Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial.

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial. Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone. Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022. Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing. Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm. Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals. Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

Palliation or Prolongation? The Impact of a Peer-Review Intervention on Shortening Radiotherapy Schedules for Bone Metastases.

PURPOSE: Shorter fractionation radiation regimens for palliation of bone metastases result in lower financial and social costs for patients and their caregivers and have similar efficacy as longer fractionation schedules, although practice patterns in the United States show poor adoption. We investigated whether prospective peer review can increase use of shorter fractionation schedules. METHODS: In June 2016, our practice mandated peer review of total dose and fractionation for all patients receiving palliative treatment during our weekly chart rounds. We used descriptive statistics and Fisher's exact test to compare lengths of treatment of uncomplicated bone metastases before and after implementation of the peer review process. RESULTS: Between July 2015 and December 2016, a total of 242 palliative treatment courses were delivered, including 105 courses before the peer review intervention and 137 after the intervention. We observed greater adoption of shorter fractionation regimens after the intervention. The use of 8 Gy in one fraction increased from 2.8% to 13.9% of cases postadoption. Likewise, the use of 20 Gy in five fractions increased from 25.7% to 32.8%. The use of 30 Gy in 10 fractions decreased from 55.2% to 47.4% ( P = .002), and the use of ≥ 11 fractions decreased from 16.2% before the intervention to 5.8% after ( P = .006). CONCLUSION: Prospective peer review of palliative regimens for bone metastases can lead to greater adoption of shorter palliative fractionation schedules in daily practice, in accordance with national guidelines. This simple intervention may therefore benefit patients and their caregivers as well as provide value to the health care system.

The Spine Instability Neoplastic Score: an independent reliability and reproducibility analysis.

BACKGROUND: Metastatic vertebral instability has not yet been clearly defined in the literature; there still exists a paucity of reliable criteria to assess the risk of vertebral collapse. PURPOSE: We performed an independent interobserver and intraobserver agreement evaluation of the Spine Instability Neoplastic Score (SINS) and correlated the score with selected clinical cases and the treatment they received. STUDY DESIGN: Independent reliability study for the newly created SINS. PATIENT SAMPLE: Thirty patients who underwent either radiotherapy alone or surgery followed by radiotherapy were randomly selected from the orthopedic surgery and radiotherapy department's databases. OUTCOME MEASURES: Patients were rated and classified for spinal stability using SINS. Intraclass correlation coefficient (ICC) and Fleiss's kappa measures were occupied for reliability analysis. METHODS: Patients who underwent either radiotherapy alone or surgery followed by radiotherapy were randomly selected and classified for spinal stability using the SINS by orthopedic surgeons and nonorthopedic oncology specialists. ICC and Fleiss's kappa were calculated for inter- and intraobserver agreement. A comparative analysis of SINS and the actual management was also conducted. RESULTS: Interobserver ICC reliability for the SINS was 0.79; κ values for location, pain, bone quality, alignment, vertebral body collapse, and posterolateral involvement were 0.81, 0.58, 0.21, 0.45, 0.42, and 0.29 respectively. Intraobserver ICC for the SINS scores was 0.96; ICC values for the same components were 0.98, 0.98, 0.87, 0.88, 0.92, and 0.86, respectively. Potentially unstable lesions (SINS score≥7) were operated on in 62.5%. CONCLUSIONS: SINS seem to be a reproducible tool that could be used equally by multiple specialists to estimate metastatic vertebral stability; however, prospective clinical validation is still pending.

Neoadjuvant chemoradiation therapy for borderline pancreatic adenocarcinoma: report of two cases.

