Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders.

Prolactin (PRL) has recently been demonstrated to elicit female-selective nociceptor sensitization and increase pain-like behaviors in female animals. Here we report the discovery and characterization of first-in-class, humanized PRL neutralizing monoclonal antibodies (PRL mAbs). We obtained two potent and selective PRL mAbs, PL 200,031 and PL 200,039. PL 200,031 was engineered as human IgG1 whereas PL 200,039 was reformatted as human IgG4. Both mAbs have sub-nanomolar affinity for human PRL (hPRL) and produce concentration-dependent and complete inhibition of hPRL signaling at the hPRL receptor (hPRLR). These two PRL mAbs are selective for hPRL as they do not inhibit other hPRLR agonists such as human growth hormone or placental lactogen. They also cross-react with non-human primate PRL but not with rodent PRL. Further, both mAbs show long clearance half-lives after intravenous administration in FcRn-humanized mice. Consistent with their isotypes, these mAbs only differ in binding affinities to Fcγ receptors, as expected by design. Finally, PL 200,019, the murine parental mAb of PL 200,031 and PL 200,039, fully blocked stress-induced and PRL-dependent pain behaviors in female PRL-humanized mice, thereby providing in vivo preclinical proof-of-efficacy for PRL mAbs in mechanisms relevant to pain in females.

Optimal overall treatment time for adjuvant therapy for women with completely resected, node-positive vulvar cancer.

INTRODUCTION: The optimal overall treatment time (OTT) from radical surgery to the end of adjuvant radiation therapy for some squamous cell carcinomas has been found to impact treatment outcomes. This study aims to identify the impact of OTT on overall survival (OS) for women with completely resected, node-positive squamous cell carcinomas of the vulva. MATERIALS AND METHODS: The National Cancer Data Base was queried for women with surgically resected, node-positive vulvar squamous cell carcinomas between 2004 and 2016 who were treated with adjuvant radiation therapy. Kaplan-Meier analysis with log-rank test and Cox proportional hazards tests were utilized for OS calculations. RESULTS: A total of 1500 women met inclusion criteria. The median OTT was 104 days. Shorter OTT was associated with age, facility volume, private insurance, and duration of post-operative hospitalization. Median OS with OTT ≤ 104 days was 56.1 months vs 45.4 months if ≥105 days (p = 0.015). On multivariable Cox analysis, OTT was independently associated with an increased risk of death of 0.4% per additional day (95%CI 1.001-1.007, p = 0.003), as were age at diagnosis (HR 1.031 [95%CI 1.024-1.037], p < 0.001), number of nodes positive (HR 1.031 [95%CI 1.024-1.037], p = 0.006), the use of concurrent chemotherapy (HR 0.815 [95%CI 0.693-0.960], p = 0.014) and increasing pT/pN stage. After propensity adjustment for factors predicting a shorter OTT, OTT continued to be associated with an increased risk of death per additional day (HR 1.004 [95%CI 1.001-1.007], p = 0.007). CONCLUSION: Overall treatment time is an independent risk factor for death in women being treated with adjuvant radiation therapy following complete resection of node-positive squamous cell carcinoma of the vulva.

Complications of intracavitary brachytherapy for gynecologic cancers and their management: A comprehensive review.

Intracavitary gynecologic brachytherapy in the form of tandem-based brachytherapy and vaginal cylinder-based brachytherapy represents a fundamental component of the treatment of women with cervical or uterine cancer due to the ability to deliver a therapeutic dose of radiation with sharp dose falloff. This results in highly effective treatment in terms of oncologic outcomes with an overall favorable toxicity profile. Still, complications and side effects of brachytherapy do exist. While advances in brachytherapy techniques have led to a significant decrease in the rates of toxicity, a thorough understanding of the potential complications is crucial to ensuring optimal outcomes for women with gynecologic cancer undergoing brachytherapy. Use of equivalent dose at 2 Gy per fraction (EQD2) models has allowed incorporation of external beam radiotherapy dose to the brachytherapy dose leading to development of consolidated dose constraints for organs-at-risk in the modern era. This manuscript offers a comprehensive review of potential complications associated with intracavitary brachytherapy for gynecologic cancer including predictive factors, mitigation tactics, and management strategies.

