A Phase 1 study Combining Pexidartinib, Radiation Therapy, and Androgen Deprivation Therapy in Men With Intermediate- and High-Risk Prostate Cancer.

PURPOSE: This study aimed to evaluate a combination of radiation therapy (RT), androgen deprivation therapy (ADT), and pexidartinib (colony-stimulating factor 1 receptor [CSF1R]) inhibitor in men with intermediate- and high-risk prostate cancer. CSF1R signaling promotes tumor infiltration and survival of tumor-associated macrophages, which in turn promote progression and resistance. Counteracting protumorigenic actions of tumor-associated macrophages via CSF1R inhibition may enhance therapeutic efficacy of RT and ADT for prostate cancer. METHODS AND MATERIALS: In this phase 1 study, the treatment regimen consisted of pexidartinib (800 mg, administered as a split-dose twice daily) and ADT (both for a total of 6 months), and RT that was initiated at the start of month 3. RT volumes included the prostate and proximal seminal vesicles. The delivered dose was 7920 cGy (180 cGy per fraction) using intensity modulated RT with daily image guidance for prostate localization. The primary objective was to identify the maximum tolerated dose based on dose-limiting toxicities. RESULTS: All 4 enrolled patients who were eligible to receive RT had T1 stage prostate cancer, 2 were intermediate risk, and 2 were high risk. The median age was 62.5 years, and the prostate-specific antigen levels were in the range 6.4 to 10.7 ng/mL. The patients' individual Gleason scores were 3 + 3, 4 + 3, 4 + 4, and 4 + 5. All 4 patients reported ≥1 adverse events before RT. Grade 1 hypopigmentation was observed in 1 patient, and grade 3 pulmonary embolus in another. One patient experienced fatigue and joint pain, and another elevated amylase and pruritus (all grade 3 toxicities). Five of the 6 adverse events noted in 3 patients were all grade 3 toxicities attributable to pexidartinib, qualifying as dose-limiting toxicities and ultimately resulting in the study closure. CONCLUSIONS: The combination was not well tolerated and does not warrant further investigation in men with intermediate- and high-risk prostate cancer.

A Three-Dimensional Bioabsorbable Tissue Marker for Volume Replacement and Radiation Planning: A Multicenter Study of Surgical and Patient-Reported Outcomes for 818 Patients with Breast Cancer.

BACKGROUND: Accurate identification of the tumor bed after breast-conserving surgery (BCS) ensures appropriate radiation to the tumor bed while minimizing normal tissue exposure. The BioZorb® three-dimensional (3D) bioabsorbable tissue marker provides a reliable target for radiation therapy (RT) planning and follow-up evaluation while serving as a scaffold to maintain breast contour. METHODS: After informed consent, 818 patients (826 breasts) implanted with the BioZorb® at 14 U.S. sites were enrolled in a national registry. All the patients were prospectively followed with the BioZorb® implant after BCS. The data collected at 3, 6, 12, and 24 months included all demographics, treatment parameters, and provider/patient-assessed cosmesis. RESULTS: The median follow-up period was 18.2 months (range, 0.2-53.4 months). The 30-day breast infection rate was 0.5 % of the patients (n = 4), and re-excision was performed for 8.1 % of the patients (n = 66), whereas 2.6 % of the patients (n = 21) underwent mastectomy. Two patients (0.2 %) had local recurrence. The patient-reported cosmetic outcomes at 6, 12, and 24 months were rated as good-to-excellent by 92.4 %, 90.6 %, and 87.3 % of the patients, respectively and similarly by the surgeons. The radiation oncologists reported planning of target volume (PTV) reduction for 46.2 % of the patients receiving radiation boost, with PTV reduction most commonly estimated at 30 %. CONCLUSIONS: This report describes the first large multicenter study of 818 patients implanted with the BioZorb® tissue marker during BCS. Radiation oncologists found that the device yielded reduced PTVs and that both the patients and the surgeons reported good-to-excellent long-term cosmetic outcomes, with low adverse effects. The BioZorb® 3D tissue marker is a safe adjunct to BCS and may add benefits for both surgeons and radiation oncologists.

Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001.

PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Challenging the conventional treatment of colon cancer by sentinel lymph node mapping and its role of detecting micrometastases for adjuvant chemotherapy.

All colon cancer patients with lymph node (LN) positive disease are treated with chemotherapy. Patients with node negative disease are usually cured by surgery alone. Yet about 20% of patients develop recurrence within 5 years despite node negative status. This may often be the result of missed micrometastases by conventional examination. Sentinel lymph node (SLN) mapping was developed to find those nodes detected by blue dye which was ultrastaged to detect micrometastases. Consecutive patients, underwent SLN mapping with the blue dye with success rate of 99.2%. Average number of LN was 18.3, average number of SLN was 3/patient and overall nodal positivity was 45%. Ten patients had skip metastases. Overall survival of 235 patients was 84 months with survival of node negative patients 97 months versus 68 months for node positive patients. For stage I-IV patients, overall survival was as follows: stage I-115 months, stage II-90 months, stage III-84 months and stage IV-24 months respectively. Patients with micrometastases after chemotherapy had average survival of 108 months versus those without chemotherapy was 50 months. Thus, SLN mapping techniques is highly successful, easily reproducible and finds micrmoetastases in over 15% of patients which could have been missed by conventional pathological examination. These patients when treated with adjuvant chemotherapy have similar survival as those of node negative disease. Similarly, patients without any nodal metastases after SLN mapping and ultrastaging, may be considered as true node negative disease and may avoid further adjuvant chemotherapy.

Systematic development of an abbreviated protocol for screening breast magnetic resonance imaging.

RATIONALE & OBJECTIVES: We sought to develop an abbreviated protocol (AP) for breast MRI that maximizes lesion detection by assessing each lesion not seen on mammography by each acquisition from a full diagnostic protocol (FDP). MATERIALS & METHODS: 671 asymptomatic women (mean 55.7 years, range 40-80) with a negative mammogram were prospectively enrolled in this IRB approved study. All lesions on MRI not visualized on mammography were analyzed, reported, and suspicious lesions biopsied. In parallel, all FDP MRI acquisitions were scored by lesion to eventually create a high-yield AP. RESULTS: FDP breast MRI detected 452 findings not visible on mammography, including 17 suspicious lesions recommended for biopsy of which seven (PPV 41.2%) were malignant in six women. Mean size of the four invasive malignancies was 1.9 cm (range 0.7-4.1), all node negative; three lesions in two women were ductal carcinoma in situ. Nine biopsied lesions were benign, mean size 1.2 cm (range 0.6-2.0). All biopsied lesions were in women with dense breasts (heterogeneously or extremely dense on mammography, n = 367), for a cancer detection rate of 16.3/1000 examinations in this subpopulation. These data were used to identify four high-yield acquisitions: T2, T1-pre-contrast, T11.5, and T16 to create the AP with a scan time of 7.5 min compared to 24 min for the FDP. CONCLUSIONS: Our analysis of a FDP MRI in a mammographically negative group identified four high-yield acquisitions that could be used for rapid screening of women for breast cancer that retains critical information on morphology, histopathology, and kinetic activity to facilitate detection of suspicious lesions.

Cisplatin and etoposide versus carboplatin and paclitaxel with concurrent radiotherapy for stage III non-small-cell lung cancer: an analysis of Veterans Health Administration data.

