Abstract OBJECTIVE For patients with HER2-positive breast cancer metastatic to brain, HER2-directed systemic therapies are increasingly used with stereotactic radiosurgery (SRS). These include monoclonal antibodies such as trastuzumab (H) and pertuzumab (P), antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1), and tyrosine kinase inhibitors such as lapatinib. Limited data exist regarding appropriate timing with SRS and outcomes of this treatment regimen. METHODS A single-institution retrospective review collected clinical data on patients with breast cancer metastatic to brain who were treated with SRS from 2009-2020. Statistical analyses were performed using the Kaplan-Meier method and chi-square statistic. RESULTS Of 82 patients with breast cancer metastatic to brain treated with SRS, 33 (40%) were HER2-positive, 18 of whom were hormone receptor-positive. At brain metastasis diagnosis, 15 patients (45%) had >1 intracranial metastasis (range 2-7), and the median brain metastasis maximal dimension was 2.0 cm. Fifteen patients had uncontrolled extracranial disease. After brain metastasis diagnosis, 9 patients (27%) were treated with systemic therapy first (T-DM1+/-HP, lapatinib+HP, chemotherapy+/-HP) followed by SRS at a median of 18.6 months after starting systemic therapy. Seven patients (21%) were treated with SRS first, followed by systemic therapy in 6 of these patients (multi-agent regimens, 4 including T-DM1 or lapatinib). Seventeen (52%) received concurrent systemic therapy and SRS (T-DM1+/-chemotherapy, lapatinib, HP, hormone therapy, chemotherapy). Median follow-up time was 21.1 months. Median overall survival was 24.8 months and not statistically different between treatment groups. Four patients (12%) developed symptomatic radionecrosis; 3 were on T-DM1 concurrent with SRS. CONCLUSION In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.

In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to the brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.

The authors here demonstrate how, with a thoughtful study design, we can use existing data to advance a timely affordable manner clinically-relevant questions oncology.

Purpose/Objective(s): We sought to assess the utility of docetaxel administered concurrently with salvage radiation therapy (SRT) following postprostatectomy biochemical failure (BF). Methods and materials: Men with postprostatectomy BF were accrued on a single-arm phase 2 clinical trial. SRT doses ranged from 64.8 to 70.2 Gy and were delivered in 1.8-Gy fractions to the prostate bed alone as the clinical target volume with a +1-cm uniform planning target volume expansion. The primary endpoint was progression-free survival at 4 years compared with the Stephenson nomogram estimate. Kaplan-Meier methods were used to assess late toxicity, BF, and distant metastases. An unplanned matched-pair analysis was performed with 19 patients treated with SRT alone. Results: Nineteen men were accrued and treated. Median follow-up was 4.8 years. Median pre-RT prostate-specific antigen level was 0.7 ng/mL (interquartile range, 0.4-1.3 ng/mL). All 8 cycles of docetaxel were completed in 17 (89%) patients. Acute grade 1-4 toxicities were observed in 79%, 50%, 58%, and 11%, respectively. A total of 68% of acute grade 1 toxicities were related to fatigue, urinary, or bowel symptoms. For grade 2 toxicities, 76% were related to neutropenia, fatigue, or urinary symptoms. Acute grade 3 and 4 toxicities were most commonly neutropenia (84% and 100%, respectively). All late toxicities were grade 1 to 2 with 89% related to bowel or urinary function. Predicted 4-year progression-free survival was 39% and observed was 42% (90% confidence interval [CI], 24-60). Matched-pair analysis demonstrated no significant improvement in BF (P = .96, hazard ratio, 0.98; 90% CI, 0.4-2.3) or distant metastases (P = .09; hazard ratio, 0.3; 90% CI, 0.07-1.2), and no difference between late bowel (P = .60) or urinary toxicity (P = .41). Conclusions: Docetaxel can safely be administered concurrently with SRT without significantly impacting posttreatment toxicity. Neutropenia was the most significant acute toxicity. Given the small sample size, no clear clinical benefit was observed. Larger studies are needed to determine the efficacy of concurrent docetaxel in this setting.