Treatment selection and survival outcomes in Early-Stage peripheral T-Cell lymphomas: does anaplastic lymphoma kinase mutation impact the benefit of consolidative radiotherapy?

The role of consolidative radiotherapy (RT) is less substantiated in uncommon peripheral T-cell lymphomas (PTCLs). Anaplastic lymphoma kinase (ALK) mutation sub-categorizes PTCLs, with ALK (+) having a distinctly favorable prognosis. We aimed to use the National Cancer Database to examine the potential role of RT in PTCLs and if ALK mutation can be used to predict the benefit of consolidative RT after multi-agent chemotherapy (combined modality therapy). We identified 3670 stage I-II PTCL patients treated with multi-agent chemotherapy alone or combined modality therapy (CMT) between 1998-2012. After adjusting for immortal-time and indication bias, CMT was associated with better OS than multi-agent chemotherapy alone for ALK (-) patients (HR 0.69, 95% CI 0.52-0.92, p = .01); no significant difference was noted for ALK (+) (HR 1.03, 95% CI 0.75-1.41, p = .85). CMT is associated with improved OS for ALK (-) PTCLs; while no such benefit was seen for the ALK (+) subgroup.

Ureteral stenosis after 3D MRI-based brachytherapy for cervical cancer - Have we identified all the risk factors?

BACKGROUND AND PURPOSE: Ureteral stenosis (US) is a known complication from image-guided brachytherapy (IGBT); however, no dosimetric parameter has been associated with ureteral toxicity. We aimed to report the rate of late grade ≥3 US after MRI-based IGBT, and to identify clinical factors and dosimetric parameters predictive for US. MATERIALS AND METHODS: A retrospective review was performed on all cervical cancer patients treated with MRI-based IGBT between 2007 and 2017. Late grade ≥3 US was recorded according to CTCAE 4.03. The minimum dose to the maximally irradiated 0.1 cm3 of ureter (D0.1cm3) was extracted from dose-volume histograms. Binary logistic regression was performed to identify predictors of late grade ≥3 US. RESULTS: 242 patients with a median follow-up of 35.8 months (IQR, 19.2-60.8) were identified. Late grade ≥3 US occurred in 18 patients, and the actuarial 3-year rate was 7.3% (95% CI 3.3-11.3). After excluding patients with pre-existing hydronephrosis, late grade ≥3 US occurred in 11 patients with an actuarial 3-year rate of 4.4% (95% CI 1.7-7.1). Ureters with D0.1cm3 ≥77 Gy had a 28.6% incidence of late grade ≥3 US compared to 7.5% in those with D0.1cm3 <77 Gy (OR 2.39; 95% CI 1.23-4.65; p = 0.01). The incidence of late grade ≥3 US was 33.3%, and 40.0% for ureters receiving ≥85 and ≥90 Gy, to D0.1cm3, respectively. CONCLUSION: After MRI-based IGBT, there is an estimated 4.4% risk of developing late grade ≥3 US among patients without pre-existing hydronephrosis. Ureteral dose ≥77 Gy to D0.1cm3 correlates with development of late grade ≥3 US.

Race-driven survival differential in women diagnosed with endometrial cancers in the USA.