PURPOSE: The optimal chemotherapy regimen to use with radiotherapy in stage III non-small-cell lung cancer is unknown. Here, we compare the outcome of patents treated within the Veterans Health Administration with either etoposide-cisplatin (EP) or carboplatin-paclitaxel (CP). METHODS: We identified patients treated with EP and CP with concurrent radiotherapy from 2001 to 2010. Survival rates were compared using Cox proportional hazards regression models with adjustments for confounding provided by propensity score methods and an instrumental variables analysis. Comorbidities and treatment complications were identified through administrative data. RESULTS: A total of 1,842 patients were included; EP was used in 27% (n = 499). Treatment with EP was not associated with a survival advantage in a Cox proportional hazards model (hazard ratio [HR], 0.97; 95% CI, 0.85 to 1.10), a propensity score matched cohort (HR, 1.07; 95% CI, 0.91 to 1.24), or a propensity score adjusted model (HR, 0.97; 95% CI, 0.85 to 1.10). In an instrumental variables analysis, there was no survival advantage for patients treated in centers where EP was used more than 50% of the time as compared with centers where EP was used in less than 10% of the patients (HR, 1.07; 95% CI, 0.90 to 1.26). Patients treated with EP, compared with patients treated with CP, had more hospitalizations (2.4 v 1.7 hospitalizations, respectively; P < .001), outpatient visits (17.6 v 12.6 visits, respectively; P < .001), infectious complications (47.3% v 39.4%, respectively; P = .0022), acute kidney disease/dehydration (30.5% v 21.2%, respectively; P < .001), and mucositis/esophagitis (18.6% v 14.4%, respectively; P = .0246). CONCLUSION: After accounting for prognostic variables, patients treated with EP versus CP had similar overall survival, but EP was associated with increased morbidity.

Validation of normal tissue complication probability predictions in individual patient: late rectal toxicity.

PURPOSE: To perform validation of risk predictions for late rectal toxicity (LRT) in prostate cancer obtained using a new approach to synthesize published normal tissue complication data. METHODS AND MATERIALS: A published study survey was performed to identify the dose-response relationships for LRT derived from nonoverlapping patient populations. To avoid mixing models based on different symptoms, the emphasis was placed on rectal bleeding. The selected models were used to compute the risk estimates of grade 2+ and grade 3+ LRT for an independent validation cohort composed of 269 prostate cancer patients with known toxicity outcomes. Risk estimates from single studies were combined to produce consolidated risk estimates. An agreement between the actuarial toxicity incidence 3 years after radiation therapy completion and single-study or consolidated risk estimates was evaluated using the concordance correlation coefficient. Goodness of fit for the consolidated risk estimates was assessed using the Hosmer-Lemeshow test. RESULTS: A total of 16 studies of grade 2+ and 5 studies of grade 3+ LRT met the inclusion criteria. The consolidated risk estimates of grade 2+ and 3+ LRT were constructed using 3 studies each. For grade 2+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.537 compared with 0.431 for the best-fit single study. For grade 3+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.477 compared with 0.448 for the best-fit single study. No evidence was found for a lack of fit for the consolidated risk estimates using the Hosmer-Lemeshow test (P=.531 and P=.397 for grade 2+ and 3+ LRT, respectively). CONCLUSIONS: In a large cohort of prostate cancer patients, selected sets of consolidated risk estimates were found to be more accurate predictors of LRT than risk estimates derived from any single study.

Consolidating risk estimates for radiation-induced complications in individual patient: late rectal toxicity.

PURPOSE: To test the feasibility of a new approach to synthesize published normal tissue complication data using late rectal toxicity in prostate cancer as an example. METHODS AND MATERIALS: A data survey was performed to identify the published reports on the dose-response relationships for late rectal toxicity. The risk estimates for Grade 1 or greater, Grade 2 or greater, and Grade 3 or greater toxicity were obtained for a test cohort of patients treated at our institution. The influence of the potential factors that might have affected the reported toxicity levels was investigated. The studies that did not conform to the general data trends were excluded, and single, combined risk estimates were derived for each patient and toxicity level. RESULTS: A total of 21 studies of nonoverlapping patient populations were identified. Three studies provided dose-response models for more than one level of toxicity. Of these 21 studies, 6, 14, and 5 were used to derive the initial risk estimates for Grade 1, 2, and 3 or greater toxicity, respectively. A comparison of risk estimates between the studies reporting rectal bleeding and rectal toxicity (bleeding plus other symptoms) or between studies with follow-up <36 months and ≥36 months did not reveal significant differences (p ≥ .29 for all comparisons). After excluding three reports that did not conform to the general data trends, the combined risk estimates were derived from 5 reports (647 patients), 11 reports (3,369 patients), and 5 reports (1,330 patients) for Grade 1, 2, and 3 or greater toxicity, respectively. CONCLUSIONS: The proposed approach is feasible and allows for more systematic use of published dose-response data to estimate the complication risks for the individual patient.

Low-dose neoadjuvant external beam radiation therapy for soft tissue sarcoma.

