T. Strom

Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma

Abstract Purpose. Limited data are available to guide neoadjuvant treatment of borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer. Material and methods. We updated our institutional outcomes with a neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT) approach. An IRB-approved analysis was performed of all BRPC and LAPC patients treated with our departmental treatment protocol. After staging, medically fit patients underwent chemotherapy for 2–3 months, with regimen at the discretion of the treating medical oncologist. Patients then received SBRT delivered in five consecutive daily fractions with median total radiation doses of 30 Gy to tumor and 40 Gy dose painted to tumor-vessel interfaces. This was followed by restaging imaging for possible resection. Overall survival (OS), event free survival (EFS), and locoregional control (LRC) rates were estimated and compared by Kaplan-Meier and log-rank methods. Results. We identified 159 patients, 110 BRPC and 49 LAPC, with 14.0 months median overall follow-up. The resection and margin negative (R0) rate for BRPC patients who completed neoadjuvant therapy was 51% and 96%, respectively. Estimated median OS was 19.2 months for BRPC patients and 15.0 months for LAPC patients (p = 0.402). Median OS was 34.2 months for surgically resected patients versus 14.0 months for unresected patients (p < 0.001). Five of 21 (24%) LAPC patients receiving FOLFIRINOX chemotherapy underwent R0 resection. In LAPC, FOLFIRINOX recipients underwent R0 resection more often than other chemotherapy recipients (5 of 21 vs. 0 of 28, p = 0.011). There was a trend for improved survival in those resected LAPC patients (p = 0.09). For those not undergoing resection, one year LRC was 78%. Any grade ≥ 3 potentially radiation-related toxicity rate was 7%. Conclusions. These data underscore the feasibility, safety, and effectiveness of neoadjuvant SBRT and chemotherapy for BRPC and LAPC.

Active drug transport of immunosuppressants: new insights for pharmacokinetics and pharmacodynamics.

Immunosuppressants have a narrow therapeutic index, and pharmacokinetic variability negatively affects long-term outcome of transplantation. Recently, it has become clear that active transport is a major determinant of the inter-and intraindividual variability of the pharmacokinetics and pharmacodynamics of immunosuppressants. Active transport plays a key role in (1) the poor correlation between oral doses and systemic exposure of cyclosporine, tacrolimus, sirolimus, and everolimus, (2) tissue distribution including distribution into lymphocytes, (3) hepatic and intestinal metabolism, (4) the pharmacokinetic variability of immunosuppressants after oral dosing, (5) drug-drug interactions, (6) disease-drug interactions, and (7) age, gender, and ethnicity-based differences in pharmacokinetics of immunosuppressants. Those new insights may significantly improve patient management and long-term outcome not only by reducing pharmacokinetic variability and avoidance of drug-drug interactions but also by identification of sensitive patient populations. They will also significantly impact preclinical and clinical development strategies of new immunosuppressants.

Identification of everolimus metabolite patterns in trough blood samples of kidney transplant patients

Everolimus is used as an immunosuppressant after organ transplantation. It is extensively metabolized, mainly by cytochrome P4503A enzymes, resulting in several hydroxylated and demethylated metabolites. The structures of these metabolites after in vitro metabolism of everolimus by human liver microsomes have recently been identified. It was the goal to elucidate the everolimus metabolite patterns in 128 trough blood samples from kidney graft patients using high-performance liquid chromatography (LC)-ion trap mass spectrometry (MS) in combination with analysis of the fragmentation patterns of the metabolites isolated from patient blood and comparison with the metabolites generated in vitro. After identification, concentrations of the metabolites were estimated using LC-MS. Relative to the everolimus concentrations in trough blood samples, metabolite concentrations were [median (range), n = 128] 46-hydroxy 44.1% (0-784%), 24-hydroxy 7.7% (0-85.6%), and 25-hydroxy 14.4% (0-155.4%); 11-Hydroxy, 12-hydroxy, 14-hydroxy, 49-hydroxy, two hydroxy-piperidine everolimus metabolites, 16-O-desmethyl, 16,39-O-didesmethyl, 16,27-O-didesmethyl, and 27,39-O-didesmethyl everolimus were also detected. However, when detectable, concentrations were consistently between the lower limit of detection (0.1 μg/L) and the lower limit of quantification (0.25 μg/L) of our LC-MS assay. In most trough blood samples, the total metabolite concentrations were between 50% and 100% of the everolimus concentrations. The clinical importance of everolimus metabolites in blood of patients including pharmacodynamics, toxicodynamics, and cross-reactivity with the antibodies of immunoassays used for therapeutic drug monitoring remains to be evaluated.

