Q. Nguyen

Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer?

PURPOSE To retrospectively compare the toxicity and efficacy of concurrent gemcitabine-based chemoradiation with that of concurrent 5-fluorouracil (5-FU)-based chemoradiation in patients with unresectable pancreatic cancer. PATIENTS AND METHODS Between September 1996 and May 2000, 114 patients with localized unresectable adenocarcinoma of the pancreas were treated with concurrent chemoradiation. Locally advanced unresectable disease was defined as low-density tumor in contact with the superior mesenteric artery (SMA) or celiac artery, or occlusion of the superior mesenteric-portal venous confluence. Fifty-three patients were selected to receive gemcitabine in 7 weekly cycles (250-500 mg/m(2)) with concurrent radiotherapy (median dose 30 Gy, range 30-33 Gy in 10-11 fractions). The remaining 61 patients received continuous-infusion 5-FU (200-300 mg/m(2)) with concurrent radiotherapy (30 Gy in 10 fractions). Radiotherapy was delivered to the primary tumor and regional lymphatics. Patients receiving gemcitabine and those receiving 5-FU had a similar mean Karnofsky performance status (KPS, 89% vs. 86%), distribution of tumor grade (43% vs. 33% poorly differentiated), and percent weight loss (all p = NS). However, patients treated with gemcitabine had a significantly larger median maximum cross-sectional tumor area (TA, 8.8 cm(2) vs. 5.7 cm(2), p = 0.046) and were significantly younger (median age 60 vs. 68 years, p <0.001). Severe acute toxicity (ST) was defined as toxicity requiring a hospital stay of more than 5 days, mucosal ulceration with bleeding, more than 3 dose deletions of gemcitabine or discontinuation of 5-FU, or toxicity resulting in surgical intervention or death. Kaplan-Meier analysis was used to calculate the actuarial rate of local progression on imaging (LP), the rate of distant metastasis (DM), and the overall survival (OS) rate. The imaging was reviewed in resected patients. RESULTS Patients receiving gemcitabine developed significantly more ST during treatment (23% vs. 2%, p < 0.0001) than did those receiving 5-FU. Patients treated with gemcitabine had a similar 10-month LP rate (62% vs. 61%), 10-month DM rate (55% vs. 47%), 1-year OS rate (42% vs. 28%), and median OS duration (11 months vs. 9 months) to patients treated with 5 FU (all p = NS). Five patients who received gemcitabine and 1 patient who received 5-FU underwent margin-negative pancreaticoduodenectomy after chemoradiation. Three patients had a short segment (<or= 1 cm in length) of low-density tumor abutting the SMA, 1 had involvement of the common hepatic artery, and 1 had a short-segment occlusion of the superior mesenteric vein, amenable to venous resection and reconstruction. The other patient was thought to have inflammatory changes discontiguous with the tumor surrounding the SMA, which resolved after therapy. TA >10 cm(2) (p = 0.03) and poor differentiation (p = 0.07) were associated with a worse survival duration; however, other factors, such as KPS and weight loss >10% and age did not influence OS. CONCLUSION Despite the selection of healthier patients to receive gemcitabine, there was a significantly higher severe toxicity rate than with 5-FU. The median and 1-year survivals were not significantly different with the use of concurrent gemcitabine; however, the tumors treated were significantly larger. Additionally, a small number of patients with minimal arterial involvement whose disease met our radiographic definition of unresectable disease had margin-negative resections after treatment with gemcitabine-based chemoradiation. These possible benefits and the high rate of severe toxicity define a very narrow therapeutic index for concurrent gemcitabine-based chemoradiation given by this schedule of administration.

Toxicity and Efficacy of Concurrent Gemcitabine and Radiotherapy for Locally Advanced Pancreatic Cancer.

