NCCN Guidelines® Insights: Prostate Cancer, Version 3.2024.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

PSMA guided approach for bIoCHEmical relapse after prostatectomy- (PSICHE) trial (NCT05022914). Detection rate and treatment decision after 68Ga-PSMA PET/CT within a prospective study.

BACKGROUND: Ultrasensitive imaging has been demonstrated to influence biochemical relapse treatment. PSICHE is a multicentric prospective study, aimed at exploring detection rate with 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) and outcomes with a predefined treatment algorithm tailored to the imaging. METHODS: Patients affected by biochemical recurrence after surgery (prostate specific antigen [PSA] > 0.2 < 1 ng/mL) underwent staging with 68Ga-PSMA PET/CT. Management followed this treatment algorithm accordingly with PSMA results: prostate bed salvage radiotherapy (SRT) if negative or positive within prostate bed, stereotactic body radiotherapy (SBRT) if pelvic nodal recurrences or oligometastatic disease, androgen deprivation therapy (ADT) if nonoligometastatic disease. Chi-square test was used to evaluate the relationship between baseline features and rate of positive PSMA PET/CT. RESULTS: One hundred patients were enrolled. PSMA results were negative/positive in the prostate bed in 72 patients, pelvic nodal or extrapelvic metastatic disease were detected in 23 and 5 patients. Twenty-one patients underwent observation because of prior postoperative radiotherapy (RT)/treatment refusal. Fifty patients were treated with prostate bed SRT, 23 patients underwent SBRT to pelvic nodal disease, five patients were treated with SBRT to oligometastatic disease. One patient underwent ADT. NCCN high-risk features, stage > pT3 and ISUP score >3 reported a significantly higher rate of positive PSMA PET/CT after restaging (p = 0.01, p = 0.02, and p = 0.002). By quartiles of PSA, rate of positive PSMA PET/CT was 26.9% (>0.2; <0.29 ng/mL), 24% (>0.3; <0.37 ng/mL), 26.9% (>0.38; <0.51 ng/mL), and 34.7% (>0. 52; <0.98 ng/mL). CONCLUSIONS: PSICHE trial constitute a useful platform to collect data within a clinical framework where modern imaging and metastasis-directed therapy are integrated.

Body composition and mortality in men receiving prostate radiotherapy: A pooled analysis of NRG/RTOG 9406 and NRG/RTOG 0126.

PURPOSE: To validate the association between body composition and mortality in men treated with radiation for localized prostate cancer (PCa). Secondarily, to integrate body composition as a factor to classify patients by risk of all-cause mortality. MATERIALS AND METHODS: Participants of NRG/Radiation Therapy Oncology Group (RTOG) 9406 and NRG/RTOG 0126 with archived computed tomography were included. Muscle mass and muscle density were estimated by measuring the area and attenuation of the psoas muscles on a single slice at L4-L5. Bone density was estimated by measuring the attenuation of the vertebral body at mid-L5. Survival analyses, including Cox proportional hazards models, assessed the relationship between body composition and mortality. Recursive partitioning analysis (RPA) was used to create a classification tree to classify participants by risk of death. RESULTS: Data from 2066 men were included in this study. In the final multivariable model, psoas area, comorbidity score, baseline prostate serum antigen, and age were significantly associated with survival. The RPA yielded a classification tree with four prognostic groups determined by age, comorbidity, and psoas area. Notably, the classification among older (≥70 years) men into prognostic groups was determined by psoas area. CONCLUSIONS: This study strongly supports that body composition is related to mortality in men with localized PCa. The inclusion of psoas area in the RPA classification tree suggests that body composition provides additive information to age and comorbidity status for mortality prediction, particularly among older men. More research is needed to determine the clinical impact of body composition on prognostic models in men with PCa.

Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

Adjuvant and Salvage Radiotherapy after Prostatectomy: ASTRO/AUA Guideline Amendment 2018-2019.