Radiotherapy influences local control in patients with desmoplastic melanoma

Desmoplastic melanoma may have a high risk of local recurrence after wide excision. The authors hypothesized that adjuvant radiotherapy (RT) would improve local control in patients with desmoplastic melanoma, resulting in at least a 10% absolute decrease in local recurrence rate.

Resected pancreatic cancer outcomes in the elderly.

OBJECTIVE To determine if age affects outcome in patients with resected pancreatic head cancer. MATERIALS AND METHODS An IRB-approved pancreatic cancer database was queried for patients with upfront resected pancreatic head cancer treated at our institution between 2000 and 2012. Overall survival (OS) curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis was performed using the Cox proportional hazard model. RESULTS We identified 193 patients. Patients ≥70 years were less likely to receive adjuvant treatment (p = 0.002); however there were no other significant differences between age groups. There was a trend towards increased pancreatic leaks in the elderly group (p = 0.06), but no difference in post-operative complications or mortality. There was no difference in overall survival based on age. Median and 5-year OS were 23 months and 26.7% in patients <70 years, 23.4 months and 23% in those 70-75, 16.1 months and 0% in those 76-80, and 18.7 months and 15.4% in those >80 years (p = 0.62). On univariate analysis, there was increased OS in patients with lower T stage, N0 status, post-operative CA19-9 level <90, and use of chemoradiotherapy (p< 0.05). Multivariate analysis revealed that lower tumor stage, N0, post-operative CA19-9 level <90, and use of any adjuvant therapy predicted decreased mortality (p < 0.05). Age, gender, tumor site, tumor grade, and positive margins were not prognostic on multivariate analysis. CONCLUSIONS There is no difference in outcomes when comparing elderly patients with resected pancreatic cancer to those patients <70 years of age.

Characterization of sirolimus metabolites in pediatric solid organ transplant recipients

Abstract:  Potential age‐dependent changes of sirolimus metabolite patterns in pediatric renal transplant recipients remain elusive. Thirteen pediatric solid organ transplant recipients (10 kidney, one combined liver–kidney, two liver, mean age 8.0 ± 5.0 yr) underwent a sirolimus pharmacokinetic profile in steady‐state with 10 samples drawn over 12 h post‐intake to calculate the AUC0–12 h. Concentrations of sirolimus and metabolite were quantified using a validated LC‐MS/MS assay and metabolite structures were identified directly in blood extracts using LC‐MS/iontrap. Average sirolimus AUC0–12 h was 64.9 ± 29.7 ng h/mL. Median (range) AUC0–12 h for each metabolite (ng h/mL) was: 12‐hydroxy‐sirolimus 7.6 (0.2–18.8), 46‐hydroxy sirolimus 3.1 (0.0–12.4), 24‐hydroxy sirolimus 4.3 (0.0–12.6), piperidine‐hydroxy sirolimus 3.5 (0.0–8.3), 39‐O‐desmethyl sirolimus 3.6 (0.0–11.3), 16‐O‐desmethyl sirolimus 5.0 (0.1–9.9), and di‐hydroxy sirolimus 4.3 (0.0–32.5). The metabolites reached a median total AUC0–12 h of 60% of that of sirolimus. The range was 2.6–136%, indicating significant variability. In all, 77.5% of the metabolites were hydroxylated, while 39‐O‐desmethyl sirolimus accounted for only 8.4% of the AUC0–12 h. This is clinically relevant as 39‐O‐desmethyl sirolimus shows 86–127% cross‐reactivity with the antibody of the widely used Abbott sirolimus immunoassay. The metabolism of sirolimus in the children included in our study differed from that reported in adults, which should be considered when monitoring sirolimus exposure immunologically.

Development and validation of a high-throughput assay for quantification of the proliferation inhibitor ABT-578 using LC/LC-MS/MS in blood and tissue samples.

We report here a specific, automated LC/LC-MS/MS assay for the quantification of ABT-578 in human and rabbit blood and rabbit tissues for drug-eluting stent development. After protein precipitation, samples were injected into the HPLC system and extracted online using a high flow of 5 mL/min. The extracts were then backflushed onto the analytic column. The [M + Na]+ of ABT-578 (m/z 988.6 → 369.4) and its internal standard sirolimus (m/z 936.5 → 409.3) were monitored. Extraction and analysis took 4 minutes. The assay was validated following the US Food & Drug Administration guidelines. Linearity was 0.025-25 ng/mL for most matrices. In human blood, interday accuracies were 81.8% (at 0.025 ng/mL), 91.0% (1 ng/mL), and 99.5% (50 ng/mL), and interday precisions were 10.7% (0.025 ng/mL), 3.0% (1 ng/mL), and 1.8% (50 ng/mL).