Pancreatic cancer remains as one of the most aggressive human neoplasms, with overall poor survival rates. Radical surgery of the primary lesion is the best option for treatment. Borderline resectable pancreatic tumors (BRPT), defined as partial involvement of peripancreatic vasculature, may benefit from neoadjuvant therapy. We report on the first two BRPT cases treated with neoadjuvant chemoradiation at our institution. Preoperative CT and MRI demonstrated pancreatic tumors encasing the porto-mesenteric confluence suggestive of BRPT. Patients received neoadjuvant chemotherapy (gemcitabine/cisplatin), followed by radiochemotherapy. After treatment, follow-up images demonstrated tumor downsize, allowing for the tumors to be considered then as resectable. They underwent partial pancreatoduodenectomies (Whipple procedure). In case 1, histopathology revealed a complete, margin-free resection, whereas in case 2 there was a complete pathological response, with no evidence of residual tumor. According to the literature, our initial experience using neoadjuvant chemoradiotherapy on BRPT allowed us to downsize the tumor and, subsequently, to perform a curative surgery.

Tratamiento del cáncer de próstata con radioterapia por modulación de intensidad, primera experiencia en Chile / Intensity modulated radiotherapy treatment for prostate cancer, first experience in Chile

Background: Intensity modulated radiotherapy (IMRT) is an important step forward in cancer treatment. Aim: To report the first experience in Chile with IMRT for prostate cancer and compare the results obtained with different doses. Patients and Methods: From January 1997 through June 2008, 156 patients with a mean age of 70 years, were treated with radiotherapy and 121 with IMRT. Patients were staged according to American Commission on Cancer Staging. Their biochemical relapse risk was classified according to the MD Anderson classification. Patients were routinely checked during and after therapy to evaluate side effects and relapse. Results: Median follow up was 46 months (4-120). Overall five years survival was 85%. Biochemical relapse free five years survival for low, intermediate and high risk patients was 100, 82 and 70%, respectively. Biochemical relapse free survival for patients receiving radiotherapy doses over 76 Gy was 83%, compared to 30% for those receiving lower doses (p < 0.05). Urinary and gastrointestinal acute toxicity was low in 80% and 90% of patients respectively. Late toxicity developed in less than 3% of patients. Conclusions: IMRTforprostate cancer is readily available and safe in Chile. Biochemical disease free survival improved with higher doses with low toxicity rates.

[Intensity modulated radiotherapy treatment for prostate cancer, first experience in Chile]. / Tratamiento del cáncer de próstata con radioterapia por modulación de intensidad, primera experiencia en Chile.

BACKGROUND: Intensity modulated radiotherapy (IMRT) is an important step forward in cancer treatment. AIM: To report the first experience in Chile with IMRT for prostate cancer and compare the results obtained with different doses. PATIENTS AND METHODS: From January 1997 through June 2008, 156 patients with a mean age of 70 years, were treated with radiotherapy and 121 with IMRT. Patients were staged according to American Commission on Cancer Staging. Their biochemical relapse risk was classified according to the MD Anderson classification. Patients were routinely checked during and after therapy to evaluate side effects and relapse. RESULTS: Median follow up was 46 months (4-120). Overall five years survival was 85%. Biochemical relapse free five years survival for low, intermediate and high risk patients was 100, 82 and 70%, respectively. Biochemical relapse free survival for patients receiving radiotherapy doses over 76 Gy was 83%, compared to 30% for those receiving lower doses (p < 0.05). Urinary and gastrointestinal acute toxicity was low in 80% and 90% of patients respectively. Late toxicity developed in less than 3% of patients. CONCLUSIONS: IMRT for prostate cancer is readily available and safe in Chile. Biochemical disease free survival improved with higher doses with low toxicity rates.

Extrahepatic bile duct adenocarcinoma: patients at high-risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard-risk treated with surgery alone.

