Recurrent early stage endometrial cancer: Patterns of recurrence and results of salvage therapy.

OBJECTIVE: To analyze our institutional experience and oncologic outcomes for salvage treatment for the recurrence of early-stage endometrial cancer patients. METHODS: We included women of all ages diagnosed with FIGO stage I-II, any grade endometrial cancer from 2000 to 2016 at our institutions who were treated with at least a hysterectomy. Recurrences in the pelvis and/or vagina were considered locoregional recurrences (LRR). Overall survival (OS) was assessed using Kaplan-Meier survival analysis. Univariate (UV) and multivariate (MV) Cox proportional hazards modeling was also used. RESULTS: A total of 2691 women were analyzed. The majority had endometrioid histology (91%), stage IA disease (61%), and were grade 1 (57%). With a median follow-up of 6.1 years, the overall rate of recurrence was 7.2%, and the rate of LRR was 3.7%. Women with vaginal-only recurrences had a longer median OS after recurrence (14.0 years) compared to both pelvic (1.2 years) and distant (1.0 year) failures. For women with vaginal-only recurrences, salvage radiotherapy (RT) was the only factor associated with improved OS on MVA (HR 0.1, p = .04). For women with pelvic recurrences, salvage surgery (HR 0.3, p = .01), salvage RT (HR 0.3, p < .01), and salvage chemotherapy (HR 0.4, p = .03) were associated with improved OS. CONCLUSIONS: Failure rates for women with early-stage endometrial cancer are low. Women with vaginal-only recurrences have improved OS compared to pelvic or distant recurrences. Salvage RT appears to be an important factor for treatment of women with vaginal-only recurrences. Aggressive multimodality treatment may be beneficial for women with pelvic recurrences.

Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo.

We report potent radiosensitization of prostate cancers in vitro and in vivo using goserelin-conjugated gold nanorods. Progressive receptor-mediated internalization of conjugated nanorods over time increases the radiation interaction cross-section of cells and contributes to the effects observed in vitro. The low concentrations of gold required, the long interval between injection of nanoparticles and radiation, and the use of megavoltage radiation to generate radiosensitization in vivo foretell the possibility of eventual clinical translation of this approach. FROM THE CLINICAL EDITOR: The ability of gold nanoparticles (AuNPs) to enhance the effect of physical radiation dose on tumor cells is known. This radiosensitization effect is thought to result from an increased number of photoelectric absorption events and the increased number of electrons present in gold. The authors here sought to further increase the amount and specificity of gold accumulation in prostatic cancer cells by conjugating gold nanorods to goserelin, a synthetic luteinizing hormone releasing hormone (LHRH) analogue that would bind to the LHRH receptor overexpressed in prostate cancers. It was shown that tumour cells were more sensitive to megavoltage radiation therapy. It is hoped that there would be eventual clinical translation of this approach.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol.

PURPOSE: The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. METHODS AND MATERIALS: SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.5 Gy × 4 fx to 5 mm, and 6 Gy × 5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD23). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. RESULTS: The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy × 3 and 5 to 5.5 Gy × 4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy × 5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD23 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy × 3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. CONCLUSIONS: Experimental short-course VCB of 11 Gy × 2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD23 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects.

Does hormone therapy exacerbate the adverse effects of radiotherapy in men with prostate cancer? A quality of life study.

PURPOSE: We examined whether short course androgen deprivation therapy as an adjunct to radiotherapy would impact health related quality of life outcomes in patients with localized prostate cancer treated definitively with external beam radiation therapy or permanent brachytherapy. MATERIALS AND METHODS: From 1999 to 2003 patients were enrolled in a prospective study at our institution and completed validated health related quality of life surveys at defined pretreatment and posttreatment intervals. A total of 81 men received radiotherapy alone and 67 received radiotherapy plus androgen deprivation therapy. Median androgen deprivation therapy duration was 4 months. Univariate and multivariate analysis was done to compare time to return to baseline in 6 distinct health related quality of life domains. RESULTS: On univariate analysis the radiotherapy plus androgen deprivation therapy group achieved baseline urinary symptoms more rapidly than the radiotherapy group (5 months, p = 0.002). On multivariate analysis time to return to baseline in any of the 6 health related quality of life domains was not significantly affected by adding androgen deprivation therapy. Factors associated with longer time to return to baseline mental composite scores on multivariate analysis included nonwhite ethnicity, cerebrovascular disease history and alcohol abuse history. Men treated with permanent brachytherapy monotherapy experienced longer time to return to baseline for urinary function and symptoms. Baseline sexual function and lack of a partner were associated with longer time to sexual recovery. CONCLUSIONS: Adding androgen deprivation therapy to definitive radiotherapy does not significantly impact the time to return to baseline health related quality of life. These data may be valuable for patients and physicians when weighing the toxicity and benefits of androgen deprivation therapy when added to definitive radiotherapy.