OBJECTIVE: African American women are increasingly being diagnosed with advanced and type II histology endometrial cancers. Outcomes have been observed to be worse in African American women, but whether or not race itself is a factor is unclear. We sought to evaluate the rates of diagnosis and outcomes on a stage-by-stage basis with respect to race using a large national cancer registry database. METHODS: The National Cancer Data Base was searched for patients with surgically staged non-metastatic endometrial cancer between 2004 and 2015. Women were excluded if surgical stage/histology was unknown, there was no follow-up, or no information on subsequent treatment. Pairwise comparison was used to determine temporal trends and Cox hazards tests with Bonferroni correction were used to determine overall survival. RESULTS: A total of 286 920 women were diagnosed with endometrial cancer and met the criteria for analysis. Median follow-up was 51 months (IQR 25.7-85.3). In multivariable models, in women with stage I disease, African American women had a higher risk of death than Caucasian women (HR 1.262, 95% CI 1.191 to 1.338, p<0.001) and Asian/Pacific Islander women had a lower risk of death than Caucasian women (HR 0.742, 95% CI 0.689 to 0.801, p<0.001). This held for African American women with stage II type I and type II disease (HR 1.26, 95% CI 1.109 to 1.444, p<0.001 and HR 1.235, 95% CI 1.098 to 1.388, p<0.001) but not for Asian/Pacific Islander women. African American women with stage IIIA-B disease also had a higher risk of death for type I and type II disease versus Caucasian women (HR 1.221, 95% CI 1.045 to 1.422, p=0.010 and HR 1.295, 95% CI 1.155 to 1.452, p<0.001). Asian/Pacific Islander women had a lower risk of death than Caucasian women with type I disease (HR 0.783, 95% CI 0.638 to 0.960, p=0.019) and type II disease (HR 0.790, 95% CI 0.624 to 0.999, p=0.05). African American women with stage IIIC1-2 had a higher risk of death with type I disease (HR 1.343, 95% CI 1.207 to 1.494, p<0.001) and type II disease (HR 1.141, 95% CI 1.055 to 1.233, p=0.001) whereas there was no significant difference between Caucasian women and Asian/Pacific Islander women. CONCLUSION: Race appears to play an independent role in survival from endometrial cancer in the USA, with African American women having worse survival on a stage-for-stage basis compared with Caucasian women.

A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.

Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition, and responses. We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform employing a pooled-protein strategy to test all 318,096 PPI combinations. Screen results, augmented by phylogenetic homology analysis, revealed ∼380 previously unreported PPIs. We validated a subset using surface plasmon resonance and cell binding assays. Observed PPIs reveal a large and complex network of interactions both within and across biological systems. We identified new PPIs for receptors with well-characterized ligands and binding partners for "orphan" receptors. New PPIs include proteins expressed on multiple cell types and involved in diverse processes including immune and nervous system development and function, differentiation/proliferation, metabolism, vascularization, and reproduction. These PPIs provide a resource for further biological investigation into their functional relevance and may offer new therapeutic drug targets.

Declining brachytherapy utilization for cervical cancer patients - Have we reversed the trend?

OBJECTIVE: Studies examining temporal trends in cervical brachytherapy use are conflicting and examined different health insurance populations. This study examined brachytherapy utilization over time by health insurance type and whether reported declines in brachytherapy have reversed. METHODS: The National Cancer Database (NCDB) was queried for patients with FIGO IIB-IVA cervical cancer treated with definitive chemoradiotherapy between 2004 and 2014, identifying 17,442 patients. Brachytherapy utilization over time and by insurance type and other sociodemographic factors were compared using binary logistic regression. A sensitivity analysis was done in a sub-cohort of patients using the boost modality variable in the NCDB. RESULTS: Brachytherapy utilization declined during 2008-10 (52.6%) compared to 2004-2007 (54.4%; odds ratio [OR] 0.93, 95% confidence interval [CI] 0.86-1.01) and declines were disproportionately larger for patients with government insurance (49.4% vs 52.3%, respectively) than privately-insured patients (57.6% vs 58.9%, respectively). However, rates of brachytherapy use subsequently recovered during 2011-14 in all insurance groups (58.0%, OR 1.24, 95% CI 1.16-1.34) and was especially improved for Medicaid (OR 1.44, 95% CI 1.26-1.65) and uninsured patients (OR 1.28, 95% CI 1.03-1.57). Sensitivity analysis using the boost modality variable confirmed these trends. CONCLUSIONS: In patients with FIGO IIB-IVA cervical cancer treated with definitive chemoradiotherapy from 2004 to 2014, brachytherapy utilization declined during the late 2000s and disproportionately affected patients with government insurance, but subsequently recovered in the early 2010s. Since government insurance covers vulnerable patient populations at-risk for future declines in brachytherapy use, proposed alternative payment models should incentivize cervical brachytherapy to solidify gains in brachytherapy utilization.

Drivers of 30- and 90-day Postoperative Death After Neoadjuvant Chemoradiation for Esophageal Cancer.

BACKGROUND: Neoadjuvant chemoradiation, followed by esophagectomy, is a standard of care for locally advanced esophageal cancers. The ChemoRadiOtherapy plus Surgery versus Surgery alone (CROSS) trial reported a 30-day mortality rate of 6%. We sought to evaluate 30- and 90-day mortality in similar patients in the United States and identify predictors of higher mortality rates. METHODS: The National Cancer Database was used to identify patients with cT3-4/N+ esophageal cancers treated with neoadjuvant chemoradiation followed by esophagectomy. Bivariate univariable and multivariable regression analysis was used to identify predictors of 30- and 90-day mortality. RESULTS: We identified 7691 patients. Readmission within 30 days of surgery occurred in 6.0% of patients. Mortality was 2.9% at 30 days and 7.2% at 90 days. Positive surgical margins conferred a more than doubled risk of 30- and 90-day mortality, 5.5% vs 2.7% and 14.6% vs 6.8% (both P < .001). Facility surgical volume impacted 30-day mortality, whereas readmission was associated with 90-day mortality, both exceeding 10% (P = .004 and P = .001, respectively). In patients undergoing minimally invasive surgery converted to open, 90-day mortality was 12.1% (P < .01). For patients 69 years and older, 90-day mortality was also 12.1% (P < .001). Patients who underwent esophagectomy more than 45 days from completion of chemoradiation also had higher 90-day mortality at 8.3% vs 6.2% (P < .001). CONCLUSIONS: Postoperative death at 30 and 90 days after neoadjuvant chemoradiation and esophagectomy appears to be on par with randomized data. Positive surgical margins, squamous cell carcinomas, age 69 and older, readmission within 30 days, and conversion from a minimally invasive operation to an open operation all carry a 90-day mortality risk exceeding 10%.

A High-Throughput System for Transient and Stable Protein Production in Mammalian Cells.

Recombinant protein expression and purification is an essential component of biomedical research and drug discovery. Advances in automation and laboratory robotics have enabled the development of highly parallel and rapid processes for cell culture and protein expression, purification, and analysis. Human embryonic kidney (HEK) cells and Chinese hamster ovary (CHO) cells have emerged as the standard host cell workhorses for producing recombinant secreted mammalian proteins by using both transient and stable production strategies. In this chapter we describe a fully automated custom platform, Protein Expression and Purification Platform (PEPP), used for transient protein production from HEK cells and stable protein production from CHO cells. Central to PEPP operation is a suite of custom robotic and instrumentation platforms designed and built at GNF, custom cell culture ware, and custom scheduling software referred to as Runtime. The PEPP platform enables cost-effective, facile, consistent production of proteins at quantities and quality useful for early stage drug discovery tasks such as screening, bioassays, protein engineering, and analytics.

National patterns of care for early-stage penile cancers in the United States: How is radiation and brachytherapy utilized?

PURPOSE: Per American Brachytherapy Society guidelines, cT1-2N0 penile cancers <4 cm in diameter are excellent candidates for curative brachytherapy. Using that criterion, we evaluated national patterns of care and predictors of use of radiation techniques using the National Cancer Database. METHODS AND MATERIALS: The National Cancer Database was queried for men with cT1-2N0 penile cancers <4 cm in size. Comparative statistics for treatment modality were generated using bivariate logistic regression analysis. RESULTS: Among 1235 cases eligible for analysis, median age was 69 years. Median tumor size was 2.0 cm. 95.8% of men underwent surgery alone, with 91 (7.4%) undergoing radical penectomy, 673 (54.5%) partial penectomy, and 419 (33.9%) cosmesis-preserving surgical procedure. Only 4 (0.3%) men were treated with brachytherapy alone, 48 (3.9%) with external-beam radiation therapy (EBRT) alone, and 8 (0.6%) with EBRT after surgery. Surgical margins were positive in 118 (9.6%) patients, 14 of whom received adjuvant EBRT (11.9%) and two adjuvant brachytherapy (1.7%). There was no difference in demographic or clinical characteristics in groups treated with surgery vs. radiation (all p > 0.2). Age >70, lesions >2 cm, and T2 tumors were more likely to undergo non-organ-preserving therapy vs. radiation or a cosmesis-preserving procedure (all p < 0.05). The propensity-matched 5-year survival was not different between definitive radiation vs. surgery (61.6% vs. 62.2%, p = 0.70). CONCLUSIONS: Men with penile-preserving eligible lesions in the United States are overwhelmingly treated with surgery. Penile-preserving radiation techniques including brachytherapy and EBRT are underutilized and should be offered as curative interventions.