BACKGROUND: Patients with resected extrahepatic bile duct adenocarcinoma who have microscopically positive resection margins and/or pathologic locoregional nodal involvement (R1pN1) have a high-risk of locoregional recurrence, and therefore, we advocate the use of adjuvant chemoradiation. To evaluate the safety and effectiveness of this treatment, we compared survival and side effects outcomes between such patients and patients with negative resection margins and pathologically negative nodes (R0pN0) who did not receive adjuvant treatment. METHODS: Between 1984 and 2005, 65 patients were treated with curative-intended resection for extrahepatic bile duct adenocarcinoma. Patients with tumors arising in the gallbladder and periampullary region were excluded. Pathology and diagnostic images were centrally reviewed. Overall survival and locoregional recurrence outcomes for patients with standard-risk R0pN0 (surgery alone, or S group, n = 23) were compared with those of patients with high locoregional recurrence risk, R1 and/or pN1 (R1pN1) status who received adjuvant chemoradiation (S-CRT group, n = 42). RESULTS: The median follow-up for the entire group was 31 months. Patients in the S-CRT and S groups had a similar 5-year overall survival (36% vs. 42%, P = .6) and locoregional recurrence (5-year rate: 38% vs. 37%, P = .13). In the S-CRT group, three patients (7%) experienced an acute (grade 3 or more) side effect. CONCLUSIONS: Our finding of a lack of a survival difference between the S and S-CRT groups suggests that for patients with extrahepatic bile duct adenocarcinoma at high risk for locoregional recurrence (i.e., R1 resection or pN1 disease), adjuvant chemoradiation provides an equivalent overall survival despite of these worse prognostic features.

Preserving functional lung using perfusion imaging and intensity-modulated radiation therapy for advanced-stage non-small cell lung cancer.

PURPOSE: To assess quantitatively the impact of incorporating functional lung imaging into intensity-modulated radiation therapy planning for locally advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Sixteen patients with advanced-stage NSCLC who underwent radiotherapy were included in this study. Before radiotherapy, each patient underwent lung perfusion imaging with single-photon-emission computed tomography and X-ray computed tomography (SPECT-CT). The SPECT-CT was registered with simulation CT and was used to segment the 50- and 90-percentile hyperperfusion lung (F50 lung and F90 lung). Two IMRT plans were designed and compared in each patient: an anatomic plan using simulation CT alone and a functional plan using SPECT-CT in addition to the simulation CT. Dosimetric parameters of the two types of plans were compared in terms of tumor coverage and avoidance of normal tissues. RESULTS: In incorporating perfusion information in IMRT planning, the median reductions in the mean doses to the F50 and F90 lung in the functional plan were 2.2 and 4.2 Gy, respectively, compared with those in the anatomic plans. The median reductions in the percentage of volume irradiated with >5 Gy, >10 Gy, and >20 Gy in the functional plans were 7.1%, 6.0%, and 5.1%, respectively, for F50 lung, and 11.7%, 12.0%, and 6.8%, respectively, for F90 lung. A greater degree of sparing of the functional lung was achieved for patients with large perfusion defects compared with those with relatively uniform perfusion distribution. CONCLUSION: Function-guided IMRT planning appears to be effective in preserving functional lung in locally advanced-stage NSCLC patients.

Comparison of outcomes for patients with unresectable, locally advanced non-small-cell lung cancer treated with induction chemotherapy followed by concurrent chemoradiation vs. concurrent chemoradiation alone.

PURPOSE: To retrospectively compare outcomes for patients with unresectable locally advanced non-small-cell lung cancer (NSCLC) treated at our institution with concurrent chemoradiation with or without induction chemotherapy. METHODS AND MATERIALS: We retrospectively analyzed 265 consecutive patients who received definitive treatment with three-dimensional conformal radiation and concurrent chemotherapy. Of these, 127 patients received induction chemotherapy before concurrent chemoradiation. RESULTS: The two groups of patients (with induction vs. without induction chemotherapy) were similar in age, performance status, weight loss, histology, grade, and stage. Patients who received induction chemotherapy had better overall survival (median, 1.9 vs. 1.4 years; 5-year rate, 25% vs. 12%; p < 0.001) and distant metastasis-free survival (5-year rate, 42% vs. 23%; p = 0.021). Locoregional control was not significantly different between the two groups. Multivariate analysis showed that induction chemotherapy was the most significant factor affecting overall survival, with a hazard ratio of 0.55 (95% confidence interval 0.40-0.75; p < 0.001). A planned subgroup analysis showed that induction chemotherapy was associated with a significant overall survival benefit for patients with adenocarcinoma or large-cell carcinoma (5-year rate, 24% vs. 8%; p = 0.003) but not for those with squamous cell carcinoma. A multivariate analysis of patients with adenocarcinoma or large-cell carcinoma confirmed that induction chemotherapy was the most significant factor associated with better overall survival, with a hazard ratio of 0.47 (95% confidence interval, 0.28-0.78; p = 0.003). CONCLUSION: Our retrospective analysis suggests that in combination with concurrent chemoradiation, induction chemotherapy may provide a small but significant survival benefit for patients with unresectable locally advanced adenocarcinoma or large-cell carcinoma of the lung.

Multileaf field-in-field forward-planned intensity-modulated dose compensation for whole-breast irradiation is associated with reduced contralateral breast dose: a phantom model comparison.

PURPOSE: Static multileaf collimated field-in-field forward-planned intensity-modulated radiation treatment (FiF-IMRT) has been shown to improve dose homogeneity compared to conventional wedged fields. However, a direct comparison of the scattered dose to the contralateral breast resulting from wedged and FiF-IMRT plans remains to be documented. METHODS: The contralateral scattered breast dose was measured in a custom-designed anthropomorphic breast phantom in which 108 thermoluminescent dosimeters (TLDs) were volumetrically placed every 1-2cm. The target phantom breast was treated to a dose of 50Gy using three dose compensation techniques: No medial wedge and a 30-degree lateral wedge (M0-L30), 15-degree lateral and medial wedges (M15-L15), and FiF-IMRT. TLD measurements were compared using analysis of variance. RESULTS: For FiF-IMRT, the mean doses to the medial and lateral quadrants of the contralateral breast were 112cGy (range 65-226cGy) and 40cGy (range 18-91 cGy), respectively. The contralateral breast doses with FiF-IMRT were on average 65% and 82% of the doses obtained with the M15-L15 and M0-L30 techniques, respectively (p<0.001). Compared to the M15-L15 technique, the maximum dose reduction obtained with FiF-IMRT was 115cGy (range 13-115cGy). CONCLUSIONS: The dose to the contralateral breast is significantly reduced with FiF-IMRT compared to wedge-compensated techniques. Although long-term follow-up is needed to establish the clinical relevance of this finding, these results, along with the previously reported improvement in ipsilateral dose homogeneity, support the use of FiF-IMRT if resources permit.

Quantification of regional ventilation from treatment planning CT.

PURPOSE: We describe a method of quantifying regional ventilation from the radiotherapy treatment planning computed tomography (CT) images, with the goal of developing functional images for treatment planning and optimization. METHODS AND MATERIALS: A series of exhalation breath-hold (eBH-CT) and inhalation breath-hold (iBH-CT) CT images obtained using a feedback-guided breath-hold technique for radiotherapy treatment planning was selected. The eBH-CT was mapped on a voxel-by-voxel basis to the iBH-CT using a deformable image registration algorithm. By using the average CT number over a 3 mm(3) region surrounding each pair of mapped voxels, the change in fraction of air per voxel (i.e., regional ventilation) was calculated. This methodology was applied to a series of 22 patients. The calculated total ventilation was compared to the change in contoured lung volumes between the exhalation and inhalation CTs (measured tidal volume). RESULTS: A significant correlation was found between the calculated and measured tidal volumes for the left (R = 0.982) and right (R = 0.985), and for both lungs combined (R = 0.985). In the resulting images, the regional ventilation was highly variable and corresponded with the spatial distribution of differences in the CT values (Hounsfield units) between the eBH-CT and the iBH-CT images. CONCLUSIONS: A method of quantifying regional ventilation from radiotherapy treatment planning CT data sets was demonstrated. The ventilation images can be used in plan optimization to minimize injury to functioning lung.