PURPOSE: For soft tissue sarcoma, neoadjuvant external beam radiation therapy (EBRT) to 50 Gy has the same local control (LC) and overall survival as postoperative radiation therapy (PORT) to 60 Gy, but with increased wound complications. We examined whether low-dose neoadjuvant EBRT would decrease acute toxicity while maintaining LC. METHODS AND MATERIALS: From 1971 to 2008, 1,765 patients with nonmetastatic soft tissue sarcoma were treated with radiation therapy at Massachusetts General Hospital. We identified 42 patients treated with low-dose neoadjuvant EBRT (median, 20 Gy; range, 16-26) followed by surgical resection and PORT. PORT included EBRT (25 patients; median, 40 Gy; range, 20-56.2), brachytherapy (13 patients; median, 42 Gy; range, 26-50), and intraoperative radiation therapy (IORT) (4 patients; median, 12.5 Gy; range, 8-20). The median total dose was 63.3 Gy (range, 28-78.4). RESULTS: Median follow-up was 36 months (range, 4-318). Severe acute wound complications were reported in 15 patients (36%) and correlated to PORT technique (16% EBRT, 69% brachytherapy, 50% IORT, p = 0.004). The 5-year LC was 73% and correlated to PORT technique (68% EBRT, 100% brachytherapy, 50% IORT, p = 0.03) and histology (p = 0.05), with a trend to improvement if >60 Gy (p = 0.10). The 5-year overall survival was 65% and correlated to extent of resection (p < 0.001) and margin status (p < 0.001). CONCLUSIONS: Despite using low-dose neoadjuvant EBRT, we report a high rate of severe acute wound complications that was strongly associated with brachytherapy. Modification of the brachytherapy technique may decrease acute toxicity while maintaining excellent local control. Further study must be conducted before recommending broader application.

External beam radiation therapy after transurethral resection of the prostate: a report on acute and late genitourinary toxicity.

PURPOSE: To describe genitourinary (GU) toxicity in men with a history of transurethral resection of the prostate (TURP) treated with external beam radiation therapy (EBRT) for prostate cancer. METHODS AND MATERIALS: Seventy-one men with a history of TURP were treated with EBRT for prostate cancer. The median time from TURP to EBRT was 15 months. The median EBRT dose was 70 Gy, and 21 men (30%) received androgen deprivation therapy (ADT). Acute GU toxicity and late GU toxicity were scored by Radiation Therapy Oncology Group criteria and compared with a cohort of 538 men without prior TURP. The median follow-up for men with TURP and men without TURP was 40 months and 50 months, respectively (p = 0.7605). RESULTS: The rate of acute Grade 2 GU toxicity or higher was 41%, and was increased with a history of more than 1 TURP (73% vs. 31%, p = 0.0036). The 4-year rate of freedom from late Grade 3 GU toxicity or higher was 84%, and was decreased with ADT (45% vs. 95% without ADT, p = 0.0024). By last follow-up, maximal GU toxicity tended to resolve (p < 0.0001) and there was no worsening of urinary symptom scores (p = 0.6911). Compared to men without a prior TURP, TURP patients had a lower rate of freedom from late Grade 3 toxicity or higher (84% vs. 96%, p = 0.0483). Multivariate analysis suggested a higher rate of late Grade 3 toxicity or higher with TURP (risk ratio, 2.87; p = 0.0612) and EBRT dose of 74 Gy or greater (risk ratio, 2.26; p = 0.0521). CONCLUSIONS: Men treated for prostate cancer with EBRT after TURP have a higher risk of severe GU toxicity; however, the overall incidence is low, and toxicity tends not to persist.

A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy.

Using previous dosimetric analysis methods, we identified the volume of bowel receiving 30 Gy (V(30)) correlated with acute gastrointestinal (GI) toxicity in anal cancer patients treated with intensity-modulated radiation therapy and concurrent chemotherapy. For V(30)>450 cc and < or =450 cc, acute GI toxicity was 33% and 8%, respectively (p=0.003).

Association between bone marrow dosimetric parameters and acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy.

PURPOSE: To test the hypothesis that the volume of pelvic bone marrow (PBM) receiving 10 and 20 Gy or more (PBM-V(10) and PBM-V(20)) is associated with acute hematologic toxicity (HT) in anal cancer patients treated with concurrent chemoradiotherapy. METHODS AND MATERIALS: We analyzed 48 consecutive anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiation therapy. The median radiation dose to gross tumor and regional lymph nodes was 50.4 and 45 Gy, respectively. Pelvic bone marrow was defined as the region extending from the iliac crests to the ischial tuberosities, including the os coxae, lumbosacral spine, and proximal femora. Endpoints included the white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin, and platelet count nadirs. Regression models with multiple independent predictors were used to test associations between dosimetric parameters and HT. RESULTS: Twenty patients (42%) had Stage T3-4 disease; 15 patients (31%) were node positive. Overall, 27 (56%), 24 (50%), 4 (8%), and 13 (27%) experienced acute Grade 3-4 leukopenia, neutropenia, anemia, and thrombocytopenia, respectively. On multiple regression analysis, increased PBM-V(5), V(10), V(15), and V(20) were significantly associated with decreased WBC and ANC nadirs, as were female gender, decreased body mass index, and increased lumbosacral bone marrow V(10), V(15), and V(20) (p < 0.05 for each association). Lymph node positivity was significantly associated with a decreased WBC nadir on multiple regression analysis (p < 0.05). CONCLUSION: This analysis supports the hypothesis that increased low-dose radiation to PBM is associated with acute HT during chemoradiotherapy for anal cancer. Techniques to limit bone marrow irradiation may reduce HT in anal cancer patients.

Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: a multicenter experience.

PURPOSE: To report a multicenter experience treating anal canal cancer patients with concurrent chemotherapy and intensity-modulated radiation therapy (IMRT). PATIENTS AND METHODS: From October 2000 to June 2006, 53 patients were treated with concurrent chemotherapy and IMRT for anal squamous cell carcinoma at three tertiary-care academic medical centers. Sixty-two percent were T1-2, and 67% were N0; eight patients were HIV positive. Forty-eight patients received fluorouracil (FU)/mitomycin, one received FU/cisplatin, and four received FU alone. All patients underwent computed tomography-based treatment planning with pelvic regions and inguinal nodes receiving a median of 45 Gy. Primary sites and involved nodes were boosted to a median dose of 51.5 Gy. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All late toxicity was scored using Radiation Therapy Oncology Group criteria. RESULTS: Median follow-up was 14.5 months (range, 5.2 to 102.8 months). Acute grade 3+ toxicity included 15.1% GI and 37.7% dermatologic toxicity; all acute grade 4 toxicities were hematologic; and acute grade 4 leukopenia and neutropenia occurred in 30.2% and 34.0% of patients, respectively. Treatment breaks occurred in 41.5% of patients, lasting a median of 4 days. Forty-nine patients (92.5%) had a complete response, one patient had a partial response, and three had stable disease. All HIV-positive patients achieved a complete response. Eighteen-month colostomy-free survival, overall survival, freedom from local failure, and freedom from distant failure were 83.7%, 93.4%, 83.9%, and 92.9%, respectively. CONCLUSION: Preliminary outcomes suggest that concurrent chemotherapy and IMRT for anal canal cancers is effective and tolerated favorably compared with historical standards.

Evolving use of radiotherapy and radiosurgery in the treatment of pituitary adenomas.

Conventional external beam radiotherapy has been historically employed in the treatment of pituitary adenomas either as a single modality or following suboptimal surgical resection. However, with the widespread adoption of the trans-sphenoidal surgery, the role of radiation therapy has been limited to cases deemed resectable or in those with subtotal resections. Advances in radiotherapy have improved the dose distribution to the pituitary mass while minimizing the volume of normal tissues receiving doses of radiation near or exceeding their inherent tolerances, permitting radiation oncologists to migrate from simple 2D radiation planning to 3D planning. Fractionated radiosurgery, linear-accelerator/gamma source-based radiosurgery, or image-guided/intensity-modulated radiotherapy is now commonly employed. Long-term follow-up data demonstrate excellent progression-free survival and local control along with few complications for all radiation treatment modalities whether employed as monotherapy or following subtotal resection.