PURPOSE: The purpose of this amendment is to incorporate newly-published literature into the original ASTRO/AUA Adjuvant and Salvage Radiotherapy after Prostatectomy Guideline and to provide an updated clinical framework for clinicians. MATERIALS AND METHODS: The original systematic review yielded 294 studies published between January 1990 and December 2012. In April 2018, the guideline underwent an amendment and incorporated 155 references that were published from January 1990 through December 2017. Two new key questions were added. One on the use of genomic classifiers and the other on the treatment of oligo-metastases with radiation post-radical prostatectomy. RESULTS: A new statement on the use of hormone therapy with salvage radiotherapy after radical prostatectomy was added and long-term data was used to update an existing statement on adjuvant radiotherapy. The balance of the guideline statements were re-affirmed and references were added to the existing literature base. A discussion on the use of genomic classifiers as a risk stratification tool was added to the future research discussion. No relevant data on oligo-metastases was found. CONCLUSIONS: Hormone therapy should be offered to patients who have had radical prostatectomy and who are candidates for salvage radiotherapy. The clinician should discuss possible short- and long-term side effects with the patient as well as the potential benefits of preventing recurrence. The decision to use hormone therapy should be made by the patient and a multi-disciplinary team of providers with full consideration of the patient's history, values, preferences, quality of life, and functional status.

Underutilization of brachytherapy and disparities in survival for patients with cervical cancer in California.

PURPOSE: The treatment for locally advanced cervical cancer is external beam radiation (EBRT), concurrent chemotherapy, and brachytherapy (BT). We investigated demographic and socioeconomic factors that influence trends in BT utilization and disparities in survival. METHODS: Using the California Cancer Registry, cervical cancer patients FIGO IB2-IVA from 2004 to 2014 were identified. We collected tumor, demographic and socioeconomic (SES) factors. We used multivariable logistic regression analysis to determine predictors of use of BT. Using Cox proportional hazards, we examined the impact of BT vs EBRT boost on cause specific (CSS) and overall survival (OS). RESULTS: We identified 4783 patients with FIGO stage 11% IB2; 32% II, 54% III, 3% IVA. Nearly half (45%) of patients were treated with BT, 18% were treated with a EBRT boost, and 37% had no boost. Stage II and III were more likely to be treated with BT (p = 0.002 and p = 0.0168) vs Stage IB2. As patients aged, the use of BT decreased. Using multivariate analysis, BT impacted CCS (HR 1.16, p = 0.0330) and OS (HR 1.14, p = 0.0333). Worse CSS was observed for black patients (p = 0.0002), low SES (p = 0.0263), stage III and IVA (p < 0.0001. Black patients, low and middle SES had worse OS, (p = 0.0003). CONCLUSIONS: The utilization of BT in locally advanced cervical cancer was low at 45%, with a decrease in CSS and OS. Black patients and those in low SES had worse CSS. As we strive for outcome improvement in cervical cancer, we need to target increasing access and disparities for quality and value.

The impact of concurrent granulocyte-macrophage colony-stimulating factor on quality of life in head and neck cancer patients: results of the randomized, placebo-controlled Radiation Therapy Oncology Group 9901 trial.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) conducted a randomized, placebo-controlled trial evaluating the efficacy of GM-CSF in reducing mucosal injury and symptom burden from curative radiotherapy for head and neck (H&N) cancer. METHODS: Eligible patients with H&N cancer receiving radiation encompassing ≥50 % of the oral cavity or oropharynx received subcutaneous GM-CSF or placebo. Quality of life (QoL) was assessed using the RTOG-modified University of Washington H&N Symptom Questionnaire at baseline 4, 13, 26, and 48 weeks from radiation initiation. RESULTS: Of 125 eligible patients, 114 were evaluable for QoL (58 GM-CSF, 56 placebo). Patient demographics, clinical characteristics, and baseline symptom scores were well balanced between the treatment arms. At the end of the acute period (13 weeks), patients in both arms reported negative change in total symptom score indicating increase in symptom burden relative to baseline (mean -18.4 GM-CSF, -20.8 placebo). There was no difference in change in total symptom score (p > 0.05) or change in mucous, pain, eating, or activity domain scores (p > 0.01) between patients in the GM-CSF and placebo arms. Analysis limited to patients treated per protocol or with an acceptable protocol deviation also found no difference in change in total symptom score (p > 0.05) or change in domain scores (p > 0.01) between treatment arms. Provider assessment of acute mucositis during treatment did not correlate with patient-reported mucous domain and total symptom scores (p > 0.05). CONCLUSION: GM-CSF administered concurrently during head and neck radiation does not appear to significantly improve patient-reported QoL symptom burden.