Do vaginal recurrence rates differ among adjuvant vaginal brachytherapy regimens in early-stage endometrial cancer?

PURPOSE: We sought to retrospectively examine clinical outcomes for three adjuvant vaginal high-dose-rate (HDR) brachytherapy regimens after hysterectomy for early-stage endometrial cancer. METHODS: Included were women of all ages from two independent hospital systems diagnosed with Stage I-II endometrial cancer of any grade between 2000 and 2016 who underwent hysterectomy followed by adjuvant vaginal cylinder HDR brachytherapy with either 7.0 Gy × 3 fractions prescribed to 0.5 cm vaginal depth, 6.5 Gy × 3 fractions prescribed to 0.5 cm vaginal depth, or 6.0 Gy × 5 fractions prescribed to the vaginal surface. Outcomes included vaginal recurrence (VR), pelvic recurrence, distant recurrence, locoregional recurrence, recurrence-free survival, and overall survival. RESULTS: Of the 348 women, 45 (13%) received 7.0 Gy × 3 fractions, 259 (74%) received 6.5 Gy × 3 fractions, and 44 (13%) received 6.0 Gy × 5 fractions. Women receiving 5-fraction brachytherapy were more likely to be younger with a higher performance status. At a median follow-up of 4.5 years, VR rates were 2.2%, 0.8%, and 4.5%, respectively. Multivariate analysis revealed no significant differences in the risks for VR among brachytherapy regimens. Risks for VR, pelvic recurrence, distant recurrence, locoregional recurrence, recurrence-free survival, and overall survival did not differ between propensity score-matched five- and 3-fraction brachytherapy cohorts. CONCLUSIONS: VR rates after hysterectomy and adjuvant vaginal brachytherapy for early-stage endometrial cancer were low and not significantly different by HDR dose fractionation.

Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: A matched-pair analysis.

PURPOSE: Pathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach. METHODS AND MATERIALS: From 1995 to 2003, a phase 2 protocol examined CRT with 5-fluorouracil and CB radiation therapy (52.5 Gy in 5 weeks) for patients with LARC. Seventy-six protocol patients were matched (case-control approach) for surgery type, tumor (T) stage, and clinical nodal (N) stage with patients who received standard dose (SD) CRT (5-fluorouracil, 45 Gy). A chart review was performed. McNemar's test and Kaplan-Meier analyses were used for statistical analysis. RESULTS: The SD and CB groups did not differ in tumor circumferential involvement and length, but the tumors of CB patients were closer to the anal verge (4.7 vs 5.7 cm; P = .02). Although tumor downstaging was higher in the CB cohort (76% vs 51%; P < .01), pathologic complete response rates did not differ (CB, 17.1% vs SD, 15.8%, P = 1.00). The incidence of grade ≥3 radiation-related toxicities was low and similar in both groups (CB, 10% vs SD, 3%, P = .22). Postoperative (anastomotic leak, wound complications/abscess, bleeding) and late (small bowel obstruction, stricture) complication rates did not differ between the groups (P > .05). The median follow-up was 11.9 years. The 5-year local control rates were higher for CB (100.0%) compared with SD (90.0%) patients (P = .01). CB patients had higher rates of 10-year progression-free survival (71.9% vs 57.6%, P < .01) and overall survival (71.6% vs 62.4%, P = .01) compared with SD patients. CONCLUSIONS: CRT dose escalation for patients with LARC is safe and effective. The improved T-downstaging and local control observed in CB patients should encourage further dose escalation studies.

The impact of induction chemotherapy on the dosimetric parameters of subsequent radiotherapy: an investigation of 30 consecutive patients with locally-advanced non-small cell lung cancer and modern radiation planning techniques.