Early mortality of stage IV non-small cell lung cancer in the United States.

Background: Early mortality is a major deterrent to oncologic management, often preventing delivery of therapy or leading to administration of treatment that offers limited benefit from aggressive interventions. Due to more recent progress in therapeutic options for stage IV non-small cell lung cancer (NSCLC) patients, identifying those at high risk of early mortality (within 30 days) could have implications for treatment selection. Because early mortality following diagnosis of metastatic non-small cell lung cancer (NSCLC) is not well-characterized, this investigation evaluated national trends and predictors thereof. Material and methods: The National Cancer Database was queried for cases of pathologically confirmed metastatic NSCLC with complete vital status and clinical information, diagnosed between 2006 and 2014. Multivariable logistic regression ascertained factors associated with 30-day mortality. Results: Of 346,681 patients, 45,861 (13%) experienced early mortality over the past decade, which remained relatively constant over time. Predictors of early mortality included advancing age (>65 years), male gender, Caucasian race, non-private insurance, lower income, greater comorbidities, residence in metropolitan and/or lesser-educated areas, treatment at community centers, patients with no prior history of cancer and regional differences (p < .01 for all). Early mortality was highest in patients older than 80 years with multiple comorbidities (29%). The majority of patients (71%) who died within 30 days did not receive any therapy. Conclusions: A fair proportion of NSCLC patients experience early mortality, which has not decreased over time. The majority of patients with early mortality do not receive treatment. Prognostic factors for early mortality should be considered during initial evaluation and subsequent follow-up of these patients. Doing so may impact systemic treatment selection by medical oncologists, management of (oligo)metastatic disease by radiation and surgical oncologists and cost-effective administration of these therapies in the stage IV NSCLC population.

Outcomes after definitive re-irradiation with 3D brachytherapy with or without external beam radiation therapy for vaginal recurrence of endometrial cancer.

BACKGROUND: Limited outcome data exists on salvage re-irradiation for vaginal relapse of previously-irradiated endometrial cancer. We report our 10-year experience with management of vaginal recurrence using definitive intent re-irradiation brachytherapy with or without EBRT. METHODS: A retrospective review was performed on 22 patients treated with definitive-intent re-irradiation brachytherapy ±â€¯EBRT for vaginal recurrence of endometrial cancer. The cumulative rectosigmoid and bladder D2cc (EQD2) were limited to <75 Gy and <90 Gy, respectively. Kaplan-Meier and Cox proportional hazards modeling were used to estimate survival. Severe (grade 3 or higher) radiation-related toxicities, defined according to CTCAE v4, were recorded. RESULTS: Prior radiation therapy consisted of vaginal brachytherapy (54.5%), pelvic EBRT (22.7%), or combination pelvic EBRT and brachytherapy (22.7%). Median re-irradiation interval was 26.6 months. Salvage re-irradiation consisted of EBRT with brachytherapy in 50.0% and brachytherapy alone in 50.0%. Median HR-CTV D90 (EQD2) was 64.5 Gy (IQR: 49.6-75.8). Median cumulative D2cc for bladder, rectum, and sigmoid were 72.1 Gy (range: 30.3-81.8), 70.6 Gy (range: 32.0-80.5), and 52.7 Gy (range: 29.6-75.3), respectively. At a median follow-up of 27.6 months, 3-year local control, regional control, disease-free survival, and overall survival rates were 65.8%, 76.6%, 40.8%, and 68.1%, respectively. There were no grade ≥ 3 acute or late rectosigmoid or bladder toxicities. CONCLUSION: Re-irradiation with 3D conformal brachytherapy for vaginal recurrence is feasible and safe as long as cumulative dose to surrounding normal organs is limited, and offers a chance to potentially salvage 40% of patients presenting with vaginal recurrence in the setting of prior pelvic radiation.

