Thomas Dipetrillo | Brown University (original) (raw)
Papers by Thomas Dipetrillo
Journal of Clinical Oncology, Jun 20, 2007
9101 Background: Radiofrequency Ablation (RFA) can destroy tissue in a defined area. Single insti... more 9101 Background: Radiofrequency Ablation (RFA) can destroy tissue in a defined area. Single institutions have reported that RFA can reduce pain from bone metastases. To confirm this, the American College of Radiology Imaging Network (ACRIN) completed a multicenter study of RFA for bone metastases. Methods: Eligible patients had bone pain in one dominant site: tumor size < 8 cm, and location > 1 cm from the spinal cord or cauda equina. RFA was performed under CT guidance. The Memorial Pain Assessment Card was used prior to RFA and repeated daily for two weeks, and at 1 and 3 months after RFA. AEs were recorded in addition to four different pain assessment measures: pain relief, patient mood, pain intensity, and pain severity. Results: Fifty-six patients had RFA at 9 centers. Metastatic sites were pelvis (24), chest wall (19), thoracolumbar spine (8), and extremities (5). Six out of 56 patients experienced at least one adverse event of grade 3 or higher, yielding an AE rate of 10.7% (95%CI is 2.6% to18.8%). AEs attributed directly to RFA were nerve injury in 2 patients. Of the 56 participants, 43 completed the 1 month follow-up and 33 completed the 3 month follow-up. At the time of this analysis, assuming that missing data were missing at random and after adjusting for all covariates, RFA showed significant effect in reducing pain at 1 and 3 month follow-up for all 4 pain assessment measures. The average increase in pain relief from pre-RFA to 1 month follow-up is 26.4 (P<0.0001) and the increase from pre-RFA to 3 month follow-up is 17.2 (P=0.003). The average increase in mood from pre-RFA to 1 month follow-up is 21.5 (P<0.0001) and the increase from pre-RFA to 3 month follow-up is 16.3 (P=0.001). The average decrease in pain intensity from pre-RFA to 1 month follow-up is 25.9 (P<0.0001) and the decrease from pre-RFA to 3 month follow-up is 13.0 (P=0.02). The odds of being in lower pain severity at 1 month follow-up is 12.6 (P
Background: Novel strategies are needed to improve the long-term outcomes of patients (pts) with ... more Background: Novel strategies are needed to improve the long-term outcomes of patients (pts) with high-risk prostate cancer treated with hormonal ablation and external beam radiation therapy (XRT). Preclinical data suggest that angiogenesis inhibitors normalize vasculature, reduce hypoxia, and improve the therapeutic index of XRT. To assess the feasibility of combined VEGFR/PDGFR inhibition in combination with XRT, a Phase I study with sunitinib was initiated. Methods: Seventeen men with adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or PSA > 20ng/ml received initial hormonal ablation (leuprolide 22.5mg every 12 weeks + oral bicalutamide 50mg daily) for 4-8 weeks prior to oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks post XRT (prostate and proximal seminal vesicles received 75.6 Gy in 42 fractions with at least 50 Gy for the distal seminal vesicles). A 3+3 sequential dose-escalation design was employed to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose (MTD) of sunitinib. Results: The first 4 pts enrolled on 37.5 mg experienced a DLT during lead-in. *With 2 pts unexpectedly experiencing Grade 3 neutropenia and a third experiencing Grade 3 thrombocytopenia, a drug-interaction with bicalutamide was suspected. The protocol was revised to replace these pts and omit concurrent bicalutamide. Of these first 4 pts, 3 were dose reduced to 25 mg and successfully completed full treatment, while 1 pt withdrew. Of the next 3 pts subsequently enrolled at 37.5 mg, 2 of 3 on concurrent therapy have experienced DLTs (G3 diarrhea with concomitant sunitinib-induced thyrotoxicosis; G3 proctitis). Conclusions: Using a daily dosing regimen and a lead-in phase, the MTD of concurrent sunitinib, hormonal ablation and XRT was 37.5mg daily. The recommended Phase 2 dose of sunitinib for further study is 25mg daily. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 741. doi:1538-7445.AM2012-741
Journal of Clinical Oncology, Jun 20, 2007
15130 Background: PPX is a conjugate of paclitaxel to a polyglutamate polymer. Preclinically, PPX... more 15130 Background: PPX is a conjugate of paclitaxel to a polyglutamate polymer. Preclinically, PPX demonstrated a radiation enhancement factor (REF) >7.0, versus 1.5–2.0 for paclitaxel. (Milas et al Int J Rad Onc 55:2003, Li et al. Clin Cancer Res 6:2000). The maximally tolerated dose (MTD) of PPX was determined previously to be 70 mg/m2 /week with concurrent radiation. We initiated a phase I study of PPX, cisplatin, and concurrent radiation with patients with esophageal and gastric cancer. Methods: Patients with esophageal or gastric cancer receiving chemoradiation for locoregional control, adjuvant, or neoadjuvant treatment were eligible. All patients received radiation at a dose of 50.4 Gy delivered in 28 fractions (5 fractions per week for 5 1/2 weeks), and cisplatin (25 mg/m2) on days 1, 8, 15, 22, 29, and 36. PPX was given as a 10 minute infusion in escalating dosages prior to each cisplatin dose. Dose limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity, esophagitis, nausea/vomiting, or dehydration, or any other grade 3/4 non-hematologic toxicity. Patients were enrolled in successive cohorts of three. The MTD was defined as the dose level at which no more than 2 of 6 patients have DLTs. Results: Eleven patients have been entered over 2 dose levels of PPX: 50 mg/m2 (six patients, dose level 1), and 60mg/m2 (5 patients, dose level 2). Five patients had esophageal cancer and six had gastric cancer. All histologies were adenocarcinomas. One of six patients treated at dose level had a DLT (esophagitis). Three of five patients had DLTs at dose level 2, including esophagitis, nausea, vomiting, and dehydration. Conclusions: PPX is a novel radiation sensitizer for patients with esophageal and gastric cancer. The MTD for PPX is 50 mg/m2 /week in combination with cisplatin 25mg/ m2 /week for 6 weeks, and 50.4 Gy concurrent radiation for patients with esophagogastric cancer. A phase II study of PPX/cisplatin and radiation will be initiated. No significant financial relationships to disclose.