Noninferiority of Hypofractionated vs Conventional Postprostatectomy Radiotherapy for Genitourinary and Gastrointestinal Symptoms: The NRG-GU003 Phase 3 Randomized Clinical Trial.

Importance: No prior trial has compared hypofractionated postprostatectomy radiotherapy (HYPORT) to conventionally fractionated postprostatectomy (COPORT) in patients primarily treated with prostatectomy. Objective: To determine if HYPORT is noninferior to COPORT for patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms at 2 years. Design, Setting, and Participants: In this phase 3 randomized clinical trial, patients with a detectable prostate-specific antigen (PSA; ≥0.1 ng/mL) postprostatectomy with pT2/3pNX/0 disease or an undetectable PSA (<0.1 ng/mL) with either pT3 disease or pT2 disease with a positive surgical margin were recruited from 93 academic, community-based, and tertiary medical sites in the US and Canada. Between June 2017 and July 2018, a total of 296 patients were randomized. Data were analyzed in December 2020, with additional analyses occurring after as needed. Intervention: Patients were randomized to receive 62.5 Gy in 25 fractions (HYPORT) or 66.6 Gy in 37 fractions (COPORT). Main Outcomes and Measures: The coprimary end points were the 2-year change in score from baseline for the bowel and urinary domains of the Expanded Prostate Cancer Composite Index questionnaire. Secondary objectives were to compare between arms freedom from biochemical failure, time to progression, local failure, regional failure, salvage therapy, distant metastasis, prostate cancer-specific survival, overall survival, and adverse events. Results: Of the 296 patients randomized (median [range] age, 65 [44-81] years; 100% male), 144 received HYPORT and 152 received COPORT. At the end of RT, the mean GU change scores among those in the HYPORT and COPORT arms were neither clinically significant nor different in statistical significance and remained so at 6 and 12 months. The mean (SD) GI change scores for HYPORT and COPORT were both clinically significant and different in statistical significance at the end of RT (-15.52 [18.43] and -7.06 [12.78], respectively; P < .001). However, the clinically and statistically significant differences in HYPORT and COPORT mean GI change scores were resolved at 6 and 12 months. The 24-month differences in mean GU and GI change scores for HYPORT were noninferior to COPORT using noninferiority margins of -5 and -6, respectively, rejecting the null hypothesis of inferiority (mean [SD] GU score: HYPORT, -5.01 [15.10] and COPORT, -4.07 [14.67]; P = .005; mean [SD] GI score: HYPORT, -4.17 [10.97] and COPORT, -1.41 [8.32]; P = .02). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT vs COPORT for biochemical failure, defined as a PSA of 0.4 ng/mL or higher and rising (2-year rate, 12% vs 8%; P = .28). Conclusions and Relevance: In this randomized clinical trial, HYPORT was associated with greater patient-reported GI toxic effects compared with COPORT at the completion of RT, but both groups recovered to baseline levels within 6 months. At 2 years, HYPORT was noninferior to COPORT in terms of patient-reported GU or GI toxic effects. HYPORT is a new acceptable practice standard for patients receiving postprostatectomy radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03274687.

Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline.

PURPOSE: The purpose of this guideline is to provide a clinical framework for the use of radiotherapy after radical prostatectomy as adjuvant or salvage therapy. MATERIALS AND METHODS: A systematic literature review using the PubMed®, Embase, and Cochrane databases was conducted to identify peer-reviewed publications relevant to the use of radiotherapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed. RESULTS: Guideline statements are provided for patient counseling, the use of radiotherapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a re-staging evaluation. CONCLUSIONS: Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy (i.e., seminal vesicle invasion, positive surgical margins, extraprostatic extension) and should offer salvage radiotherapy to patients with prostatic specific antigen or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiotherapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiotherapy as well as the potential benefits of preventing recurrence. The decision to administer radiotherapy should be made by the patient and the multi-disciplinary treatment team with full consideration of the patient's history, values, preferences, quality of life, and functional status. Please visit the ASTRO and AUA websites (http://www.redjournal.org/webfiles/images/journals/rob/RAP%20Guideline.pdf and http://www.auanet.org/education/guidelines/radiation-after-prostatectomy.cfm) to view this guideline in its entirety, including the full literature review.