Disparities Predict for Higher Rates of Cut-through Hysterectomies in Locally Advanced Cervical Cancer.

OBJECTIVES: The treatment of choice for locally advanced cervical cancer is definitive chemoradiation (CRT). Hysterectomy is not indicated due to higher-rates of cut-through resections leaving gross disease behind, requiring additional therapy with increasing morbidity and no benefit in overall survival (OS). The objectives of this study were to determine factors associated with cut-through hysterectomies and evaluate OS outcomes. MATERIALS AND METHODS: The National Cancer Database (NCDB) was queried for patients 18 years and older with clinical Federation of Gynecology and Obstetrics stage IB2 to IVA. All patients underwent upfront hysterectomy and had known margin status. Cut-through hysterectomy was classified as presence of microscopic or macroscopic disease at the margin. RESULTS: A total of 11,638 patients were included; 993 (8.5%) had positive margins. In patients with positive margins, 560 (56.4%) received postoperative CRT and 148 (14.9%) underwent postoperative radiation. Five-year OS was worse for those with cut-through resections when compared with those with negative margins, 66.0% versus 86.7%, respectively (hazard ratios, 3.08; P<0.001). Under multiple logistic regression, African American race (odds ratio [OR], 1.45; P=0.001), older age (OR per year increase, 1.03; P<0.001), patients with government insurance (OR, 1.21; P=0.019), and those treated at community practices (OR, 1.31; P=0.001) were more likely to undergo cut-through hysterectomies. CONCLUSIONS: A review of national patterns of care over the past decade confirms women with positive margins after hysterectomy for cervical cancer have significantly worse OS. Disparities in surgical results for women with cervical cancer exist. In response, further causality evaluation and corrective action are warranted to address these inequalities.

Mammalian cell culture density determination using a laser through-beam sensor.

High-throughput protein expression platforms are increasingly used to produce proteins for many applications: to support studies in structure/function, regulation and proteomics, as well as for direct use as potential biotherapeutic agents for medical applications. Here we describe a device that we refer to as the flask density reader (FDR) consisting of a through-beam laser and sensor, and a customized culture flask-receiving nest. The FDR has been integrated onto GNF System™'s automated protein expression platform to enable rapid, noninvasive, fully automated spectrophotometric determination of cell densities in suspension mammalian cell cultures. The FDR reduces the risk of culture contamination from frequent flask sampling and greatly reduces the time and effort needed to count cells using off-line methods.

Rising Rates of Upfront Surgery in Early Locally Advanced Cervical Cancer: What Factors Predict for This Treatment Paradigm?

OBJECTIVE: In this study, we analyzed patterns of care for patients with locally advanced cervical cancer to identify predictors for upfront surgery compared with definitive chemoradiation (CRT). METHODS: The National Cancer Database was queried for patients aged 18 years or older with Federation of Gynecology and Obstetrics IB2-IIB cervical cancer. All patients underwent either upfront hysterectomy with or without postoperative radiation therapy versus definitive CRT. Logistic regression was used to assess variables associated with modality of treatment (surgery vs CRT). RESULTS: Of the 9494 patients included, 2151 (22.7%) underwent upfront surgery. Of those undergoing surgery, 380 (17.7%) had positive margins, 478 (22.2%) had positive nodes, and 458 (21.3%) had pathologic involvement of the parametrium. Under multiple logistic regression, rates of surgery significantly increased from 2004 (12.2%) to 2012 (31.2%) (odds ratio [OR] per year increase, 1.15; confidence interval [CI], 1.12-1.17; P < 0.001). Upfront surgery was more commonly performed in urban (OR, 1.21; 95% CI, 1.03-1.41; P = 0.018) and rural counties (OR, 1.79; 95% CI, 1.24-2.58; P = 0.002), for adenocarcinoma (OR, 2.14; 1.88-2.44; P < 0.001) and adenosquamous (OR, 2.69; 2.11-3.43; P < 0.001) histologies, and in patients from higher median income communities (ORs, 1.19-1.37). Upfront surgery was less common at academic centers (OR, 0.73; 95% CI, 0.58-0.93; P = 0.011). CONCLUSIONS: Rates of upfront surgery relative to definitive CRT have increased significantly over the past decade. In the setting of level 1 evidence supporting the use of definitive CRT alone for these women, the rising rates of upfront surgery raises concern for both unnecessary surgical procedures with higher rates of treatment-related morbidity and greater health care costs.