American Journal of Clinical Oncology, Jan 23, 2020
Purpose: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine... more Purpose: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. Methods: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9 < 180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α = 0.15) to detect the hypothesized OS signal (hazard ratio = 0.72) in favor of the arm 2. Results: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤ 90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥ 3 and arm 2: 28%, (P = 0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P = 0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). Conclusions: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.
Journal of Clinical Oncology, May 20, 2020
4500 Background: Trastuzumab is a monoclonal antibody against human epidermal growth factor recep... more 4500 Background: Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). The primary objective of RTOG 1010 was to determine if trastuzumab increases disease-free survival (DFS) when combined with trimodality treatment for patients with HER2 overexpressing esophageal adenocarcinoma. Methods: This open label, randomized phase III trial included patients with newly diagnosed stage T1N1-2, T2-3N0-2 adenocarcinoma of the esophagus involving the mid, distal, or esophagogastric junction and up to 5cm of the stomach. All patients received chemotherapy (C) of paclitaxel, 50mg/m2 and carboplatin AUC = 2, weekly for 6 weeks, with radiation (XRT: 3D-CRT or IMRT, 50.4 Gy in 28 fractions) followed by surgery. Patients were randomized 1:1 to receive weekly trastuzumab 4mg/kg week 1 then 2mg/kg/weekly x 5 during CXRT then 6 mg/kg for 1 dose prior to surgery and 6mg/kg every 3 weeks for 13 treatments after surgery. HER2 status was determined by IHC and gene amplification by FISH. With a 2-sided alpha of 0.05, 162 DFS events provide 90% power to detect a signal for an increase in median DFS from 15 to 25 months. DFS and overall survival (OS) were estimated by the Kaplan-Meier method. and arms were compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 571 patients were entered for assessment of HER2 expression, 203 HER2+ patients randomized. The median follow-up for alive patients is 5.0 years. The estimated 2, 3, and 4-year DFS (95% CI) for the CXRT +trastuzumab arm were 41.8% (31.8%, 51.7%), 34.3% (24.7%, 43.9%), and 33.1% (23.6%, 42.7%), respectively, and for the CXRT arm were 40.0% (30.0%, 49.9%), 33.4% (23.8%, 43.0%), and 30.1% (20.7%, 39.4%), respectively; log-rank p = 0.85. The median DFS time is 19.6 months (13.5-26.2) for the CXRT +trastuzumab arm compared to 14.2 months (10.5-23.0) for the CXRT arm. The hazard ratio (95% CI) comparing the DFS of CXRT+trastuzumab arm to the CXRT arm was 0.97 (0.69, 1.36). The median OS time was 38.5 months (26.2-70.4) for the CXRT+trastuzumab arm compared to 38.9 months (29.0-64.5) for the CXRT arm, hazard ratio (95% CI): 1.01 (0.69, 1.47). There was no statistically significant increase in treatment-related toxicities with the addition of trastuzumab including no increase in cardiac events. Conclusions: The addition of trastuzumab to trimodality treatment did not improve DFS for patients with HER2 overexpressing esophageal adenocarcinoma. Supported by NCI grants U10CA180868, UG1CA189867, U10CA180822 and Genentech. Clinical trial information: NCT01196390 .
Journal of Clinical Oncology, Mar 1, 1992
The study was undertaken to assess the relationship among cosmesis and complications to factors r... more The study was undertaken to assess the relationship among cosmesis and complications to factors related to disease presentation, surgical and radiotherapeutic technique, and adjuvant systemic therapy in conservative treatment for early-stage breast carcinoma. Between 1982 and 1988, 234 women with stage I/II breast carcinoma were treated with conservation therapy by a highly standardized protocol of limited excision and radiotherapy. Radiation boost and/or reexcision were determined by careful quantitation of the normal tissue margin around the primary tumor. Boosts to 20 Gy were preferentially performed with interstitial iridium-192 (192Ir) implants. Axillary node dissections were performed in all patients aged less than 70 years. Adjuvant therapy consisted of cyclophosphamide, methotrexate, (doxorubicin), and fluorouracil (CM[A]F) six to eight times for node-positive premenopausal women and tamoxifen for node-positive or -negative postmenopausal women. Median follow-up was 50 months (range, 20 to 80 months). Cosmesis was graded by defined criteria, and complications were individually scored. Factors found to impact cosmesis adversely were palpable tumors (P = .046), volume of breast tissue resected (P = .027), reexcision of the tumor bed (P = .01), number of radiation fields (P = .03), radiation boost (P = .01), and chest wall separation (P = .01). There was a trend toward worse cosmesis (P = .062) in patients receiving tamoxifen. Cosmesis was not adversely affected by interstitial implant in spite of a higher prescribed dose. Factors influencing complication risk were axillary node dissection (P = .02), number of lymph nodes harvested (P = .05), and chemotherapy (P = .03). Optimal cosmesis and minimal complication risk require careful attention to the technical details of surgery and radiotherapy. The impact of systemic therapies needs to be more thoroughly examined.
Journal of Clinical Oncology, Feb 1, 2013
477 Background: Per the 2012 NCCN guidelines, pelvic radiation therapy (RT) is one of the preferr... more 477 Background: Per the 2012 NCCN guidelines, pelvic radiation therapy (RT) is one of the preferred treatment regimens for patients with metastatic rectal cancer (MRC). This study aims to analyze patterns of care and outcomes data for the use of neoadjuvant/adjuvant pelvic RT in patients with MRC using the SEER database. Methods: Patients with stage IV rectal or rectosigmoid cancer were identified in the SEER database (1973-2009). Patients were stratified according to their primary site of disease (rectum vs. rectosigmoid), T-, and N-stage. Treatment regimens (+/- surgical resection, +/-RT, or a combination of both) were recorded. Fischer's exact test was used to compare RT rates based on stratified factors. 2-yr survival rates were compared among treatment groups. Results: A total of 6,873 patients with stage IV rectal CA and 3,417 patients with rectosigmoid CA were identified. In total, 20.5% of rectal CA patients received surgery alone while 38.7% received RT alone or RT + surgery. Within the rectosigm...