Interfraction motion of the vaginal apex during postoperative intensity modulated radiation therapy: are we missing the target?

OBJECTIVE: This study aimed to evaluate changes in vaginal cuff position and rectal distention during whole pelvic intensity modulated radiation therapy using daily image guidance for patients with gynecologic malignancies. MATERIALS AND METHODS: We reviewed 145 daily images from 5 patients treated with intensity modulated radiation therapy after total abdominal hysterectomy for endometrial or cervical cancer. A fiducial marker was placed in the vaginal cuff tissue before computed tomographic simulation. The 2008 ASTRO consensus guidelines for delineation of clinical target volumes were used to deliver 45 to 50 Gy to the target structures. Daily megavoltage computed tomographic images were reviewed and changes in position of the fiducial marker as compared to the initial planning scan were recorded in the anterior-posterior (AP), lateral, and superior-inferior dimensions. Changes in rectal distention were also recorded. The position of the fiducial marker relative to the planning target volumes was reviewed on each daily image. RESULTS: The average shifts of the gold seed in the AP, lateral, and superior-inferior dimensions were 7 mm (range, 0-28 mm), 3 mm (range, 0-7 mm), and 2.9 mm (range, 0-12 mm), respectively. Distention of the rectum ranged from 20.5 to 60.1 mm and correlated with movement of the gold seed in the AP dimension (R = 0.53). For 2 patients, the fiducial marker was within 5 mm of the planning target volume margin on 8/40 treatments, or outside the planning target volume on 4/40 treatments. This did not significantly impact total delivered dose to the planning target volume. CONCLUSIONS: Daily image guidance confirms significant interfraction movement of the vaginal cuff tissue, which may exceed suggested guidelines for clinical target volume margins.

The impact of maximum rectal distention and tandem angle on rectal dose delivered in 3D planned gynecologic high dose-rate brachytherapy.

OBJECTIVE: Computed tomography-based treatment planning for cervical cancer has allowed investigation into the volumetric radiation dose delivered to the rectum. The goal of intracavitary brachytherapy is to maximize the tumor dose while decreasing the dose to normal tissue like the rectum. We investigated the effects of tandem angle and maximum rectal distention on rectal dose delivered in HDR brachytherapy for locally advanced cervical cancer. MATERIALS AND METHODS: Between July 2007 and January 2010, 97 brachytherapy treatment planning computed tomographic scans from the first and last implant of 51 patients with locally advanced cervical cancer were reviewed. The rectum was manually contoured from the ischial tuberosity to the bottom of the sacroiliac joint. The maximum rectal distention was determined by measuring the largest anterior-posterior diameter of the rectum superior to the tandem ring and inferior to the end of the applicator. A volumetric measurement of the maximum and mean rectal dose, dose to 2 cc (D2cc), dose to 1cc (D1cc) of the rectum was calculated. The tandem angle and the Internal Commission on Radiation Units and Measurement rectal point were recorded, and a dose volume histogram was referenced. RESULTS: The mean maximum rectal distention was 3.01 cm. The mean D1cc, D2cc, mean rectal dose, maximum rectal dose, and Internal Commission on Radiation Units and Measurement rectal dose were 3.03 Gy, 2.78 Gy, 4.19 cGy, 1.40 cGy, and 2.99 Gy per treatment, respectively. In a multivariate analysis controlling for surface area, tandem angle, and body mass index, there was a significant increase in D2cc with increasing rectal distention (P = 0.016). There were no significant findings when observing the effects of tandem angle on D2cc. CONCLUSION: Rectal distention significantly affects D2cc delivered in HDR brachytherapy. In contrast, tandem angle does not. Concerted efforts to decrease rectal distention should be considered during treatment planning and delivery.

Ribonucleotide reductase expression in cervical cancer: a radiation therapy oncology group translational science analysis.

OBJECTIVE: To evaluate pretherapy ribonucleotide reductase (RNR) expression and its effect on radiochemotherapeutic outcome in women with cervical cancer. METHODS/MATERIALS: Pretherapy RNR M1, M2, and M2b immunohistochemistry was done on cervical cancer specimens retrieved from women treated on Radiation Therapy Oncology Group (RTOG) 0116 and 0128 clinical trials. Enrollees of RTOG 0116 (node-positive stages IA-IVA) received weekly cisplatin (40 mg/m(2)) with amifostine (500 mg) and extended-field radiation then brachytherapy (85 Gy). Enrollees of RTOG 0128 (node-positive or bulky ≥5 cm, stages IB-IIA or stages IIB-IVA) received cisplatin (75 mg/m(2)) on days 1, 23, and 43 and 5-FU (1 g/m(2) for 4 days) during pelvic radiation then brachytherapy (85 Gy), plus celecoxib (400 mg twice daily, day 1 through 1 year). Disease-free survival (DFS) was estimated univariately by the Kaplan-Meier method. Cox proportional hazards models evaluated the impact of RNR immunoreactivity on DFS. RESULTS: Fifty-one tissue samples were analyzed: 13 from RTOG 0116 and 38 from RTOG 0128. M1, M2, and M2b overexpression (3+) frequencies were 2%, 80%, and 47%, respectively. Low-level (0-1+, n = 44/51) expression of the regulatory subunit M1 did not associate with DFS (P = 0.38). High (3+) M2 expression occurred in most (n = 41/51) but without impact alone on DFS (hazard ratio, 0.54; 95% confidence interval, 0.2-1.4; P = 0.20). After adjusting for M2b status, pelvic node-positive women had increased hazard for relapse or death (hazard ratio, 5.5; 95% confidence interval, 2.2-13.8; P = 0.0003). CONCLUSIONS: These results suggest that RNR subunit expression may discriminate cervical cancer phenotype and radiochemotherapy outcome. Future RNR biomarker studies are warranted.

Stereotactic Body Radiation Therapy and Abiraterone Acetate for Patients Affected by Oligometastatic Castrate-Resistant Prostate Cancer: A Randomized Phase II Trial (ARTO).

PURPOSE: ARTO (ClinicalTrials.gov identifier: NCT03449719) is a multicenter, phase II randomized clinical trial testing the benefit of adding stereotactic body radiation therapy (SBRT) to abiraterone acetate and prednisone (AAP) in patients with oligometastatic castrate-resistant prostate cancer (CRPC). MATERIALS AND METHODS: All patients were affected by oligometastatic CRPC as defined as three or less nonvisceral metastatic lesions. Patients were randomly assigned 1:1 to receive either AAP alone (control arm) or AAP with concomitant SBRT to all the sites of disease (experimental arm). Primary end point was the rate of biochemical response (BR), defined as a prostate-specific antigen (PSA) decrease ≥50% from baseline measured at 6 months from treatment start. Complete BR (CBR), defined as PSA < 0.2 ng/mL at 6 months from treatment, and progression-free survival (PFS) were secondary end points. RESULTS: One hundred and fifty-seven patients were enrolled between January 2019 and September 2022. BR was detected in 79.6% of patients (92% v 68.3% in the experimental v control arm, respectively), with an odds ratio (OR) of 5.34 (95% CI, 2.05 to 13.88; P = .001) in favor of the experimental arm. CBR was detected in 38.8% of patients (56% v 23.2% in the experimental v control arm, respectively), with an OR of 4.22 (95% CI, 2.12 to 8.38; P < .001). SBRT yielded a significant PFS improvement, with a hazard ratio for progression of 0.35 (95% CI, 0.21 to 0.57; P < .001) in the experimental versus control arm. CONCLUSION: The trial reached its primary end point of biochemical control and PFS, suggesting a clinical advantage for SBRT in addition to first-line AAP treatment in patients with metastatic castration-resistant prostate cancer.

Early biochemical outcomes following PSMA guided approach for bIoCHEmical relapse after prostatectomy-PSICHE trial (NCT05022914): preliminary results.