SummaryBackground. Gemcitabine and radiotherapy are a potent combination. A clinical assessment of the therapeutic ratio for locally advanced pancreatic cancer patients has not yet been reported.Aim of Study. To assess the toxicity, survival, and pattern of failure of locally advanced pancreatic cancer patients treated with concurrent gemcitabine-based chemoradiation.Patients and Methods. Between the dates of December 1996 and August 2000 51 patients with locally advanced unresectable adenocarcinoma of the pancreas were treated with concurrent gemcitabine and radiotherapy at MDACC. Patients received 250–500 mg/m2 of gemcitabine weekly ×7 over 30 min and 30–33 Gy in 10–11 fractions over two weeks to the primary tumor and regional lymphatics. Severe toxicity was defined as admission >5 d, mucosal ulceration, >3 dose deletions of gemcitabine or toxicity resulting in surgical intervention or that resulted in death.Results. The median survival was 11 mo. Overall, 37 of 51 patients had objective evidence of local progression. The actuarial rate of local progression rate at 9 mo was 70%. The 9-mo distant metastasis rate was 52%. Tumors ≥ 10 cm2 had worse local control, distant control, and overall survival. Six patients underwent pancreaticoduodenectomy after therapy. After review of the imaging, only four of these patients had minimal arterial involvement, one was incorrectly staged, and one had initial inflammatory change on CT that resolved. Twelve of 51 (24%) patients suffered severe acute toxicity, and 17 of 51 (33%) patients were admitted for supportive care.Conclusion. Concurrent gemcitabine and radiotherapy can be a very difficult combination to administer safely. Our results do not suggest a prolongation of median survival for patients with localized pancreatic cancer treated with this therapy. It is possible that gemcitabine-based chemoradiation contributes to the margin-negative resectability of a small number of patients with minimal arterial involvement, but this benefit is obscured by the frequent toxicity encountered in most patients. Locally advanced pancreatic cancer patients should continue to be enrolled on prospective studies investigating novel combinations of cytotoxic and/or biologic agents with concurrent radiotherapy.

Is androgen deprivation therapy necessary in all intermediate-risk prostate cancer patients treated in the dose escalation era?

PURPOSE The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). METHODS Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. RESULTS Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). CONCLUSIONS Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose-escalated RT did improve FFF.

Improvement in prostate cancer survival over time: A 20-year analysis

PurposeThis study aimed to evaluate the changes in outcome for men with localized prostate cancer treated with definitive external beam radiation therapy during a 20-year period at a comprehensive cancer center. MethodsWe categorized 2675 men with prostate cancer treated at MD Anderson Cancer Center with definitive external beam radiation therapy with or without androgen deprivation therapy into 3 treatment eras: 1987 to 1993 (n = 722), 1994 to 1999 (n = 828), and 2000 to 2007 (n = 1125). To help adjust for stage migration, patients were stratified according to risk group as defined by the National Comprehensive Cancer Network. Biochemical (Phoenix definition), local, distant, and any clinical failure, prostate-cancer specific survival, and overall survival were analyzed according to the Kaplan-Meier method. ResultsMedian age was 68.5 years and median follow-up was 6.4 years. Fewer men in the most recent era had high-risk disease, and a higher proportion received 72 Gy or higher (99% vs 4%) and androgen deprivation therapy (60% vs 6%) than the earliest era. All risk groups treated in the modern era experienced improved rates of biochemical, local, and distant failure. In high-risk patients, decreased rates of distant failure and clinical failure led to improved prostate cancer–specific survival and overall survival. Local control was improved for intermediate- and high-risk patients, with a trend toward improvement in low-risk patients. On multivariate analysis, recent treatment era was closely correlated with a dose of 72 Gy or higher and treatment with androgen deprivation therapy and predicted for lower rates of biochemical, local, and distant failure. Androgen deprivation therapy, higher dose, and more recent treatment era predicted for improved prostate cancer–specific survival. DiscussionDuring the last 20 years of prostate cancer irradiation, disease control outcomes have improved in all patients, leading to improved prostate cancer–specific survival and overall survival for men with high-risk disease. This may reflect advances in workup, staging accuracy, and prostate cancer treatment in the modern era.

Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer

BACKGROUND Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P=0.004). Recursive partitioning analysis of men without ADT classified Gleason 4+3=7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P=0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P=0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P=0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P=0.380). CONCLUSION The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.BACKGROUND Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P = 0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P = 0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P = 0.380). CONCLUSION The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.

Association Between White Blood Cell Count Following Radiation Therapy With Radiation Pneumonitis in Non-Small Cell Lung Cancer

PURPOSE Radiation pneumonitis (RP) is an inflammatory response to radiation therapy (RT). We assessed the association between RP and white blood cell (WBC) count, an established metric of systemic inflammation, after RT for non-small cell lung cancer. METHODS AND MATERIALS We retrospectively analyzed 366 patients with non-small cell lung cancer who received ≥60 Gy as definitive therapy. The primary endpoint was whether WBC count after RT (defined as 2 weeks through 3 months after RT completion) was associated with grade ≥3 or grade ≥2 RP. Median lung volume receiving ≥20 Gy (V20) was 31%, and post-RT WBC counts ranged from 1.7 to 21.2 × 10(3) WBCs/μL. Odds ratios (ORs) associating clinical variables and post-RT WBC counts with RP were calculated via logistic regression. A recursive-partitioning algorithm was used to define optimal post-RT WBC count cut points. RESULTS Post-RT WBC counts were significantly higher in patients with grade ≥3 RP than without (P<.05). Optimal cut points for post-RT WBC count were found to be 7.4 and 8.0 × 10(3)/μL for grade ≥3 and ≥2 RP, respectively. Univariate analysis revealed significant associations between post-RT WBC count and grade ≥3 (n=46, OR=2.6, 95% confidence interval [CI] 1.4‒4.9, P=.003) and grade ≥2 RP (n=164, OR=2.0, 95% CI 1.2‒3.4, P=.01). This association held in a stepwise multivariate regression. Of note, V20 was found to be significantly associated with grade ≥2 RP (OR=2.2, 95% CI 1.2‒3.4, P=.01) and trended toward significance for grade ≥3 RP (OR=1.9, 95% CI 1.0-3.5, P=.06). CONCLUSIONS Post-RT WBC counts were significantly and independently associated with RP and have potential utility as a diagnostic or predictive marker for this toxicity.