PURPOSE: To investigate the influence of induction chemotherapy (ICT) on dosimetric outcomes in patients with inoperable non-small cell lung cancer (NSCLC) treated with definitive chemoradiation (CRT). MATERIALS AND METHODS: 30 patients with inoperable stage II-III NSCLC treated with 2-4 cycles of ICT followed by definitive CRT to ≥ 60 Gy were selected. Tumor response to chemotherapy was scored by RECIST criteria. Treatment plans based on tumor extent prior to chemotherapy were generated based on equivalent planning constraints and techniques as the original post-chemotherapy plans. Dosimetric parameters predictive of toxicity for lung, esophagus, heart, and spinal cord were compared amongst the pre- and post-ICT plans. RESULTS: The majority of patients (70%) experienced an overall reduction in GTV size between the pre-ICT imaging and the time of simulation. Comparing pre-and post-ICT diagnostic imaging, 5 patients met the RECIST criteria for response, 23 were classified as stable, and 2 experienced disease progression on diagnostic imaging. Despite a significantly reduced GTV size in the post-ICT group, no systematic improvements in normal tissue doses were seen amongst the entire cohort. This result persisted amongst the subgroup of patients with larger pre-ICT GTV tumor volumes (>100 cc(3)). Among patients with RECIST-defined response, a significant reduction in lung mean dose (1.9 Gy absolute, median 18.2 Gy to 16.4 Gy, p = 0.04) and V20, the percentage of lung receiving 20 Gy (3.1% absolute, median 29.3% to 26.3%, p = 0.04) was observed. In the non-responding group of patients, an increased esophageal V50 was found post-chemotherapy (median 28.9% vs 30.1%, p = 0.02). CONCLUSIONS: For patients classified as having a response by RECIST to ICT, modest improvements in V20 and mean lung dose were found. However, these benefits were not realized for the cohort as a whole or for patients with larger tumors upfront. Given the variability of tumor response to ICT, the a priori impact of induction chemotherapy to reduce RT dose to normal tissue in these patients is minimal in the setting of modern treatment planning.

Radiotherapy-Induced Malfunction in Contemporary Cardiovascular Implantable Electronic Devices: Clinical Incidence and Predictors.

IMPORTANCE: Risk stratification and management paradigms for patients with cardiovascular implantable electronic devices (CIEDs) requiring radiotherapy (RT) vary widely and are based on limited clinical data. OBJECTIVE: To identify the incidence and predictors of CIED malfunction and describe associated clinical consequences in a large cohort of patients treated with photon- and electron-based RT. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of all patients with a functioning CIED who underwent RT between August 2005 and January 2014 with CIED interrogation data following RT at an academic cancer center. We identified 249 courses of photon- and electron-based RT in 215 patients (123 pacemakers [57%]; 92 implantable cardioverter-defibrillators [43%]). Substantial neutron production was generated in 71 courses (29%). EXPOSURE: Implantation of CIED with subsequent therapeutic radiation treatment (neutron producing with 15- or 18-MV photons and non-neutron producing with electrons, GammaKnife, or 6-MV photons). MAIN OUTCOMES AND MEASURES: Malfunction of CIED, characterized as single-event upset (data loss, parameter resets, unrecoverable resets), and delayed effects including signal interference, pacing threshold changes, and premature battery depletion. RESULTS: Malfunction of CIED attributable to RT occurred during 18 courses (7%), with 15 CIEDs experiencing single-event upsets, and 3, transient signal interference. All single-event upsets occurred during neutron-producing RT, at a rate of 21%, 10%, and 34% per neutron-producing course for CIEDs, pacemakers, and implantable cardioverter-defibrillators, respectively. No single-event upsets were found among 178 courses of non-neutron-producing RT. Incident CIED dose did not correlate with device malfunction. Patients treated to the abdomen and pelvis region were more likely to undergo a single-event upset (hazard ratio, 5.2 [95% CI, 1.2-22.6]; P = .03). Six patients with a CIED parameter reset developed clinical symptoms: 3 experienced hypotension and/or bradycardia, 2 experienced abnormal chest ticking consistent with pacemaker syndrome, and 1 developed congestive heart failure. The 3 episodes of signal interference did not result in clinical effects. No delayed malfunctions were directly attributed to RT. CONCLUSIONS AND RELEVANCE: In a cohort of contemporary CIEDs, all cases of single-event upset malfunction occurred in the setting of notable neutron production, at a rate of 21% for neutron-producing RT and 0% for non-neutron-producing RT. Where clinically feasible, the use of non-neutron-producing RT is recommended. Given the lack of correlation between CIED malfunction and incident dose observed up to 5.4 Gy, invasive CIED relocation procedures in these settings can be minimized.

Incidence and predictors of severe acute esophagitis and subsequent esophageal stricture in patients treated with accelerated hyperfractionated chemoradiation for limited-stage small cell lung cancer.

PURPOSE: Clinical and dosimetric predictors of severe (grade 3 or greater) acute esophageal toxicity and subsequent esophageal dilation were explored in patients with limited-stage small cell lung cancer treated with accelerated hyperfractionated chemoradiation. METHODS AND MATERIALS: A total of 130 patients were identified who were treated to 45 Gy in 1.5-Gy twice-daily fractions with concurrent platinum-based chemotherapy between 2000 and 2009. Data on clinical, disease-related, and treatment-related variables were collected. Patients with percutaneous endoscopic gastrostomy tube insertion or intravenous hydration because of poor oral intake were designated as having acute grade 3 esophagitis. Univariate and multivariate analyses that associated treatment characteristics with esophagitis were assessed via logistic regression, and optimal cut points were identified with recursive partitioning analysis. RESULTS: Twenty-five patients developed severe acute esophagitis, at a rate of 26% (18/69) in patients treated with earlier 3-dimensional conformal radiation therapy techniques and 11.5% (7/61) in patients treated with intensity modulated radiation therapy techniques and omission of elective nodal irradiation. The incidence of esophageal stricture was 6% overall (8 of 128 eligible) but 26% (6/23) among those who experienced prior grade 3 acute esophagitis and 2% (2/105) among those with acute esophagitis less than or equal to grade 2. Significant multivariate predictors of acute esophagitis were mean dose and volume of esophagus receiving at least 5% to 35% of the prescribed dose (V5 to V40). Patients with V5 ≥ 74% had a 44.4% risk of severe acute esophagitis (12/27) versus 12.6% (13/103) among those with V5 < 74%. V45 was the only dosimetric predictor for esophageal stricture, with 13.7% of patients in whom V45 was ≥37.5% requiring subsequent dilation. CONCLUSIONS: Modern radiation techniques are associated with a lower frequency of severe acute esophagitis than previous paradigms. The proportion of esophagus receiving low- to moderate-range doses (mean, V5 through V40) predicts acute esophagitis, whereas the proportion of esophagus that receives high doses (V45) predicts the development of esophageal stricture that requires dilation. Patients who develop grade 3 acute esophagitis are at significant risk for subsequent esophageal stricture, whereas those with acute esophagitis of grade 2 or less display minimal risk.

Proton-based stereotactic ablative radiotherapy in early-stage non-small-cell lung cancer.

Stereotactic ablative radiotherapy (SABR), a recent implementation in the practice of radiation oncology, has been shown to confer high rates of local control in the treatment of early stage non-small-cell lung cancer (NSCLC). This technique, which involves limited invasive procedures and reduced treatment intervals, offers definitive treatment for patients unable or unwilling to undergo an operation. The use of protons in SABR delivery confers the added physical advantage of normal tissue sparing due to the absence of collateral radiation dose delivered to regions distal to the target. This may translate into clinical benefit and a decreased risk of clinical toxicity in patients with nearby critical structures or limited pulmonary reserve. In this review, we present the rationale for proton-based SABR, principles relating to the delivery and planning of this modality, and a summary of published clinical studies.

Comprehensive craniospinal radiation for controlling central nervous system leukemia.

PURPOSE: To determine the benefit of radiation therapy (RT) in resolution of neurologic symptoms and deficits and whether the type of RT fields influences central nervous system (CNS) control in adults with CNS leukemia. METHODS AND MATERIALS: A total of 163 adults from 1996 to 2012 were retrospectively analyzed. Potential associations between use of radiation and outcome were investigated by univariate and multivariate analysis. RESULTS: The median survival time was 3.8 months after RT. Common presenting symptoms were headache in 79 patients (49%), cranial nerve VII deficit in 46 (28%), and cranial nerve II deficit in 44 (27%). RT was delivered to the base of skull in 48 patients (29%), to the whole brain (WB) in 67 (41%), and to the craniospinal axis (CS) in 48 (29%). Among 149 patients with a total of 233 deficits, resolution was observed in 34 deficits (15%), improvement in 126 deficits (54%), stability in 34 deficits (15%), and progression in 39 deficits (17%). The 12-month CNS progression-free survival was 77% among those receiving CS/WB and 51% among those receiving base of skull RT (P=.02). On multivariate analysis, patients who did not undergo stem cell transplantation after RT and base of skull RT were associated with worse CNS progression-free survival. CONCLUSIONS: Improvement or resolution of symptoms occurred in two thirds of deficits after RT. Comprehensive radiation to the WB or CS seems to offer a better outcome, especially in isolated CNS involvement.

Prospective randomized double-blind study of atlas-based organ-at-risk autosegmentation-assisted radiation planning in head and neck cancer.

BACKGROUND AND PURPOSE: Target volumes and organs-at-risk (OARs) for radiotherapy (RT) planning are manually defined, which is a tedious and inaccurate process. We sought to assess the feasibility, time reduction, and acceptability of an atlas-based autosegmentation (AS) compared to manual segmentation (MS) of OARs. MATERIALS AND METHODS: A commercial platform generated 16 OARs. Resident physicians were randomly assigned to modify AS OAR (AS+R) or to draw MS OAR followed by attending physician correction. Dice similarity coefficient (DSC) was used to measure overlap between groups compared with attending approved OARs (DSC=1 means perfect overlap). 40 cases were segmented. RESULTS: Mean ± SD segmentation time in the AS+R group was 19.7 ± 8.0 min, compared to 28.5 ± 8.0 min in the MS cohort, amounting to a 30.9% time reduction (Wilcoxon p<0.01). For each OAR, AS DSC was statistically different from both AS+R and MS ROIs (all Steel-Dwass p<0.01) except the spinal cord and the mandible, suggesting oversight of AS/MS processes is required; AS+R and MS DSCs were non-different. AS compared to attending approved OAR DSCs varied considerably, with a chiasm mean ± SD DSC of 0.37 ± 0.32 and brainstem of 0.97 ± 0.03. CONCLUSIONS: Autosegmentation provides a time savings in head and neck regions of interest generation. However, attending physician approval remains vital.

Diagnosis and management of upper extremity deep-vein thrombosis in adults.

Upper extremity deep-vein thrombosis (UEDVT) is common and can cause important complications, including pulmonary embolism and post-thrombotic syndrome. An increase in the use of central venous catheters, particularly peripherally inserted central catheters has been associated with an increasing rate of disease. Accurate diagnosis is essential to guide management, but there are limitations to the available evidence for available diagnostic tests. Anticoagulation is the mainstay of therapy, but interventional treatments may be considered in select situations. The risk of UEDVT may be reduced by more careful selection of patients who receive central venous catheters and by use of smaller catheters. Herein we review the diagnosis, management and prevention of UEDVT. Due to paucity of research, some principles are drawn from studies of lower extremity DVT. We present a practical approach to diagnosing the patient with suspected deep-vein thrombosis of the upper extremity.

Bronchial and pulmonary arterial and venous interventions.

With advancement of interventional techniques and increasing complexity of patients, the involvement of interventional radiologists in the pulmonary critical care (PCC) setting has increased in recent years. Particularly, interventional radiologists have evolved to play a significant role in treating patients with vascular pathologies such as massive pulmonary embolism. In this article, we discuss management of these critically ill patients using four pulmonary and bronchial vascular interventional procedures: bronchial artery embolization in the setting of hemoptysis; pulmonary artery embolization in the setting of the treatment of AVM; thrombectomy and thrombolysis of the pulmonary arteries for the treatment of pulmonary embolism; and catheter-directed stent placement in the treatment of superior vena cava syndrome.

Incidental PET/CT Detection of Breast Cancer in a Patient with Negative Mammogram and Breast Sonogram.

We present the case of a 57-year-old woman with known Hodgkins lymphoma who presented with PET/CT findings of a breast mass and diseased axillary lymph node despite negative results from a recent routine mammogram and ultrasound. Needle biopsy of the mass and lymph node confirmed a diagnosis of infiltrating ductal carcinoma of the breast with nodal metastases.