Purpose/Objective(s)Low-risk PCa patients have excellent outcomes, with treatment selection often determined by patient preference and perceived impact of treatment modality on QOL. Acute urinary symptoms are common during external beam therapy, while chronic symptoms have been linked to urethral dose. Since most low risk PCa occurs in the peripheral zone, we hypothesized that US-IMRT could improve urinary toxicity while maintaining biochemical control.Materials/MethodsLow-risk PCa patients (Gleason < or = 6, PSA < or = 10, and T1c) with no visible lesion within 5 mm of the prostatic urethra on MRI were randomized to US-IMRT or standard (S) IMRT. The PTV was the MRI-defined peripheral zone + 3-5 mm for US-IMRT and the prostate + 3 mm for S-IMRT. The PTV was prescribed 75.6 Gy in 41 fractions (max < or = 115%; min > or = 93%). The prostatic urethral planning organ-at-risk volume (U-PRV) was the urethra + 3 mm, limited to 65 Gy to the proximal and 74 Gy to the distal U-PRV. Fiducial markers were used for image guidance. The expanded prostate cancer index (EPIC) QOL questionnaire was completed at baseline, during treatment, and at each follow-up. The primary endpoint was the change in EPIC Urinary Function Score at 3 months. To demonstrate a 9 point improvement (1/2 SD) in urinary QOL at 3 months (80% power using a two-sided t-test at a 0.05 significance level) would require 63 pts per arm. Secondary endpoints included PSA failure (nadir + 2) (BF), time to progression, and overall survival.ResultsFrom 6/04-11/06, 16 evaluable pts were enrolled with median follow-up of 4.7 years. An unplanned futility analysis concluded that continued accrual was unlikely to demonstrate a difference in the primary endpoint. There was no difference in baseline EPIC urinary QOL (85.4 and 86.8) in the control and experimental arms, respectively. The mean change in EPIC urinary QOL at 3 months was +0.7 in the S-IMRT arm and -1.4 in the US-IMRT arm. There were no differences between arms in the remaining 4 EPIC domains. Median PSA nadir was higher in the US-IMRT arm (0.7 vs. 1.3, p = 0.05). Three pts with US-IMRT and 0 pts with S-IMRT experienced BF, with 2 year BF 25% in the US-IMRT arm and 0% in the S-IMRT arm (p = 0.08, log-rank; HR 7.8, 95% CI 0.8 - 75). All 3 failures underwent biopsy (2.2, 3.1, and 4.4 years since end of RT) and 2 were positive (one with and one without treatment effect). Both biopsy proven recurrences were contralateral to the original site of PCa. No distant failures or deaths occurred.ConclusionsUS-IMRT failed to improve urinary QOL, but resulted in a higher PSA nadir and inferior biochemical control. The contralateral local failures, despite low-risk features and MRI screening, should serve as a cautionary tale for focal PCa treatments. Purpose/Objective(s)Low-risk PCa patients have excellent outcomes, with treatment selection often determined by patient preference and perceived impact of treatment modality on QOL. Acute urinary symptoms are common during external beam therapy, while chronic symptoms have been linked to urethral dose. Since most low risk PCa occurs in the peripheral zone, we hypothesized that US-IMRT could improve urinary toxicity while maintaining biochemical control. Low-risk PCa patients have excellent outcomes, with treatment selection often determined by patient preference and perceived impact of treatment modality on QOL. Acute urinary symptoms are common during external beam therapy, while chronic symptoms have been linked to urethral dose. Since most low risk PCa occurs in the peripheral zone, we hypothesized that US-IMRT could improve urinary toxicity while maintaining biochemical control. Materials/MethodsLow-risk PCa patients (Gleason < or = 6, PSA < or = 10, and T1c) with no visible lesion within 5 mm of the prostatic urethra on MRI were randomized to US-IMRT or standard (S) IMRT. The PTV was the MRI-defined peripheral zone + 3-5 mm for US-IMRT and the prostate + 3 mm for S-IMRT. The PTV was prescribed 75.6 Gy in 41 fractions (max < or = 115%; min > or = 93%). The prostatic urethral planning organ-at-risk volume (U-PRV) was the urethra + 3 mm, limited