Outcomes after high-dose radiation in the management of neuroendocrine neoplasms.

BACKGROUND: Neuroendocrine neoplasms (NENs) comprise a rare and heterogenous group of cancers, for which the role of radiation therapy continues to evolve. The purpose of this study is to analyze oncologic outcomes after the use of high-dose radiation in management of NENs at a tertiary hospital. MATERIALS AND METHODS: We performed a retrospective review of patients who received high-dose radiation with intent to cure or provide durable local control (defined as biologically effective dose (BED) ≥40, α/ß = 10) for a localized or metastatic NEN from 2006 to 2019. Evaluation of disease status after radiation was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria when possible. Patients were grouped by differentiation (well-differentiated (WD) or poorly-differentiated (PD)) and stage (localized/locally advanced disease (L) or metastatic (M)) in analysis of probabilities of progression after radiation. RESULTS: 45 patients completed a radiation course with BED ≥40 for a NEN (median BED 72). With a median follow-up of 24 months after radiation, the 2-year actuarial rates of local relapse-free survival, new metastasis-free survival, progression-free survival, and overall survival after radiation were 98%, 45%, 41%, and 69%, respectively. 25 patients (56%) developed new metastases after completion of radiation, including 33% (n = 3) of patients with WD-L disease, 44% (n = 8) of WD-M, 77% (n = 10) of PD-L, and 80% (n = 4) of PD-M, with progressively shorter median times to progression (26, 9, 8, and 3 months, respectively; p = 0.093). Of the 25 patients evaluable by RECIST, 68% (n = 17) achieved either a complete or partial best response in the irradiated lesion. CONCLUSIONS: These data suggest that focal, high-dose radiation has a role in the management of selected patients with NENs. Local failure is rare in patients with both well-differentiated and poorly-differentiated disease, although the predominant pattern of failure remains development of new metastases.

An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses.

Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and immune cells leads to tumor resistance to oncolytic immunotherapy. In this study, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. We find that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.

Single-fraction brachytherapy as monotherapy for early-stage prostate cancer: The UCSF experience.

PURPOSE: High-dose-rate (HDR) brachytherapy as monotherapy is an effective treatment option for localized prostate cancer, but experience with single-fraction brachytherapy is limited by studies with small sample size. We report a large single-institution experience with single-fraction HDR brachytherapy as monotherapy for early-stage prostate cancer. METHODS AND MATERIALS: Retrospective chart review was performed for men treated with HDR brachytherapy as monotherapy for low- to intermediate-risk prostate cancer. Competing risk analyses were performed to estimate subdistribution hazard ratio and cumulative incidence of biochemical recurrence (BCR) and prostate cancer-specific mortality. RESULTS: We identified 124 men with a median followup of 2.2 years (interquartile range 25th to 75th percentile: 1.8-3). Overall, 21.0% of patients (n = 26) were low risk, 44.4% (n = 55) were favorable intermediate risk, and 34.7% (n = 43) were unfavorable intermediate risk. At 2 years, the cumulative incidence of BCR was 3.5%: 0% for low risk, 4.0% for favorable intermediate risk patients, and 4.5% for unfavorable intermediate risk patients. In total, 12 BCRs were observed (9.7%) and approximately half occurred after median followup of 2.2 years. Compared with low-risk and favorable intermediate-risk disease, unfavorable intermediate-risk disease was significantly associated with BCR (subdistribution hazard ratio: 3.6, 95% CI: 1.1 to 11.1, p = 0.03). Prostate cancer-specific mortality was 0%. No patient experienced Grade 3 or higher acute or late genitourinary toxicity. CONCLUSIONS: Single-fraction brachytherapy for early-stage prostate cancer was safe with promising short-term disease control rates, especially for low-risk patients. Longer term followup is needed as we observed an overall BCR rate of 9.7%.

Long-Term Patient-Reported Rectal Bleeding and Bowel-Related Quality of Life After Cs-131 Prostate Brachytherapy.