Image-based multichannel vaginal cylinder brachytherapy for the definitive treatment of gynecologic malignancies in the vagina.

PURPOSE: Brachytherapy is integral to vaginal cancer treatment and is typically delivered using an intracavitary single-channel vaginal cylinder (SCVC) or an interstitial brachytherapy (ISBT) applicator. Multi-channel vaginal cylinder (MCVC) applicators allow for improved organ-at-risk (OAR) sparing compared to SCVC while maintaining target coverage. We present clinical outcomes of patients treated with image-based high dose-rate (HDR) brachytherapy using a MCVC. METHODS AND MATERIALS: Sixty patients with vaginal cancer (27% primary vaginal and 73% recurrence from other primaries) were treated with combination external beam radiotherapy (EBRT) and image-based HDR brachytherapy utilizing a MCVC if residual disease thickness was 7 mm or less after EBRT. All pts received 3D image-based BT to a total equivalent dose of 70-80 Gy. RESULTS: The median high-risk clinical target volume was 24.4 cm3 (interquartile range [IQR], 14.1), with a median dose to 90% of 77.2 Gy (IQR, 2.8). After a median follow-up of 45 months (range, 11-78), the 4-year local-regional control, distant control, DFS, and OS rates were 92.6%, 76.1%, 64.0%, and 67.2%, respectively. The 4-year LRC rates were similar between the primary vaginal (92%) and recurrent (93%) groups (p = 0.290). Pts with lymph node positive disease had a lower rate of distant control at 4 years (22.7% vs. 89.0%, p < 0.001). There were no Grade 3 or higher acute complications. The 4-year rate of late Grade 3 or higher toxicity was 2.7%. CONCLUSIONS: Clinical outcomes of pts with primary and recurrent vaginal cancer treated definitively in a systematic manner with combination EBRT with image-guided HDR BT utilizing a MCVC applicator demonstrate high rates of local control and low rates of severe morbidity. The MCVC technique allows interstitial implantation to be avoided in select pts with ≤7 mm residual disease thickness following EBRT while maintaining excellent clinical outcomes with extended 4-year follow-up in this rare malignancy.

Stereotactic body radiation therapy for benign spine tumors: is dose de-escalation appropriate?