to 65 Gy to the proximal and 74 Gy to the distal U-PRV. Fiducial markers were used for image guidance. The expanded prostate cancer index (EPIC) QOL questionnaire was completed at baseline, during treatment, and at each follow-up. The primary endpoint was the change in EPIC Urinary Function Score at 3 months. To demonstrate a 9 point improvement (1/2 SD) in urinary QOL at 3 months (80% power using a two-sided t-test at a 0.05 significance level) would require 63 pts per arm. Secondary endpoints included PSA failure (nadir + 2) (BF), time to progression, and overall survival. Low-risk PCa patients (Gleason < or = 6, PSA < or = 10, and T1c) with no visible lesion within 5 mm of the prostatic urethra on MRI were randomized to US-IMRT or standard (S) IMRT. The PTV was the MRI-defined peripheral zone + 3-5 mm for US-IMRT and the prostate + 3 mm for S-IMRT. The PTV was prescribed 75.6 Gy in 41 fractions (max < or = 115%; min > or = 93%). The prostatic urethral planning organ-at-risk volume (U-PRV) was the urethra + 3 mm, limited to 65 Gy to the proximal and 74 Gy to the distal U-PRV. Fiducial markers were used for image guidance. The expanded prostate cancer index (EPIC) QOL questionnaire was completed at baseline, during treatment, and at each follow-up. The primary endpoint was the change in EPIC Urinary Function Score at 3 months. To demonstrate a 9 point improvement (1/2 SD) in urinary QOL at 3 months (80% power using a two-sided t-test at a 0.05 significance level) would require 63 pts per arm. Secondary endpoints included PSA failure (nadir + 2) (BF), time to progression, and overall survival. ResultsFrom 6/04-11/06, 16 evaluable pts were enrolled with median follow-up of 4.7 years. An unplanned futility analysis concluded that continued accrual was unlikely to demonstrate a difference in the primary endpoint. There was no difference in baseline EPIC urinary QOL (85.4 and 86.8) in the control and experimental arms, respectively. The mean change in EPIC urinary QOL at 3 months was +0.7 in the S-IMRT arm and -1.4 in the US-IMRT arm. There were no differences between arms in the remaining 4 EPIC domains. Median PSA nadir was higher in the US-IMRT arm (0.7 vs. 1.3, p = 0.05). Three pts with US-IMRT and 0 pts with S-IMRT experienced BF, with 2 year BF 25% in the US-IMRT arm and 0% in the S-IMRT arm (p = 0.08, log-rank; HR 7.8, 95% CI 0.8 - 75). All 3 failures underwent biopsy (2.2, 3.1, and 4.4 years since end of RT) and 2 were positive (one with and one without treatment effect). Both biopsy proven recurrences were contralateral to the original site of PCa. No distant failures or deaths occurred. From 6/04-11/06, 16 evaluable pts were enrolled with median follow-up of 4.7 years. An unplanned futility analysis concluded that continued accrual was unlikely to demonstrate a difference in the primary endpoint. There was no difference in baseline EPIC urinary QOL (85.4 and 86.8) in the control and experimental arms, respectively. The mean change in EPIC urinary QOL at 3 months was +0.7 in the S-IMRT arm and -1.4 in the US-IMRT arm. There were no differences between arms in the remaining 4 EPIC domains. Median PSA nadir was higher in the US-IMRT arm (0.7 vs. 1.3, p = 0.05). Three pts with US-IMRT and 0 pts with S-IMRT experienced BF, with 2 year BF 25% in the US-IMRT arm and 0% in the S-IMRT arm (p = 0.08, log-rank; HR 7.8, 95% CI 0.8 - 75). All 3 failures underwent biopsy (2.2, 3.1, and 4.4 years since end of RT) and 2 were positive (one with and one without treatment effect). Both biopsy proven recurrences were contralateral to the original site of PCa. No distant failures or deaths occurred. ConclusionsUS-IMRT failed to improve urinary QOL, but resulted in a higher PSA nadir and inferior biochemical control. The contralateral local failures, despite low-risk features and MRI screening, should serve as a cautionary tale for focal PCa treatments. US-IMRT failed to improve urinary QOL, but resulted in a higher PSA nadir and inferior biochemical control. The contralateral local failures, despite low-risk features and MRI screening, should serve as a cautionary tale for focal PCa treatments.