Dosimetric impact of fiducial markers in patients undergoing photon beam radiation therapy

Fiducial markers are widely used in image-guided radiation therapy to correct for setup error and organ motion. These markers, however, can cause dose perturbations in the target volume for patients undergoing external-beam radiation therapy. The goal of this study was to determine the dosimetric impact of various types of fiducial markers commonly used in patients receiving photon radiation therapy. Monte Carlo simulations based on a newly developed EGSnrcMP user code were used to investigate three types of gold fiducial markers and a carbon marker. A single photon field with each fiducial in various orientations and two parallel-opposed beams were simulated at 6-MV and 18-MV energies. The results indicated that dose perturbations depended on marker size, material, and orientation, as well as on incident beam energy. Maximum dose perturbations were found for a single 6-MV beam. The increase in dose reached a factor of 1.58 near the upstream surface of the gold marker because of electron backscatter. At the downstream surface, the dose was reduced to a factor of 0.53 at the same point without the marker. For the 18-MV beam, the maximum dose factor was 1.48 and the minimum dose factor was 0.66. For the two parallel-opposed beams, the maximum dose reduction was within 5% at 6 MV and 2% at 18 MV. Dose enhancement, however, remained significant, reaching factors of 1.20 and 1.33 for the two energies near the fiducial surface. Carbon fiducials caused dose perturbations of only ~1%.

Association of lung fluorodeoxyglucose uptake with radiation pneumonitis after concurrent chemoradiation for non-small cell lung cancer

Background Increased uptake of fluorodeoxyglucose (FDG) by lung tissue could reflect inflammatory changes related to radiation pneumonitis (RP). In this secondary analysis of a clinical trial, we examined potential associations between posttreatment lung FDG uptake and RP severity in patients with non-small cell lung cancer (NSCLC) for up to 12 months after concurrent chemoradiation (CRT). Methods Subjects were 152 patients with NSCLC who had received concurrent CRT as part of the prospective trial NCT00915005. The following lung FDG variables were evaluated after CRT: maximum, mean, and peak standardized uptake values (SUVmax, SUVmean, SUVpeak) and global lung glycolysis (GLG; lung SUVmean × lung volume). RP severity was scored with the Common Terminology Criteria for Adverse Events v3.0. Results Significant associations were noted between PET findings and RP severity at 1–6 months (all P < 0.05), but not at 7–12 months after therapy (all P > 0.05). Lung FDG uptake at 1–3 months after treatment predicted later development of grade ≥2 RP (all P < 0.05), with cutoff values as follows: 4.54 for SUVmax, 3.69 for SUVpeak, 0.78 for SUVmean, and 2295 for GLG. Conclusions Lung FDG uptake correlated significantly with RP severity during the first 6 months after CRT. The cutoff values seem clinically meaningful for identifying patients at risk of developing RP after such therapy.

Comparative Toxicities and Cost of Intensity-Modulated Radiotherapy, Proton Radiation, and Stereotactic Body Radiotherapy Among Younger Men With Prostate Cancer

Purpose To compare the toxicities and cost of proton radiation and stereotactic body radiotherapy (SBRT) with intensity-modulated radiotherapy (IMRT) for prostate cancer among men younger than 65 years of age with private insurance. Methods Using the MarketScan Commercial Claims and Encounters database, we identified men who received radiation for prostate cancer between 2008 and 2015. Patients undergoing proton therapy and SBRT were propensity score-matched to IMRT patients on the basis of clinical and sociodemographic factors. Proportional hazards models compared the cumulative incidence of urinary, bowel, and erectile dysfunction toxicities by treatment. Cost from a payers perspective was calculated from claims and adjusted to 2015 dollars. Results A total of 693 proton therapy patients were matched to 3,465 IMRT patients. