risk of systemic recurrence, and neither CT, nor RT nor both were associated with improved survival in patients with localized ESOS. Our results do not support the use of CT; however, adjuvant RT demonstrates benefit in patients with locally resectable ESOS.

Low dose radiotherapy is associated with local complications but not disease control in sacral chordoma.

BACKGROUND: We reviewed the disease control and complications of the treatment of sacrococcygeal chordoma from four tertiary cancer centers with emphasis on the effects of radiotherapy in surgically treated patients. METHODS: A total of 193 patients with primary sacrococcygeal chordoma from 1990 to 2015 were reviewed. There were 124 males, with a mean age of 59 ± 15 years and a mean follow-up of 7 ± 4 years. Eighty-nine patients received radiotherapy with a mean total dose of 61.8 ± 10.9 Gy. RESULTS: The 10-year disease-free and disease-specific survival was 58% and 72%, respectively. Radiation was not associated with local recurrence (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.59-2.17; P = 0.71), metastases (HR, 0.93; 95% CI, 0.45-1.91; P = 0.85) or disease-specific survival (HR, 0.96; 95% CI, 0.46-2.00; P = 0.91). Higher doses (≥70 Gy; HR, 0.52; 95% CI, 0.20-1.32; P = 0.17) may be associated with reduced local recurrence. Radiotherapy was associated with wound complications (HR, 2.76; 95% CI, 1.64-4.82;, P < 0.001) and sacral stress fractures (HR, 4.73; 95% CI, 1.88-14.38; P < 0.001). CONCLUSIONS: In this multicenter review, radiotherapy was not associated with tumor outcome but associated with complications. The routine use of radiotherapy with en-bloc resection of sacrococcygeal chordomas should be reconsidered in favor of a selective, individualized approach with a radiation dose of ≥70 Gy.