To identify predictive factors for local control (LC), overall survival (OS), and long-term morbidity for a large, single-institution cohort of patients with soft tissue sarcoma (STS). From 1985 to 2006, 233 patients with non-metastatic STS were treated with surgical resection and radiotherapy. Kaplan-Meier methodology was used to compute rates of LC and OS, and uni/multivariate Cox regression analyses were conducted to determine their association with patient characteristics, tumor features, and treatment methods. The association between joint stiffness at one year post-treatment and the above parameters was tested using chi-squared and Fisher's exact tests. Two-hundred ten patients (90.1%) presented with primary malignancy, while 23 patients (9.9%) sought treatment for disease recurrence. The primary site was in the extremity in 88% of patients and in the superficial abdomen/thorax in 12%. Radiotherapy was preoperative, postoperative, or both in 4%, 93%, and 3% of patients, respectively. Median dose was 63 Gy (range, 1.8 – 100). The planning target volume (PTV) involved a joint in 121 cases (51.9%). Median follow-up was 3.9 years for all patients and 4.3 years for living patients. LC was 81.5% at five years for all patients. Both univariate and multivariate analysis showed that only radiation dose was significantly associated with LC (p = 0.03). At five years, LC was 83.5% for those treated with 63 Gy or greater, compared to 58.9% for those treated to less than 63 Gy. OS was 76.2% at five years and 52.9% at ten years. On multivariate analysis, positive margins (p = 0.048), chemotherapy (p<0.01), truncal location (p = 0.04), advanced age (p<0.01), and synovial sarcoma and MFH histologies (p = 0.01) were associated with decreased survival. Higher radiation doses were associated with increased survival (p = 0.02). At five years, OS was 77.5% for those treated with 63 Gy or greater, compared to 60.0% for those treated to less than 63 Gy. With regard to morbidity, 36 (15.4%) and 29 (12.4%) patients experienced edema or joint stiffness, respectively, at 1 year. Joint involvement within the PTV was significantly associated with stiffness (p = 0.03). In this large retrospective series, radiation dose was the only predictor of local control in patients treated with surgery and radiation for soft tissue sarcomas. Our analysis suggests that doses of 63 Gy or higher are required for optimal local control and survival. To avoid the morbidity associated with PTV encroachment upon a joint, more sophisticated/conformal planning is required.

Studies have demonstrated a dosimetric advantage for IMRT in breast/chest wall (CW) and regional nodal irradiation, especially when targeting internal mammary nodes (IMN). Yet clinical data remains limited. This analysis is one of the first, and largest, clinical data presented to date on women treated with IMRT and IGRT for adjuvant loco-regional breast cancer treatment. Forty-three women received IMRT radiotherapy on a Tomotherapy machine between 2004 and 2007. Median follow-up is 7 months. Median age is 53 years. Fifteen were premenopausal and 28 postmenopausal. All women received definitive breast and axillary surgery. Average number of lymph nodes removed was 15. Average number of lymph nodes positive was 7. Forty-two of 43 women received chemotherapy, 58% of whom received adriamycin-based regimens and 33% had herceptin. Seventy-eight percent were ER positive. All women received CW/breast, supraclavicular, infraclavicular, and internal mammary radiotherapy. Sixty-nine percent received axillary radiation. An IMRT was used to treat all targets. All patients received daily megavoltage CTs to adjust for set-up errors. Average CW/breast, SCV, IFCV, Axilla, and IMN doses were 49.8 Gy +/− 2.0, 50 Gy +/− 2.7, 51.4 +/− 2.3, 50.7 +/− 3.6, and 50 +/− 2.1, respectively. Mean heart max point dose is 40.9 Gy +/− 6.1. Average mean lung dose as 13.7 Gy +/− 2.7. Mean cord max point dose is 31 Gy +/− 8.0. No patient has suffered a loco-regional recurrence. One-year disease free survival is 95.3%. Eleven percent experienced Grade 2 or 3 acute skin toxicity. Nine percent had nausea during treatment. Nine percent had dysphagia. One patient had clinical pneumonitis, which resolved. No patient has had documented heart complications to date. An IMRT and IGRT for adjuvant loco-regional radiotherapy are feasible in breast cancer patients. Acute skin toxicity, nausea, and dysphagia have been tolerable. There has been no local recurrences, no long-term heart or lung complications, but follow-up has been short and longer follow-up will be required.