OBJECTIVE Akin to the nonoperative management of benign intracranial tumors, stereotactic body radiation therapy (SBRT) has emerged as a nonoperative treatment option for noninfiltrative primary spine tumors such as meningioma and schwannoma. The majority of initial series used higher doses of 16-24 Gy in 1-3 fractions. The authors hypothesized that lower doses (such as 12-13 Gy in 1 fraction) might provide an efficacy similar to that found with the dose de-escalation commonly used for intracranial radiosurgery to treat acoustic neuroma or meningioma and with a lower risk of toxicity. METHODS The authors identified 38 patients in a prospectively maintained institutional radiosurgery database who were treated with definitive SBRT for a total of 47 benign primary spine tumors between 2004 and 2016. SBRT consisted of 9-21 Gy in 1-3 fractions using the CyberKnife (n = 11 [23%]), Synergy S (n = 21 [45%]), or TrueBeam (n = 15 [32%]) radiosurgery platform. For a comparison of SBRT doses, patients were dichotomized into 1 of 2 groups (low-dose or high-dose SBRT) using a cutoff biologically effective dose (BED10Gy) of 30 Gy. Tumor control was calculated from the date of SBRT to the last follow-up using Kaplan-Meier survival analysis, with comparisons between groups completed using a log-rank method. To account for potential indication bias, a propensity score analysis was completed based on the conditional probabilities of SBRT dose selection. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0 with a focus on grade 3+ toxicity and the incidence of pain flare. RESULTS For the 38 patients, the most common histological findings were meningioma (15 patients), schwannoma (13 patients), and hemangioblastoma (7 patients). The median age at SBRT was 58 years (range 25-91 years). The 47 treated lesions were located in the cervical (n = 18), thoracic (n = 19), or lumbosacral (n = 10) spine. Five (11%) lesions were lost to follow-up after SBRT. The median follow-up duration for the remaining 42 lesions was 54 months (range 1.2-133 months). Six (16%) patients (with a total of 8 lesions) experienced pain flare after SBRT; no significant predictor of pain flare was identified. No grade 3+ acute- or late-onset complication was noted. The 5-year local control rate was 76% (95% CI 61%-91%). No significant difference in local control according to dose, fractionation, previous radiation, surgery, tumor histology, age, treatment platform, planning target volume, or spine level treated was found. The 5-year local control rates for low- and high-dose treatments were 73% (95% CI 53%-93%) and 83% (95% CI 61%-100%) (p = 0.52). In propensity score-adjusted multivariable analysis, no difference in local control was identified (HR 0.30, 95% CI 0.02-5.40; p = 0.41). CONCLUSIONS Long-term follow-up of patients treated with SBRT for benign spinal lesions revealed no significant difference between low-dose (BED10Gy ≤ 30) and high-dose SBRT in local control, pain-flare rate, or long-term toxicity.

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.

Use of Functional Magnetic Resonance Imaging in Cervical Cancer Patients With Incomplete Response on Positron Emission Tomography/Computed Tomography After Image-Based High-Dose-Rate Brachytherapy.

PURPOSE: To investigate the correlation between positron emission tomography/computed tomography (PET/CT) response and outcome in the era of magnetic resonance imaging (MRI)-based planning and to assess whether the addition of diffusion-weighted MRI (DW-MRI) could more accurately classify treatment response and prognosis. METHODS AND MATERIALS: A retrospective chart review identified 244 consecutive patients with International Federation of Gynecology and Obstetrics stage IB1-IVA cervical cancer treated with concurrent chemoradiation, including high-dose-rate image-based brachytherapy, between 2007 and 2016. Image-based brachytherapy was delivered with 5 intracavitary/interstitial fractions, each 5 to 6 Gy per fraction. RESULTS: An complete response on posttreatment PET/CT (PET-CR) was discovered in 50 of 244 patients (20%) at a median interval of 3.3 months (range, 2.1-7.7 months) after treatment. After a median follow-up of 27 months, 2-year overall survival was 83% in all patients. Metabolic response significantly impacted 2-year overall survival (94% complete response on posttreatment PET/ CT vs 62.4% PET-IR, P < .001). Of those with a PET-IR, 16 of 50 patients (32%) suffered a local recurrence. A total of 27 of 50 patients with a PET-IR underwent DW-MRI; 11 of 27 posttreatment DW-MRI scans (40%) were interpreted as positive by central review (median apparent diffusion coefficient of 0.973 × 10-3 mm2/s). Of the DW-MRI-positive patients, 9 of 11 (81.8%) suffered a histologically confirmed local recurrence, and 2 of 11 patients are without evidence of disease. Additionally, 16 of 27 DW-MRI studies were interpreted as negative, and 2 of 16 (12.5%) of these patients suffered a local recurrence. Diffusion-weighted MRI findings significantly impacted 2-year overall survival (83% negative DW-MRI vs 36% positive DW-MRI, P = .049). CONCLUSION: Incomplete PET/CT response was documented in 20% of patients after image-based brachytherapy for locally advanced cervical cancer. Integration of DW-MRI helped accurately identify patients at risk for persistent disease and worse long-term outcome. The value of DW-MRI requires further validation in a large prospective dataset as this modality may allow earlier evaluation and salvage treatment in those with PET-IR.