International Journal of Radiation Oncology Biology Physics, Oct 1, 2016
Purpose/Objective(s): Single fraction stereotactic radiosurgery (SF-SRS) has become standard prac... more Purpose/Objective(s): Single fraction stereotactic radiosurgery (SF-SRS) has become standard practice for patients with a small number of brain metastases in favor of whole brain radiation therapy. Fractionated stereotactic radiosurgery (MF-SRS) is being increasingly used for patients with metastatic disease of the brain, particularly in those with larger lesions or those close to dose limiting structures. There are few studies comparing the outcomes of SF-SRS and MF-SRS. The purpose of this study was to compare the outcomes and toxicity using a case matched analysis between a cohort of SF-SRS and MF-SRS for metastatic disease of the brain. Materials/Methods: Patients treated with SF-SRS or MF-SRS for brain metastases at a single institution between 2003 and 2013 were retrospectively collected. 307 patients treated with SF-SRS and 73 treated with MF-SRS were identified. Using a Statistical Package for the Social Sciences randomized case match algorithm, patients treated with MF-SRS were matched in a 1:1 fashion with patients treated with SF-SRS to reduce the effect of confounding variables. Patients were matched on tumor size (2 cm, 2-4 cm, >4 cm), pre SRS surgical resection, primary histology (renal cell carcinoma and melanoma vs other), and BED within 5 Gy. BED was calculated assuming an alpha/beta of 10. Kaplan-Meier method and log rank test was used to assess Local Control (LC) and Overall Survival (OS). Chi-square and independent t-tests were used to assess correlations and clinical factors in the two groups. Results: Sixty matches between MF-SRS and SF-SRS were obtained to create two cohorts with a total sample size of 120 patients. Median follow up was 8.3 months. Median age was 60 in the SF-SRS cohort and 63 in the MF-SRS cohort (P Z 0.105). Median dose for SF-SRS was 17 Gy. Median total dose for MF-SRS was 24 Gy with median fractional dose of 8 Gy. MF-SRS was delivered over 3 fractions for all 60 patients. The average BED was 46.8 Gy in the SF-SRS cohort and 45.7 Gy in the MF-SRS cohort (P Z 0.257). There was no difference in actuarial LC between the two cohorts with 65.6% and 65.6% for SF-SRS and 76.8% and 66.9% in the MF-SRS at 12 and 18 months respectively (P Z 0.511). Tumor size, histology, and surgical resection were not associated with decreased LC. There was no difference in OS with 12 month OS of 46.6% for SF-SRS and 29.6% for MF-SRS (P Z 0.114). There was a trend toward decreased radiation necrosis (RN) in the MF-SRS group with rates of 13.3% and 5.0% with SF-SRS and MF-SRS respectively (P Z 0.114). Conclusion: MF-SRS is safe and effective in the treatment of brain metastases. There was no difference in LC with MF-SRS compared with SF-SRS. However, a trend toward decreased RN rates with MF-SRS was noted.
Journal of Clinical Oncology, May 20, 2019
8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a... more 8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.
International Journal of Radiation Oncology Biology Physics, Oct 1, 2017
17% in the FSRT alone group (P Z 0.024). The Kaplan-Meier estimate of 12-month local control was ... more 17% in the FSRT alone group (P Z 0.024). The Kaplan-Meier estimate of 12-month local control was 71% in the S+SRS group as compared to 67% in the FSRT alone group (P Z 0.789). Conclusion: Although many patients need surgical resection of a brain metastasis due to mass effect, it appears that S+SRS may increase the risk of LMD as compared to FSRT alone. As the two treatment strategies seem to have similar LC, FSRT appears to be a viable alternative to S+SRS in selected patients with large brain metastases. Author Disclosure: S. Marcrom: I serve on the executive committee of ARRO, and we work to improve the training process for Radiation Oncology Residents; ARRO.
Table S3. Multivariable Cox Proportional Hazards Models of Disease-free Survival Without CA19-9 (... more Table S3. Multivariable Cox Proportional Hazards Models of Disease-free Survival Without CA19-9 (n=163)
Table S2. Multivariable Cox Proportional Hazards Models of Overall Survival Without CA19-9 (n=163)
Purpose: GSK3b is a protein kinase that can suppress a number of key oncoproteins. We have previo... more Purpose: GSK3b is a protein kinase that can suppress a number of key oncoproteins. We have previously shown in preclinical models of pancreatic ductal adenocarcinoma (PDAC) that inhibition of GSK3b causes stabilization and nuclear translocation of b-catenin, poor differentiation, proliferation, and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes. Experimental Design: Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3b was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. On the basis of findings in an exploratory cohort, GSK3b was analyzed as a categorical variable using its upper quartile (>Q3) as a cut point. Overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan-Meier method, and GSK3b groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3b and OS/DFS. Results: The 3-year OS rates for GSK3bQ3 versus GSK3b >Q3 were 16% (95% confidence intervals; CI, 10%-23%) and 30% (95% CI, 17%-44%), respectively, P ¼ 0.0082. The 3-year DFS rates were 9% (95% CI, 5%-15%) and 20% (95% CI, 9%-33%) respectively, P value ¼ 0.0081. On multivariable analysis, GSK3b was a significant predictor of OS. Patients with GSK3b >Q3 had a 46% reduced risk of dying of pancreatic cancer (HR, 0.54; 95% CI, 0.31-0.96, P value ¼ 0.034). The HR for DFS was 0.65 (95% CI, 0.39-1.07; P value ¼ 0.092). Conclusions: GSK3b expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA19-9.
Table S1. Distribution of GSK3β Expression (fluorescence intensity units) for Patients Entered on... more Table S1. Distribution of GSK3β Expression (fluorescence intensity units) for Patients Entered on RTOG 97-04 (n=163)
International Journal of Radiation Oncology Biology Physics, Nov 1, 2020
equal to 45 Gy). Cumulative incidence of local progression with death as a competing risk was cal... more equal to 45 Gy). Cumulative incidence of local progression with death as a competing risk was calculated with Gray's tests for statistical significance based on the presence of alterations in TCGA driver genes in each treatment group by BED. Results: The incidence of progression after treatment was evaluated at different dose levels and a BED of greater than 45 Gy was chosen as a cutoff between high and low BED treatment because the risk of progression clustered differently in these groups. Six months after treatment, the risk of local progression was 28% after conventional RT and 11% with high BED RT. High BED treatment was associated with a lower risk of local progression (p Z 0.025). IMPACT sequencing revealed that 29 of the identified TCGA cancer driver genes were altered in at least 5% of analyzed cases. After Holm-Sidak corrections for multiple hypothesis testing, alterations in three driver genes were associated with a higher risk of local progression after conventional RT: AMER1 (1.80e-7), PTEN (p Z 0.045), and ZFHX3 (p Z 0.049). There were no gene alteration associations for progression after high BED treatment, nor were any genes associated with lower risk of progression. Conclusion: High BED radiation treatment to colorectal cancer spine metastases resulted in a more durable response with reduced incidence of local failure after high dose hypofractionated treatment compared to conventional RT. Three cancer driver genes were identified in which mutations were associated with increased risk of local progression after conventional radiation treatment, suggesting these genes or associated pathways may confer radioresistance. High BED treatment techniques may overcome these resistance factors since no genetic associations were seen after high dose hypofractionated treatment.