PURPOSE: There is limited long-term data on outcome and side effects of Cs-131 prostate brachytherapy and minimal patient-reported data on rectal bleeding with any isotope. We aimed to describe the incidence, prevalence, and predictors of late patient-reported rectal bleeding after Cs-131 brachytherapy. METHODS AND MATERIALS: We reviewed a prospectively collected database of 620 men treated with Cs-131 prostate brachytherapy. Of 620 patients, 390 (62.9%) received brachytherapy as monotherapy; the remainder received combination therapy with external beam radiation therapy (EBRT). Patients were administered Expanded Prostate Cancer Index Composite questionnaires preoperatively and postoperatively at each follow-up visit. The primary outcome was late rectal bleeding, defined as rectal bleeding reported at the 6-month follow-up or later. Clinically significant rectal bleeding was defined as occurring more than "rarely," and clinically significant bother from rectal bleeding was defined as considering bleeding more than a "very small problem." Univariate and multivariate Cox regression were performed to identify factors predictive for rectal bleeding. RESULTS: With a median follow-up time of 48 months, the cumulative incidence of clinically significant late rectal bleeding was 12.4%, with 15.2% reporting clinically significant bother from bleeding. At the time of last follow-up, the prevalence of clinically significant rectal bleeding and bother were 4.0% and 4.7%, respectively. On univariate analysis, acute clinically significant rectal bleeding, defined as occurring within the first 6 months (P = .001) and combination therapy with EBRT (P = .001) predicted for clinically significant late rectal bleeding. On multivariate analysis, both EBRT (P = .001; hazard ratio, 2.50; 95% confidence interval, 1.58-3.94) and acute rectal bleeding (P < .001; hazard ratio, 3.11; 95% confidence interval, 1.75-5.53) remained significant predictors for late rectal bleeding. CONCLUSIONS: Prostate brachytherapy with Cs-131 is well tolerated in the long term. Although the incidence of clinically significant patient-reported late rectal bleeding was 12.4%, the prevalence at last follow-up was only 4.0%, suggesting that this problem tends to resolve.

Neoadjuvant Chemoradiation Therapy Followed by Extrafascial Hysterectomy in Locally Advanced Type II Endometrial Cancer Clinically Extending to Cervix.

PURPOSE: The role of neoadjuvant chemoradiation therapy in locally advanced type II endometrial cancer is controversial. We thus aimed to present our experience with the hypothesis that neoadjuvant chemoradiation therapy is associated with similarly high rates of downstaging and locoregional control for type II endometrial cancer and type I endometrial cancer. METHODS AND MATERIALS: Thirty-four patients with type II endometrial cancer with clinical evidence of cervical ± parametrium involvement treated with neoadjuvant external beam radiation therapy (45-50.4 Gy in 25-28 fractions) and high-dose-rate brachytherapy with a median total dose of 20 Gy (range, 15-27.5) in 4 fractions (range, 3-5) and concurrent platinum chemotherapy ± adjuvant chemotherapy from 2008 to 2018 were retrospectively reviewed. Patients with type I pathologic diagnoses and those treated with definitive (rather than preoperative) intent were excluded. RESULTS: Pathologic characteristics were as follows: 38% were carcinosarcoma, 18% serous, and 24% clear cell. Ninety-four percent of patients were downstaged to an extrafascial hysterectomy, and 94% had negative surgical margins. The 2-year local control, regional control, distant control, disease-free survival, and overall survival were 87.8%, 81.3%, 76.3%, 52.5%, and 63.7%, respectively. There was 1 subacute grade 3 and 1 late grade 3 small bowel obstruction, directly attributable to radiation therapy. CONCLUSIONS: Neoadjuvant chemoradiation therapy effectively downstages the majority of locally advanced type II endometrial cancers, thereby increasing the likelihood of achieving complete resection with negative margins.

Utilizing clinical pathways and web-based conferences to improve quality of care in a large integrated network using breast cancer radiation therapy as the model.

BACKGROUND: Clinical pathways outline criteria for dose homogeneity and critical organ dosimetry. Based upon an internal audit showing suboptimal compliance with dosimetric parameters in whole breast irradiation (WBI), we conducted a mandatory web-based teaching conference for the network. This study reports the impact of this initiative on subsequent treatment plans. METHODS: Radiation treatment plans were collected for the 10 most recent patients receiving WBI at 16 institutions within the UPMC Hillman Cancer Center network. Subsequently, a web-based conference was conducted to educate staff physicians, physicists, and dosimetrists with goals for dose homogeneity and critical organ dosimetry. Six months post-conference, another 10 plans were collected from each site and compared to pre-conference plans for deviations from dosimetric criteria. RESULTS: Dose homogeneity significantly improved after the conference with breast V105% decreasing from 15.6% to 11.2% (p = 0.004) and breast V110% decreasing from 1.3% to 0.04% (p = 0.008). A higher percentage of cases were compliant with dosimetric criteria, with breast V105% > 20% decreasing from 22.5% to 7.5% of cases (p = 0.0002) and breast V110% > 0% decreasing from 13.8% to 4.4% of cases (p = 0.003). CONCLUSIONS: Implementation of a web-based teaching conference helped improve adherence to clinical pathway dosimetric guidelines for WBI. In radiation oncology networks, this may be an effective model to ensure quality in routine practice and can be extrapolated to other disease sites.

Outcomes of stage II endometrial cancer: The UPMC Hillman Cancer Center experience.

PURPOSE: Previous studies of stage II endometrial cancer have included cancers with cervical glandular involvement, a factor no longer associated with risk of recurrence. In order to better assess relapse patterns and the impact of adjuvant therapy, a retrospective analysis was conducted for patients with modern stage II endometrial cancer, defined as cervical stromal invasion. MATERIALS AND METHODS: Patients diagnosed with surgically staged FIGO stage II endometrial cancer at the UPMC Hillman Cancer Center from 1990-2013 were reviewed. Factors associated with rates of locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) were analyzed using the log rank test. RESULTS: 110 patients with FIGO stage II disease were identified. Most (84.5%) received EBRT±BT, with 13.6% receiving BT alone. With a median follow-up of 64.6months, the 5-year actuarial rates of LRC, DM, DFS, and OS were 94.9%, 85.1%, 67.9%, and 75.0%, respectively. With 5 locoregional failures, the only factor predictive of LRC was pelvic lymph node dissection. Characteristics associated with DM included age, LVSI, depth of myometrial invasion, and receipt of chemotherapy. Factors predictive of both DFS and OS were age, grade, adverse histology, LVSI, depth of myometrial invasion, and receipt of chemotherapy. CONCLUSIONS: This represents the largest single-institution study for modern stage II endometrial cancer, confirming high rates of pelvic disease control after surgery and adjuvant therapy. With most patients receiving adjuvant radiotherapy, the predominant mode of failure, albeit low in absolute number, remains distant metastases.

Differences in urethral dosimetry between CT and MR imaging in multichannel vaginal cylinder brachytherapy.

PURPOSE: In image-based brachytherapy (IBBT), the dosimetry of small structures may be particularly sensitive to changes in contouring between imaging modalities. We therefore sought to characterize differences in urethral dosimetry in vaginal brachytherapy based on contouring on MRI vs. CT. METHODS AND MATERIALS: We retrospectively identified our most recent 15 patients treated with intracavitary brachytherapy for distal vaginal malignancies. On T2-weighted MRI, both the lumen and urethral wall were contoured. On CT, the urethral lumen alone was contoured, as the wall is indistinguishable from surrounding tissue. High-dose-rate (HDR) IBBT plans were generated for all patients. RESULTS: Mean urethral volume was higher on MRI than CT at 3.7 cc vs. 1.1 cc (p < 0.0005). As a result, there were statistically significant increases on MRI in D0.1cc and D0.5cc, as well as EQD2 D0.1cc and EQD2 D0.5cc when applied to a full course of treatment (45 Gy EBRT + 25 Gy IBBT). CONCLUSIONS: We have quantified the expected differences in urethral volume and dosimetry when contoured on MRI vs. CT. Inclusion of the urethral wall on MRI, with its average thickness of 2.2 mm, likely more accurately reflects the true organ at risk and results in an increase in reported dose compared to CT.

Long-Term Quality of Life in Prostate Cancer Patients Treated With Cesium-131.

PURPOSE: To evaluate long-term patient-reported quality of life (QOL) scores in men with prostate cancer treated at our institution with 131Cs prostate brachytherapy. METHODS AND MATERIALS: Patients treated more than 4 years ago with 131Cs (n=290) were asked to fill out an Expanded Prostate Cancer Index Composite (EPIC) QOL questionnaire and American Urological Association Symptom Score (AUASS) survey, before treatment and at each follow-up appointment. We compared patients' EPIC and AUA scores at baseline with scores at a last follow-up of at least 4 years after treatment using the Wilcoxon signed-rank test. RESULTS: At a median last follow-up of 5.5 years after treatment with 131Cs prostate brachytherapy there were no clinically significant changes in the EPIC or AUA scores from baseline. There was statistical worsening in the EPIC urinary incontinence subscore. Subset analyses revealed improved QOL outcomes in patients who received external beam radiation therapy or α-blocker therapy, whereas androgen deprivation therapy was not associated with differences in QOL change. CONCLUSIONS: Our results demonstrate minimal long-term changes in urinary or bowel patient-reported QOL with 131Cs prostate brachytherapy. These findings suggest that patients treated with this isotope are able to recover and then maintain their baseline QOL in the long term.

Circulating tumor DNA detection in lung cancer patients before and after surgery.

Circulating tumor DNA (ctDNA) in peripheral blood is a "liquid biopsy" that contains representative tumor information including gene mutations. Additionally, repeated ctDNA samples can be easily obtained to monitor response to treatment and disease progression, which may be especially valuable to lung cancer patients with tumors that cannot be easily biopsied or removed. To investigate the changes in ctDNA after surgical tumor resection, tumor and blood samples obtained before and after surgery were collected prospectively from 41 non-small lung cancer (NSCLC) patients. Somatic driver mutations in tumor DNA (tDNA) and pre- and post-op plasma ctDNA sample pairs were identified by targeted sequencing in several genes including EGFR, KRAS, and TP53 with an overall study concordance of 78.1% and sensitivity and specificity of 69.2% and 93.3%, respectively. Importantly, the frequency of 91.7% of ctDNA mutations decreased after surgery and these changes were observed as little as 2 days post-op. Moreover, the presence of ctDNA had a higher positive predictive value than that of six tumor biomarkers in current clinical use. This study demonstrates the use of targeted sequencing to reliably identify ctDNA changes in response to treatment, indicating a potential utility of this approach in the clinical management of NSCLC.

Positive enteric contrast material for abdominal and pelvic CT with automatic exposure control: what is the effect on patient radiation exposure?

OBJECTIVE: To assess the effect of positive enteric contrast administration on automatic exposure control (AEC) CT radiation exposure in (1) a CT phantom, and (2) a retrospective review of patients. MATERIALS AND METHODS: We scanned a CT phantom containing simulated bowel that was sequentially filled with water and positive enteric contrast, and recorded the mean volume CT dose index (CTDIvol). We also identified 17 patients who had undergone 2 technically comparable CT scans of the abdomen and pelvis, one with positive enteric contrast and the other with oral water. Paired Student's t-tests were used to compare the mean CTDIvol between scans performed with and without positive enteric contrast. Both the phantom and patient CT scans were performed using AEC with a fixed noise index. RESULTS: The mean CTDIvol for the phantom with simulated bowel containing water and positive enteric contrast were 8.2 ± 0.2 mGy, and 8.7 ± 0.1 mGy (6.1% higher than water, p=0.02), respectively. The mean CTDIvol for patients scanned with oral water and with positive enteric contrast were 11.8 mGy and 13.1 mGy, respectively (p=0.003). This corresponded to a mean CTDIvol which was 11.0% higher (range: 0.0-20.7% higher) in scans with positive enteric contrast than those with oral water in patients. CONCLUSIONS: When automatic exposure control is utilized for abdominopelvic CT, the radiation exposure, as measured by CTDIvol, is higher for scans performed with positive enteric contrast than those with oral water.

Naltrexone aversion and treatment efficacy are greatest in humans and rats that actively consume high levels of alcohol.

The opioid antagonist naltrexone is the standard pharmacotherapy for alcoholism, although compliance is often low. The mechanism by which naltrexone reduces drinking is yet unclear. Here we show that in active alcoholics the magnitude of naltrexone treatment efficacy is correlated with the level of naltrexone-induced aversive side effects. This correlation is not observed when subjects are sober, but emerges following alcohol administration, when subjects are intoxicated. In contrast, there is no correlation following placebo administration. To clarify these results, naltrexone was administered to ethanol-consuming rats prior to quantification of naltrexone aversion. Ethanol consumption preceding naltrexone treatment was again correlated with subsequent naltrexone-induced aversion, and this aversion correlated with subsequent decrease in ethanol consumption. In contrast, when naltrexone was given to ethanol-free rats, aversion was not predictive of ethanol consumption. We conclude that naltrexone treatment efficacy is greater during active ethanol consumption and may be partly due to aversive side effects.

Cholecystokinin is necessary for the expression of morphine conditioned place preference.

There is evidence that the neuropeptide cholecystokinin (CCK) is important for the rewarding effects of drugs of abuse. However, less is known regarding the role of CCK in drug seeking and craving. The present study investigated whether the CCK(B) antagonist L-365, 260 could block morphine-induced drug seeking using the conditioned place preference paradigm and whether the dopaminergic reward pathway contributes to the effect of L-365, 260 on expression of morphine place preference. We found that systemic administration of the CCK(B) antagonist L-365, 260 attenuates the expression of morphine-induced drug seeking as assessed using conditioned place preference (CPP) and shows that this effect is mediated by CCK(B) receptors in the anterior nucleus accumbens (NAcc). Additionally, we demonstrate that this effect is dependent on D(2) receptor activation in the anterior nucleus accumbens (NAcc). These results indicate that endogenous CCK modulates the incentive-salience of morphine-associated cues and suggest that CCK antagonists may be useful in the treatment of drug craving.