PSICHE (NCT05022914) is a prospective trial to test a [68Ga]Ga- PSMA-11 PET/CT imaging tailored strategy. All evaluable patients had biochemical relapse after surgery and underwent centralized [68Ga]Ga-PSMA-11 PET/CT imaging. The treatment was performed according pre-defined criteria. Observation and re-staging at further PSA progression were proposed to patients with negative PSMA and previous postoperative RT. Prostate bed SRT was proposed to all patients with a negative staging or positive imaging within prostate bed. Stereotactic body radiotherapy (SBRT) to all sites of disease was used for all patients with pelvic nodal recurrence (nodal disease < 2 cm under aortic bifurcation) or oligometastatic disease. At 3 months after treatment, 54.7% of patients had a complete biochemical response Only 2 patients experienced G2 Genitourinary toxicity. No G2 Gastrointestinal toxicity was recorded. A PSMA targeted treatment strategy led to encouraging results and was well tolerated.

Prospective Correlation of Magnetic Resonance Tumor Regression Grade With Pathologic Outcomes in Total Neoadjuvant Therapy for Rectal Adenocarcinoma.

PURPOSE: Total neoadjuvant therapy (TNT) is a newly established standard treatment for rectal adenocarcinoma. Current methods to communicate magnitudes of regression during TNT are subjective and imprecise. Magnetic resonance tumor regression grade (MR-TRG) is an existing, but rarely used, regression grading system. Prospective validation of MR-TRG correlation with pathologic response in patients undergoing TNT is lacking. Utility of adding diffusion-weighted imaging to MR-TRG is also unknown. METHODS: We conducted a multi-institutional prospective imaging substudy within NRG-GI002 (ClinicalTrials.gov identifier: NCT02921256) examining the ability of MR-based imaging to predict pathologic complete response (pCR) and correlate MR-TRG with the pathologic neoadjuvant response score (NAR). Serial MRIs were needed from 110 patients. Three radiologists independently, then collectively, reviewed each MRI for complete response (mriCR), which was tested for positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity with pCR. MR-TRG was examined for association with the pathologic NAR score. All team members were blinded to pathologic data. RESULTS: A total of 121 patients from 71 institutions met criteria: 28% were female (n = 34), 84% White (n = 101), and median age was 55 (24-78 years). Kappa scores for T- and N-stage after TNT were 0.38 and 0.88, reflecting fair agreement and near-perfect agreement, respectively. Calling an mriCR resulted in a kappa score of 0.82 after chemotherapy and 0.56 after TNT reflected near-perfect agreement and moderate agreement, respectively. MR-TRG scores were associated with pCR (P < .01) and NAR (P < .0001), PPV for pCR was 40% (95% CI, 26 to 53), and NPV was 84% (95% CI, 75 to 94). CONCLUSION: MRI alone is a poor tool to distinguish pCR in rectal adenocarcinoma undergoing TNT. However, the MR-TRG score presents a now validated method, correlated with pathologic NAR, which can objectively measure regression magnitude during TNT.

Down-regulation of microRNA 106b is involved in p21-mediated cell cycle arrest in response to radiation in prostate cancer cells.

BACKGROUND: microRNAs (miRNAs) are endogenous short non-coding RNAs, and play a pivotal role in regulating of a variety of cellular processes, including proliferation and apoptosis, both of which are cellular responses to radiation treatment. The purpose of this study is to identify candidate miRNAs whose levels are altered in response to radiation in prostate cancer cells and to investigate the molecular pathway of such miRNAs in the regulation of radiation-induced cellular response. METHODS: Using a miRNA microarray assay, we screened 132 cancerous miRNAs in LNCaP cells in response to radiation treatment. The function of one candidate miRNA was investigated for checkpoint protein expression, cell cycle arrest, cell proliferation, and cell survival in cells transfected with precursor or antisense miRNA. RESULTS: In response to radiation, multiple miRNAs, including mi-106b, showed altered expression. Cells transfected with precursor miR-106b were able to suppress radiation-induced p21 activation. Functionally, exogenous addition of precursor miR-106b overrode the G2/M arrest in response to radiation and resulted in a transient diminishment of radiation-induced growth inhibition. CONCLUSION: We have shown a novel role of miR-106b, in the setting of radiation treatment, in regulating the p21-activated cell cycle arrest. Our finding that miR-106b is able to override radiation-induced cell cycle arrest and cell growth inhibition points to a potential therapeutic target in certain prostate cancer cells whose radiation resistance is likely due to consistently elevated level of miR-106b.

Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Initial Results From the Pembrolizumab Arm of a Phase 2 Randomized Clinical Trial.

IMPORTANCE: Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed. OBJECTIVE: To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020. INTERVENTIONS: Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. MAIN OUTCOMES AND MEASURES: The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety). RESULTS: A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found. CONCLUSIONS AND RELEVANCE: Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02921256.

Clinical feasibility of MR-assisted CT-based cervical brachytherapy using MR-to-CT deformable image registration.

PURPOSE: The purpose of this study is to evaluate the feasibility of using deformable image registration algorithms to improve high-dose-rate high-risk clinical target volume (HR-CTV) delineation between preapplicator implantation MRI (pre-MRI) and postapplicator implantation CT (post-CT) in the treatment of locally advanced cervical cancer (LACC). METHOD AND MATERIALS: Twenty-six patients were identified for the study. Regions of interest were segmented on MRI and CT. A HR-CTV was delineated on pre-MRI and compared with the previously contoured HR-CTV on the post-CT. Two commercially available algorithms, ANACONDA (anatomically constrained) and MORFEUS (biomechanical model based) with various controlling structure settings, including the cervix, uterus, etc., were used to deform pre-MRI to post-CT. MRI-to-CT deformed targets are denoted as HR-CTV'. Quantitative deformation metrics include Dice index, distance to agreement, and center of mass displacement. Qualitative clinical usefulness of deformations was scored based on HR-CTV identification on CT images. RESULTS: For ANACONDA and MORFEUS deformations, using a cervix controlling region of interest resulted in the highest Dice, lowest distance to agreement, and lowest center of mass displacement for HR-CTV'. With MORFEUS deformations, the deformed HR-CTV' proved clinically useful in 23 patients. CONCLUSIONS: Prebrachytherapy implantation MRI can aid target contours for CT-based brachytherapy through ANACONDA or MORFEUS algorithms with appropriate parameter selection for LACC patients.

Effect and Safety of Radiation Therapy Boost to Extramesorectal Lymph Nodes in Rectal Cancer.

PURPOSE: In rectal cancer, the presence of extramesorectal/lateral pelvic lymph node (LPN) is associated with higher risk of locoregional and distant recurrences. LPNs are not typically resected during a standard total mesorectal excision (TME) procedure, and the optimal management for these patients is controversial. We assessed the safety and efficacy of adding a radiation therapy boost to clinically positive LPN during neoadjuvant chemoradiation therapy for rectal cancer. METHODS AND MATERIALS: We analyzed nonmetastatic, lymph node positive rectal adenocarcinoma patients treated with neoadjuvant chemoradiation therapy followed by TME between May 2011 and February 2018. Patients without LPN involvement received external beam radiation therapy (45 Gy in 25 fractions) to the primary tumor and regional draining lymph node basins followed by a boost (5.4 Gy in 3 fractions) to gross disease. Patients with clinically positive LPN that would not be removed during TME received an additional boost (up to a total dose between 54.0 and 59.4 Gy) to the involved LPNs. We compared locoregional control, overall survival, progression-free survival, and treatment-related toxicity between these 2 groups. RESULTS: Fifty-three patients were included in this analysis with median follow-up of 30.6 months for the LPN- group (n = 41) and 19.9 months for the LPN+ group (n = 12). There was no difference in 3-year overall survival (90.04% vs 83.33%, P = .890) and progression-free survival (80.12% vs 80.21%, P = .529) between the 2 groups. We did not observe any LPN recurrences. There were no differences in rates of acute grade 3+ or chronic toxicities. CONCLUSIONS: Despite the well-documented negative prognostic effect of LPN metastasis, we observed promising outcomes for LPN+ patients treated with an additional radiation boost. Our results suggest that radiation therapy boost to clinically involved, unresected LPN is an effective treatment approach with limited toxicity. Additional studies are needed to optimize treatment strategies for this unique patient subset.