Journal of Clinical Oncology, May 20, 2019
e16603 Background: In localized prostate cancer (LPC), evolving therapeutic techniques and patter... more e16603 Background: In localized prostate cancer (LPC), evolving therapeutic techniques and patterns of care including the use of active surveillance (AS) are expected to have had a positive effect on quality of life. A longitudinal assessment of changes in disease presentations and patterns of care in LPC correlated to PROMs is required. Methods: All cases of LPC (T1-T4, N0-N1) at a tertiary care institution were identified between 2005 and 2015. Two cohorts (C1: 2005-10, C2: 2010-15) with a minimum of 2-years follow-up, were identified. Demographics, disease characteristics and management strategies were compared across cohorts. To assess PROMs, a one-time questionnaire including EPIC-26 and Clark’s Quality of Life was administered. Domain summary scores were compared across cohorts. Results: 873 patients met criteria [C1: 422, C2: 535]. Demographics were well balanced (p = 0.10): overall 64.1% white, 12.7% AA, 12.7% Asian. D’Amico risk scores increased over time (p = 0.001): fewer low-risk cases [C1: 49.2%, C2: 43.7%], higher intermediate-risk disease [C1: 34.6%, C2: 40.3%], and stable high-risk proportions [C1: 15.7%, C2: 14.9%]. Patterns of care shifted significantly (p = 0.005) with a marked decrease in radiation therapy [C1: 25.7%, C2: 15.4%], unchanged radical prostatectomy rates [C1: 47.9%, C2: 51.0%], a shift to robotic surgery [C1: 23.8%, C2: 90.3%], and an increase in AS [C1: 21.8%, C2: 30.8%], particularly in low-risk disease [C1: 32.4%, C2: 53.5%]. Questionnaire response rate was 45.1%. Using multivariate regression, C2 demonstrated an improvement in bowel function (p = 0.031) but not in urinary, sexual, or psychometric scores. Conclusions: Notwithstanding an increase in AS utilization for low-risk disease, an improvement in bowel function and lack of improvement in urinary/sexual PROMs in LPC across time-cohorts was noted. This may be accounted for by increased presentations of higher-risk disease managed with robotic surgeries at the expense of radiation therapy. Although time-length bias can influence comparisons, given national trends with a similar shift in presentation and care patterns, these PROM correlations are likely generalizable to the U.S. population.
International Journal of Radiation Oncology Biology Physics, Nov 1, 2012
Journal of Clinical Oncology, May 20, 2009
e15542 Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-... more e15542 Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-L-glutamic acid thereby increasing its radiation enhancement factor to 4.0 to 8.0 compared to 1.5–2.0 for paclitaxel. The Brown University Oncology Group previously performed a phase I study establishing the dose of single agent PPX with radiation, and the combination of PPX, cisplatin and radiation for esophagogastric cancer. A phase II study was therefore initiated to evaluate the pathologic response rate of neoadjuvant PPX, cisplatin and radiation for patients with esophageal cancer. Methods: Eligible patients had pathologically confirmed adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction with no evidence of distant metastasis. Celiac nodal disease was allowed. Patients received weekly PPX 50mg/m2 and cisplatin 25mg/m2 for 6 weeks with concurrent with 50.4Gy of radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. Results: Twenty-three eligible patients have been enrolled. The median age is 63 years. Grade 3/4 treatment related toxicities in the first 15 patients include dehydration (n=5), anorexia (n=5), esophagitis/dysphagia (n=4), electrolyte abnormalities (n=3), nausea (n=2), hypersensitivity (n=2), weight loss (n=1), and anemia (n=1). One patient developed carcinomatous meningitis during treatment. Five of the first 11 patients (45%) undergoing resection had a pathologic complete response. Conclusions: This preliminary data suggests that PPX may provide enhanced radiosensitization as compared to standard paclitaxel, consistent with the preclinical data of PPX and radiation. No significant financial relationships to disclose.
International Journal of Radiation Oncology Biology Physics, Nov 1, 2021
PURPOSE/OBJECTIVE(S) NRG/RTOG 0848 is a two-step randomized trial to evaluate the benefit of the ... more PURPOSE/OBJECTIVE(S) NRG/RTOG 0848 is a two-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiotherapy (RT) following adjuvant gemcitabine-based chemotherapy (2nd step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed for each patient who underwent RT. QA findings were reviewed, frequencies & reasons for resubmissions are reported. MATERIALS/METHODS Patients were treated using either a 3D-conformal RT (3DCRT) or intensity-modulated RT (IMRT) technique. In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume (CTV) through the creation of specific regions of interest. The planning target volume (PTV) was established by expanding the CTV by 0.5 cm in all directions. Treatment planning data, including pre-operative imaging, surgical and pathology reports, simulation images with isodose lines, structure set, and dose volume histograms were submitted for review. One of two radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and then resubmitted for review until approved. Treatment started after final approval of the RT plan. RESULTS Of the 354 patients who underwent second randomization, 180 were randomized to the RT arm. Of these, 160 received RT and were included in the QA analysis. Most patients (86%) were treated using IMRT. Resubmissions were more common for patients planned with 3D-CRT (43%) than with IMRT (31%). In total, at least one resubmission of the treatment plan was required for 33% of patients (see Table 1). Among patients requiring resubmission, the majority only needed to be resubmitted once (87%). The most common reasons for resubmission were unacceptable deviations with respect to the pre-operative gross target volume (GTV, 61%) and the pancreatojejunostomy (48%), leading to unacceptable deviations of the contours of the CTV and PTV (70% for each). Most patients requiring a resubmission had 5-9 unacceptable deviations (46%). Unacceptable deviations were similar for the few treatment plans that needed to be resubmitted more than once. CONCLUSION One third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on pretreatment QA for adjuvant pancreas cancer trials. Rigorous QA is of critical importance for clinical trials involving RT to ensure that the true impact of RT can be assessed. Moreover, RT QA serves as an educational process by training radiation oncologists on best practices.