Abstract Purpose: The PI3K/Akt/mTOR prosurvival pathway is frequently up-regulated in soft tissue sarcoma. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, have recently shown clinical benefit in soft tissue sarcoma, and mTOR inhibition has also been associated with radiosensitization of carcinoma and endothelial cells. This study tested the hypothesis that rapamycin radiosensitizes soft tissue sarcoma and endothelial cells in vitro and in vivo through the inhibition of mTOR. Experimental Design: Colony formation assays were done to determine the radiosensitizing properties of rapamycin on three human soft tissue sarcoma cell lines (SK-LMS-1, SW-872, and HT-1080) and human dermal microvascular endothelial cells (HDMEC). The functional effects of rapamycin and radiation on the endothelial compartment were evaluated with microvascular sprouting assays. The in vivo radiosensitizing activity of rapamycin was assessed with s.c. SK-LMS-1 nude mice xenografts treated with concurrent daily rapamycin, radiation, or both for three weeks. Results:In vitro radiosensitization was shown in all three soft tissue sarcoma cell lines with minimally cytotoxic doses of rapamycin. SK-LMS-1 xenografts displayed significant tumor growth delay with rapamycin and radiation compared with either treatment alone. Radiation resulted in transient increased mTOR function, whereas rapamycin abolished this signaling in irradiated and unirradiated samples. In HDMEC, rapamycin and radiation reduced microvessel sprouting, but did not alter colony formation. Conclusions: Minimally cytotoxic concentrations of rapamycin inhibited the mTOR cascade in culture and in vivo while radiosensitizing soft tissue sarcoma, and produced synergistic effects with radiation on HDMEC microvessel formation. By targeting both tumor and endothelial compartments, rapamycin produced potent radiosensitization of soft tissue sarcoma xenografts. Clinical trials combining rapamycin and radiotherapy in soft tissue sarcoma are warranted.

The identification of surrogate endpoints for survival would accelerate the conduct of prostate cancer clinical trials. We evaluated the incidence of distant metastasis (DM) and general clinical failure (GCF) as potential surrogate markers for cause-specific survival (CSS) using data from RTOG 9202. Men with locally-advanced prostate cancer were treated with 4 months of neoadjuvant and concurrent androgen deprivation (AD) with external beam radiation therapy (RT) followed by no additional therapy (standard arm) or 24 additional months of AD (experimental arm). General clinical failure (GCF) was defined as local progression, regional/distant metastasis, initiation of hormonal therapy, or PSA ≥ 25 ng/mL after completion of RT (Taylor et al, IJROBP 50:1212, 2001). DM and GCF with 5 years follow up were formally tested for surrogacy for CSS at 10 years. Surrogacy testing utilized Prentice's criteria: 1) that the treatment is prognostic for the true endpoint; 2) that the treatment is prognostic for the surrogate endpoint; 3) that the surrogate endpoint is prognostic for the true endpoint; and 4) that the full effect of treatment on the true endpoint is explained by the surrogate. Landmark analyses at 3 and 5 years were performed to address potential follow up length bias. Among 1521 eligible, randomized patients, there were 218 cause-specific deaths, 291 DMs and 726 GCFs. The 10-year CSS was 85% in the standard arm, compared with 89% in the experimental arm (p = 0.0089). The 5-year DM and GCF rates were 14% and 43% in the standard arm, compared with 9% and 33% in the experimental arm (HR = 1.7 [1.2–2.4] and 1.6 [1.3–1.9], respectively). Both 5-year DM and 5-year GCF were significantly associated with 10-year CSS (p < 0.0001 and p = 0.0005, respectively). 10-year CSS was independent of treatment among patients who experienced DM (p = 0.63) or GCF (p = 0.23), and 10-year CSS was independent of treatment among patients who did not experience DM (p = 0.60) or GCF (p = 0.69), indicating that the 5-year surrogates both capture the full effect of treatment on 10-year CSS. Therefore, without adjusting for length bias, 5-year DM and GCF both satisfied all of Prentice's criteria for 10-year CSS. The analysis using only the 1364 patients alive at landmark time 3 years, showed that both 3-year DM and GCF satisfied all of Prentice's criteria for 10-year CSS. In the 1178 patients alive at a landmark time of 5 years, there was no statistical difference in CSS between the treatment arms (p = 0.08). Nonetheless, 5-year DM and GCF met the most important of the remaining Prentice's criteria for 10-year CSS. This analysis of patient data from RTOG 9202 demonstrates that DM and GCF at 5 years satisfy Prentice's surrogacy criteria for CSS at 10 years. These endpoints should be validated in future randomized clinical trials for localized prostate cancer.