A dosimetric study of polyethylene glycol hydrogel in 200 prostate cancer patients treated with high-dose rate brachytherapy ± intensity modulated radiation therapy

BACKGROUND AND PURPOSE We sought to analyze the effect of polyethylene glycol (PEG) hydrogel on rectal doses in prostate cancer patients undergoing radiotherapy. MATERIALS AND METHODS Between July 2009 and April 2013, we treated 200 clinically localized prostate cancer patients with high-dose rate (HDR) brachytherapy±intensity modulated radiation therapy. Half of the patients received a transrectal ultrasound (TRUS)-guided transperineal injection of 10mL PEG hydrogel (DuraSeal™ Spinal Sealant System; Covidien, Mansfield, MA) in their anterior perirectal fat immediately prior to the first HDR brachytherapy treatment and 5mL PEG hydrogel prior to the second HDR brachytherapy treatment. Prostate, rectal, and bladder doses and prostate-rectal distances were calculated based upon treatment planning CT scans. RESULTS There was a success rate of 100% (100/100) with PEG hydrogel implantation. PEG hydrogel significantly increased the prostate-rectal separation (mean±SD, 12±4mm with gel vs. 4±2mm without gel, p<0.001) and significantly decreased the mean rectal D2 mL (47±9% with gel vs. 60±8% without gel, p<0.001). Gel decreased rectal doses regardless of body mass index (BMI). CONCLUSIONS PEG hydrogel temporarily displaced the rectum away from the prostate by an average of 12mm and led to a significant reduction in rectal radiation doses, regardless of BMI.

A dosimetric comparison of volumetric modulated arc therapy with step-and-shoot intensity modulated radiation therapy for prostate cancer

PURPOSE To compare variable dose-rate volumetric modulated arc therapy (VMAT) with 7-field, step-and-shoot intensity modulated radiation therapy (IMRT) in prostate cancer patients treated with a consistent planning target volume (PTV) to a uniform total radiation therapy dose. METHODS AND MATERIALS We studied 32 patients who received 8100 cGy in 45 daily fractions to their prostate and proximal 1 cm of the seminal vesicles using variable dose rate VMAT (n = 22) or 7-field, step-and-shoot IMRT (n = 10) for intermediate-risk or high-risk prostate cancer between July 2010 and April 2013. In 90% of patients, VMAT was delivered with 2 arcs. To have an unbiased comparison of plan quality, patients who were treated with VMAT were also planned with IMRT and vice versa. Each patient served as his own control for the comparison. RESULTS VMAT reduced median radiation beam-on time from 4.3 to 3.4 minutes (P = .03). There was no statistically significant difference in PTV volumes between the VMAT and step-and-shoot IMRT groups (P = .76). VMAT dose distributions were more homogeneous (P = .003). There was no difference between groups with regard to rectal V60, V65, V70, V75, bladder V65, V70, V75, V80, or femoral heads V33. CONCLUSIONS Two-arc VMAT resulted in shorter beam-on times and more homogenous dose distributions than 7-field, step-and-shoot IMRT for prostate cancer. With decreased beam-on time, the intrafraction motion during irradiation is reduced, thus improving confidence that the delivered dose distribution agrees with the plan.

Comparison of every 3 week cisplatin or weekly cetuximab with concurrent radiotherapy for locally advanced head and neck cancer

BACKGROUND Cisplatin dosed every 3 weeks (CIS) or weekly cetuximab (CTX) concurrent with radiotherapy are standards of care for locally advanced head and neck squamous cell carcinoma (LAHNC). Retrospective comparisons of CIS and CTX have offered mixed conclusions. We compared outcomes between CIS and CTX in this patient population. METHODS Between January 2006 and December 2011, we identified 279 patients who underwent definitive radiotherapy and concurrent systemic therapy for LAHNC. The median age difference between the CIS and CTX groups was relatively small (58 vs. 62 years, respectively) and CIS patients had a slightly higher rate of N2 disease than CTX patients (74% vs. 61%, respectively). RESULTS Median follow-up was 27 months. Systemic therapy consisted of CIS in 241 (86.4%) and CTX in 38 (13.6%). Actuarial locoregional control of the CIS and CTX groups at 2 years were 91% and 90% (p=0.74), respectively. Actuarial 2 year distant metastasis rates between the groups were 8% and 12%, respectively (p=0.55), and actuarial 2 year overall survival between the groups were 87% and 89%, respectively (p=0.47). CONCLUSIONS We found no difference in locoregional control, distant metastasis rate, or overall survival between patients treated with concurrent CIS or CTX.