Journal of Clinical Oncology, Jun 20, 2007
9101 Background: Radiofrequency Ablation (RFA) can destroy tissue in a defined area. Single insti... more 9101 Background: Radiofrequency Ablation (RFA) can destroy tissue in a defined area. Single institutions have reported that RFA can reduce pain from bone metastases. To confirm this, the American College of Radiology Imaging Network (ACRIN) completed a multicenter study of RFA for bone metastases. Methods: Eligible patients had bone pain in one dominant site: tumor size &amp;amp;lt; 8 cm, and location &amp;amp;gt; 1 cm from the spinal cord or cauda equina. RFA was performed under CT guidance. The Memorial Pain Assessment Card was used prior to RFA and repeated daily for two weeks, and at 1 and 3 months after RFA. AEs were recorded in addition to four different pain assessment measures: pain relief, patient mood, pain intensity, and pain severity. Results: Fifty-six patients had RFA at 9 centers. Metastatic sites were pelvis (24), chest wall (19), thoracolumbar spine (8), and extremities (5). Six out of 56 patients experienced at least one adverse event of grade 3 or higher, yielding an AE rate of 10.7% (95%CI is 2.6% to18.8%). AEs attributed directly to RFA were nerve injury in 2 patients. Of the 56 participants, 43 completed the 1 month follow-up and 33 completed the 3 month follow-up. At the time of this analysis, assuming that missing data were missing at random and after adjusting for all covariates, RFA showed significant effect in reducing pain at 1 and 3 month follow-up for all 4 pain assessment measures. The average increase in pain relief from pre-RFA to 1 month follow-up is 26.4 (P&amp;amp;lt;0.0001) and the increase from pre-RFA to 3 month follow-up is 17.2 (P=0.003). The average increase in mood from pre-RFA to 1 month follow-up is 21.5 (P&amp;amp;lt;0.0001) and the increase from pre-RFA to 3 month follow-up is 16.3 (P=0.001). The average decrease in pain intensity from pre-RFA to 1 month follow-up is 25.9 (P&amp;amp;lt;0.0001) and the decrease from pre-RFA to 3 month follow-up is 13.0 (P=0.02). The odds of being in lower pain severity at 1 month follow-up is 12.6 (P
Background: Novel strategies are needed to improve the long-term outcomes of patients (pts) with ... more Background: Novel strategies are needed to improve the long-term outcomes of patients (pts) with high-risk prostate cancer treated with hormonal ablation and external beam radiation therapy (XRT). Preclinical data suggest that angiogenesis inhibitors normalize vasculature, reduce hypoxia, and improve the therapeutic index of XRT. To assess the feasibility of combined VEGFR/PDGFR inhibition in combination with XRT, a Phase I study with sunitinib was initiated. Methods: Seventeen men with adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or PSA > 20ng/ml received initial hormonal ablation (leuprolide 22.5mg every 12 weeks + oral bicalutamide 50mg daily) for 4-8 weeks prior to oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks post XRT (prostate and proximal seminal vesicles received 75.6 Gy in 42 fractions with at least 50 Gy for the distal seminal vesicles). A 3+3 sequential dose-escalation design was employed to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose (MTD) of sunitinib. Results: The first 4 pts enrolled on 37.5 mg experienced a DLT during lead-in. *With 2 pts unexpectedly experiencing Grade 3 neutropenia and a third experiencing Grade 3 thrombocytopenia, a drug-interaction with bicalutamide was suspected. The protocol was revised to replace these pts and omit concurrent bicalutamide. Of these first 4 pts, 3 were dose reduced to 25 mg and successfully completed full treatment, while 1 pt withdrew. Of the next 3 pts subsequently enrolled at 37.5 mg, 2 of 3 on concurrent therapy have experienced DLTs (G3 diarrhea with concomitant sunitinib-induced thyrotoxicosis; G3 proctitis). Conclusions: Using a daily dosing regimen and a lead-in phase, the MTD of concurrent sunitinib, hormonal ablation and XRT was 37.5mg daily. The recommended Phase 2 dose of sunitinib for further study is 25mg daily. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 741. doi:1538-7445.AM2012-741
Journal of Clinical Oncology, Jun 20, 2007
15130 Background: PPX is a conjugate of paclitaxel to a polyglutamate polymer. Preclinically, PPX... more 15130 Background: PPX is a conjugate of paclitaxel to a polyglutamate polymer. Preclinically, PPX demonstrated a radiation enhancement factor (REF) >7.0, versus 1.5–2.0 for paclitaxel. (Milas et al Int J Rad Onc 55:2003, Li et al. Clin Cancer Res 6:2000). The maximally tolerated dose (MTD) of PPX was determined previously to be 70 mg/m2 /week with concurrent radiation. We initiated a phase I study of PPX, cisplatin, and concurrent radiation with patients with esophageal and gastric cancer. Methods: Patients with esophageal or gastric cancer receiving chemoradiation for locoregional control, adjuvant, or neoadjuvant treatment were eligible. All patients received radiation at a dose of 50.4 Gy delivered in 28 fractions (5 fractions per week for 5 1/2 weeks), and cisplatin (25 mg/m2) on days 1, 8, 15, 22, 29, and 36. PPX was given as a 10 minute infusion in escalating dosages prior to each cisplatin dose. Dose limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity, esophagitis, nausea/vomiting, or dehydration, or any other grade 3/4 non-hematologic toxicity. Patients were enrolled in successive cohorts of three. The MTD was defined as the dose level at which no more than 2 of 6 patients have DLTs. Results: Eleven patients have been entered over 2 dose levels of PPX: 50 mg/m2 (six patients, dose level 1), and 60mg/m2 (5 patients, dose level 2). Five patients had esophageal cancer and six had gastric cancer. All histologies were adenocarcinomas. One of six patients treated at dose level had a DLT (esophagitis). Three of five patients had DLTs at dose level 2, including esophagitis, nausea, vomiting, and dehydration. Conclusions: PPX is a novel radiation sensitizer for patients with esophageal and gastric cancer. The MTD for PPX is 50 mg/m2 /week in combination with cisplatin 25mg/ m2 /week for 6 weeks, and 50.4 Gy concurrent radiation for patients with esophagogastric cancer. A phase II study of PPX/cisplatin and radiation will be initiated. No significant financial relationships to disclose.
American Journal of Clinical Oncology, Jan 23, 2020
Purpose: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine... more Purpose: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. Methods: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9 < 180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α = 0.15) to detect the hypothesized OS signal (hazard ratio = 0.72) in favor of the arm 2. Results: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤ 90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥ 3 and arm 2: 28%, (P = 0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P = 0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). Conclusions: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.
Journal of Clinical Oncology, May 20, 2020
4500 Background: Trastuzumab is a monoclonal antibody against human epidermal growth factor recep... more 4500 Background: Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). The primary objective of RTOG 1010 was to determine if trastuzumab increases disease-free survival (DFS) when combined with trimodality treatment for patients with HER2 overexpressing esophageal adenocarcinoma. Methods: This open label, randomized phase III trial included patients with newly diagnosed stage T1N1-2, T2-3N0-2 adenocarcinoma of the esophagus involving the mid, distal, or esophagogastric junction and up to 5cm of the stomach. All patients received chemotherapy (C) of paclitaxel, 50mg/m2 and carboplatin AUC = 2, weekly for 6 weeks, with radiation (XRT: 3D-CRT or IMRT, 50.4 Gy in 28 fractions) followed by surgery. Patients were randomized 1:1 to receive weekly trastuzumab 4mg/kg week 1 then 2mg/kg/weekly x 5 during CXRT then 6 mg/kg for 1 dose prior to surgery and 6mg/kg every 3 weeks for 13 treatments after surgery. HER2 status was determined by IHC and gene amplification by FISH. With a 2-sided alpha of 0.05, 162 DFS events provide 90% power to detect a signal for an increase in median DFS from 15 to 25 months. DFS and overall survival (OS) were estimated by the Kaplan-Meier method. and arms were compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 571 patients were entered for assessment of HER2 expression, 203 HER2+ patients randomized. The median follow-up for alive patients is 5.0 years. The estimated 2, 3, and 4-year DFS (95% CI) for the CXRT +trastuzumab arm were 41.8% (31.8%, 51.7%), 34.3% (24.7%, 43.9%), and 33.1% (23.6%, 42.7%), respectively, and for the CXRT arm were 40.0% (30.0%, 49.9%), 33.4% (23.8%, 43.0%), and 30.1% (20.7%, 39.4%), respectively; log-rank p = 0.85. The median DFS time is 19.6 months (13.5-26.2) for the CXRT +trastuzumab arm compared to 14.2 months (10.5-23.0) for the CXRT arm. The hazard ratio (95% CI) comparing the DFS of CXRT+trastuzumab arm to the CXRT arm was 0.97 (0.69, 1.36). The median OS time was 38.5 months (26.2-70.4) for the CXRT+trastuzumab arm compared to 38.9 months (29.0-64.5) for the CXRT arm, hazard ratio (95% CI): 1.01 (0.69, 1.47). There was no statistically significant increase in treatment-related toxicities with the addition of trastuzumab including no increase in cardiac events. Conclusions: The addition of trastuzumab to trimodality treatment did not improve DFS for patients with HER2 overexpressing esophageal adenocarcinoma. Supported by NCI grants U10CA180868, UG1CA189867, U10CA180822 and Genentech. Clinical trial information: NCT01196390 .
Journal of Clinical Oncology, Mar 1, 1992
The study was undertaken to assess the relationship among cosmesis and complications to factors r... more The study was undertaken to assess the relationship among cosmesis and complications to factors related to disease presentation, surgical and radiotherapeutic technique, and adjuvant systemic therapy in conservative treatment for early-stage breast carcinoma. Between 1982 and 1988, 234 women with stage I/II breast carcinoma were treated with conservation therapy by a highly standardized protocol of limited excision and radiotherapy. Radiation boost and/or reexcision were determined by careful quantitation of the normal tissue margin around the primary tumor. Boosts to 20 Gy were preferentially performed with interstitial iridium-192 (192Ir) implants. Axillary node dissections were performed in all patients aged less than 70 years. Adjuvant therapy consisted of cyclophosphamide, methotrexate, (doxorubicin), and fluorouracil (CM[A]F) six to eight times for node-positive premenopausal women and tamoxifen for node-positive or -negative postmenopausal women. Median follow-up was 50 months (range, 20 to 80 months). Cosmesis was graded by defined criteria, and complications were individually scored. Factors found to impact cosmesis adversely were palpable tumors (P = .046), volume of breast tissue resected (P = .027), reexcision of the tumor bed (P = .01), number of radiation fields (P = .03), radiation boost (P = .01), and chest wall separation (P = .01). There was a trend toward worse cosmesis (P = .062) in patients receiving tamoxifen. Cosmesis was not adversely affected by interstitial implant in spite of a higher prescribed dose. Factors influencing complication risk were axillary node dissection (P = .02), number of lymph nodes harvested (P = .05), and chemotherapy (P = .03). Optimal cosmesis and minimal complication risk require careful attention to the technical details of surgery and radiotherapy. The impact of systemic therapies needs to be more thoroughly examined.
Journal of Clinical Oncology, Feb 1, 2013
477 Background: Per the 2012 NCCN guidelines, pelvic radiation therapy (RT) is one of the preferr... more 477 Background: Per the 2012 NCCN guidelines, pelvic radiation therapy (RT) is one of the preferred treatment regimens for patients with metastatic rectal cancer (MRC). This study aims to analyze patterns of care and outcomes data for the use of neoadjuvant/adjuvant pelvic RT in patients with MRC using the SEER database. Methods: Patients with stage IV rectal or rectosigmoid cancer were identified in the SEER database (1973-2009). Patients were stratified according to their primary site of disease (rectum vs. rectosigmoid), T-, and N-stage. Treatment regimens (+/- surgical resection, +/-RT, or a combination of both) were recorded. Fischer's exact test was used to compare RT rates based on stratified factors. 2-yr survival rates were compared among treatment groups. Results: A total of 6,873 patients with stage IV rectal CA and 3,417 patients with rectosigmoid CA were identified. In total, 20.5% of rectal CA patients received surgery alone while 38.7% received RT alone or RT + surgery. Within the rectosigm...
International Journal of Radiation Oncology Biology Physics, Oct 1, 2016
Purpose/Objective(s): Single fraction stereotactic radiosurgery (SF-SRS) has become standard prac... more Purpose/Objective(s): Single fraction stereotactic radiosurgery (SF-SRS) has become standard practice for patients with a small number of brain metastases in favor of whole brain radiation therapy. Fractionated stereotactic radiosurgery (MF-SRS) is being increasingly used for patients with metastatic disease of the brain, particularly in those with larger lesions or those close to dose limiting structures. There are few studies comparing the outcomes of SF-SRS and MF-SRS. The purpose of this study was to compare the outcomes and toxicity using a case matched analysis between a cohort of SF-SRS and MF-SRS for metastatic disease of the brain. Materials/Methods: Patients treated with SF-SRS or MF-SRS for brain metastases at a single institution between 2003 and 2013 were retrospectively collected. 307 patients treated with SF-SRS and 73 treated with MF-SRS were identified. Using a Statistical Package for the Social Sciences randomized case match algorithm, patients treated with MF-SRS were matched in a 1:1 fashion with patients treated with SF-SRS to reduce the effect of confounding variables. Patients were matched on tumor size (2 cm, 2-4 cm, >4 cm), pre SRS surgical resection, primary histology (renal cell carcinoma and melanoma vs other), and BED within 5 Gy. BED was calculated assuming an alpha/beta of 10. Kaplan-Meier method and log rank test was used to assess Local Control (LC) and Overall Survival (OS). Chi-square and independent t-tests were used to assess correlations and clinical factors in the two groups. Results: Sixty matches between MF-SRS and SF-SRS were obtained to create two cohorts with a total sample size of 120 patients. Median follow up was 8.3 months. Median age was 60 in the SF-SRS cohort and 63 in the MF-SRS cohort (P Z 0.105). Median dose for SF-SRS was 17 Gy. Median total dose for MF-SRS was 24 Gy with median fractional dose of 8 Gy. MF-SRS was delivered over 3 fractions for all 60 patients. The average BED was 46.8 Gy in the SF-SRS cohort and 45.7 Gy in the MF-SRS cohort (P Z 0.257). There was no difference in actuarial LC between the two cohorts with 65.6% and 65.6% for SF-SRS and 76.8% and 66.9% in the MF-SRS at 12 and 18 months respectively (P Z 0.511). Tumor size, histology, and surgical resection were not associated with decreased LC. There was no difference in OS with 12 month OS of 46.6% for SF-SRS and 29.6% for MF-SRS (P Z 0.114). There was a trend toward decreased radiation necrosis (RN) in the MF-SRS group with rates of 13.3% and 5.0% with SF-SRS and MF-SRS respectively (P Z 0.114). Conclusion: MF-SRS is safe and effective in the treatment of brain metastases. There was no difference in LC with MF-SRS compared with SF-SRS. However, a trend toward decreased RN rates with MF-SRS was noted.
Journal of Clinical Oncology, May 20, 2019
8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a... more 8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.
International Journal of Radiation Oncology Biology Physics, Oct 1, 2017
17% in the FSRT alone group (P Z 0.024). The Kaplan-Meier estimate of 12-month local control was ... more 17% in the FSRT alone group (P Z 0.024). The Kaplan-Meier estimate of 12-month local control was 71% in the S+SRS group as compared to 67% in the FSRT alone group (P Z 0.789). Conclusion: Although many patients need surgical resection of a brain metastasis due to mass effect, it appears that S+SRS may increase the risk of LMD as compared to FSRT alone. As the two treatment strategies seem to have similar LC, FSRT appears to be a viable alternative to S+SRS in selected patients with large brain metastases. Author Disclosure: S. Marcrom: I serve on the executive committee of ARRO, and we work to improve the training process for Radiation Oncology Residents; ARRO.
Table S3. Multivariable Cox Proportional Hazards Models of Disease-free Survival Without CA19-9 (... more Table S3. Multivariable Cox Proportional Hazards Models of Disease-free Survival Without CA19-9 (n=163)
Table S2. Multivariable Cox Proportional Hazards Models of Overall Survival Without CA19-9 (n=163)
Purpose: GSK3b is a protein kinase that can suppress a number of key oncoproteins. We have previo... more Purpose: GSK3b is a protein kinase that can suppress a number of key oncoproteins. We have previously shown in preclinical models of pancreatic ductal adenocarcinoma (PDAC) that inhibition of GSK3b causes stabilization and nuclear translocation of b-catenin, poor differentiation, proliferation, and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes. Experimental Design: Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3b was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. On the basis of findings in an exploratory cohort, GSK3b was analyzed as a categorical variable using its upper quartile (>Q3) as a cut point. Overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan-Meier method, and GSK3b groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3b and OS/DFS. Results: The 3-year OS rates for GSK3bQ3 versus GSK3b >Q3 were 16% (95% confidence intervals; CI, 10%-23%) and 30% (95% CI, 17%-44%), respectively, P ¼ 0.0082. The 3-year DFS rates were 9% (95% CI, 5%-15%) and 20% (95% CI, 9%-33%) respectively, P value ¼ 0.0081. On multivariable analysis, GSK3b was a significant predictor of OS. Patients with GSK3b >Q3 had a 46% reduced risk of dying of pancreatic cancer (HR, 0.54; 95% CI, 0.31-0.96, P value ¼ 0.034). The HR for DFS was 0.65 (95% CI, 0.39-1.07; P value ¼ 0.092). Conclusions: GSK3b expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA19-9.
Table S1. Distribution of GSK3β Expression (fluorescence intensity units) for Patients Entered on... more Table S1. Distribution of GSK3β Expression (fluorescence intensity units) for Patients Entered on RTOG 97-04 (n=163)
International Journal of Radiation Oncology Biology Physics, Nov 1, 2020
equal to 45 Gy). Cumulative incidence of local progression with death as a competing risk was cal... more equal to 45 Gy). Cumulative incidence of local progression with death as a competing risk was calculated with Gray's tests for statistical significance based on the presence of alterations in TCGA driver genes in each treatment group by BED. Results: The incidence of progression after treatment was evaluated at different dose levels and a BED of greater than 45 Gy was chosen as a cutoff between high and low BED treatment because the risk of progression clustered differently in these groups. Six months after treatment, the risk of local progression was 28% after conventional RT and 11% with high BED RT. High BED treatment was associated with a lower risk of local progression (p Z 0.025). IMPACT sequencing revealed that 29 of the identified TCGA cancer driver genes were altered in at least 5% of analyzed cases. After Holm-Sidak corrections for multiple hypothesis testing, alterations in three driver genes were associated with a higher risk of local progression after conventional RT: AMER1 (1.80e-7), PTEN (p Z 0.045), and ZFHX3 (p Z 0.049). There were no gene alteration associations for progression after high BED treatment, nor were any genes associated with lower risk of progression. Conclusion: High BED radiation treatment to colorectal cancer spine metastases resulted in a more durable response with reduced incidence of local failure after high dose hypofractionated treatment compared to conventional RT. Three cancer driver genes were identified in which mutations were associated with increased risk of local progression after conventional radiation treatment, suggesting these genes or associated pathways may confer radioresistance. High BED treatment techniques may overcome these resistance factors since no genetic associations were seen after high dose hypofractionated treatment.
Journal of Clinical Oncology, May 20, 2019
e16603 Background: In localized prostate cancer (LPC), evolving therapeutic techniques and patter... more e16603 Background: In localized prostate cancer (LPC), evolving therapeutic techniques and patterns of care including the use of active surveillance (AS) are expected to have had a positive effect on quality of life. A longitudinal assessment of changes in disease presentations and patterns of care in LPC correlated to PROMs is required. Methods: All cases of LPC (T1-T4, N0-N1) at a tertiary care institution were identified between 2005 and 2015. Two cohorts (C1: 2005-10, C2: 2010-15) with a minimum of 2-years follow-up, were identified. Demographics, disease characteristics and management strategies were compared across cohorts. To assess PROMs, a one-time questionnaire including EPIC-26 and Clark’s Quality of Life was administered. Domain summary scores were compared across cohorts. Results: 873 patients met criteria [C1: 422, C2: 535]. Demographics were well balanced (p = 0.10): overall 64.1% white, 12.7% AA, 12.7% Asian. D’Amico risk scores increased over time (p = 0.001): fewer low-risk cases [C1: 49.2%, C2: 43.7%], higher intermediate-risk disease [C1: 34.6%, C2: 40.3%], and stable high-risk proportions [C1: 15.7%, C2: 14.9%]. Patterns of care shifted significantly (p = 0.005) with a marked decrease in radiation therapy [C1: 25.7%, C2: 15.4%], unchanged radical prostatectomy rates [C1: 47.9%, C2: 51.0%], a shift to robotic surgery [C1: 23.8%, C2: 90.3%], and an increase in AS [C1: 21.8%, C2: 30.8%], particularly in low-risk disease [C1: 32.4%, C2: 53.5%]. Questionnaire response rate was 45.1%. Using multivariate regression, C2 demonstrated an improvement in bowel function (p = 0.031) but not in urinary, sexual, or psychometric scores. Conclusions: Notwithstanding an increase in AS utilization for low-risk disease, an improvement in bowel function and lack of improvement in urinary/sexual PROMs in LPC across time-cohorts was noted. This may be accounted for by increased presentations of higher-risk disease managed with robotic surgeries at the expense of radiation therapy. Although time-length bias can influence comparisons, given national trends with a similar shift in presentation and care patterns, these PROM correlations are likely generalizable to the U.S. population.
International Journal of Radiation Oncology Biology Physics, Nov 1, 2012
Journal of Clinical Oncology, May 20, 2009
e15542 Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-... more e15542 Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-L-glutamic acid thereby increasing its radiation enhancement factor to 4.0 to 8.0 compared to 1.5–2.0 for paclitaxel. The Brown University Oncology Group previously performed a phase I study establishing the dose of single agent PPX with radiation, and the combination of PPX, cisplatin and radiation for esophagogastric cancer. A phase II study was therefore initiated to evaluate the pathologic response rate of neoadjuvant PPX, cisplatin and radiation for patients with esophageal cancer. Methods: Eligible patients had pathologically confirmed adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction with no evidence of distant metastasis. Celiac nodal disease was allowed. Patients received weekly PPX 50mg/m2 and cisplatin 25mg/m2 for 6 weeks with concurrent with 50.4Gy of radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. Results: Twenty-three eligible patients have been enrolled. The median age is 63 years. Grade 3/4 treatment related toxicities in the first 15 patients include dehydration (n=5), anorexia (n=5), esophagitis/dysphagia (n=4), electrolyte abnormalities (n=3), nausea (n=2), hypersensitivity (n=2), weight loss (n=1), and anemia (n=1). One patient developed carcinomatous meningitis during treatment. Five of the first 11 patients (45%) undergoing resection had a pathologic complete response. Conclusions: This preliminary data suggests that PPX may provide enhanced radiosensitization as compared to standard paclitaxel, consistent with the preclinical data of PPX and radiation. No significant financial relationships to disclose.
International Journal of Radiation Oncology Biology Physics, Nov 1, 2021
PURPOSE/OBJECTIVE(S) NRG/RTOG 0848 is a two-step randomized trial to evaluate the benefit of the ... more PURPOSE/OBJECTIVE(S) NRG/RTOG 0848 is a two-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiotherapy (RT) following adjuvant gemcitabine-based chemotherapy (2nd step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed for each patient who underwent RT. QA findings were reviewed, frequencies & reasons for resubmissions are reported. MATERIALS/METHODS Patients were treated using either a 3D-conformal RT (3DCRT) or intensity-modulated RT (IMRT) technique. In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume (CTV) through the creation of specific regions of interest. The planning target volume (PTV) was established by expanding the CTV by 0.5 cm in all directions. Treatment planning data, including pre-operative imaging, surgical and pathology reports, simulation images with isodose lines, structure set, and dose volume histograms were submitted for review. One of two radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and then resubmitted for review until approved. Treatment started after final approval of the RT plan. RESULTS Of the 354 patients who underwent second randomization, 180 were randomized to the RT arm. Of these, 160 received RT and were included in the QA analysis. Most patients (86%) were treated using IMRT. Resubmissions were more common for patients planned with 3D-CRT (43%) than with IMRT (31%). In total, at least one resubmission of the treatment plan was required for 33% of patients (see Table 1). Among patients requiring resubmission, the majority only needed to be resubmitted once (87%). The most common reasons for resubmission were unacceptable deviations with respect to the pre-operative gross target volume (GTV, 61%) and the pancreatojejunostomy (48%), leading to unacceptable deviations of the contours of the CTV and PTV (70% for each). Most patients requiring a resubmission had 5-9 unacceptable deviations (46%). Unacceptable deviations were similar for the few treatment plans that needed to be resubmitted more than once. CONCLUSION One third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on pretreatment QA for adjuvant pancreas cancer trials. Rigorous QA is of critical importance for clinical trials involving RT to ensure that the true impact of RT can be assessed. Moreover, RT QA serves as an educational process by training radiation oncologists on best practices.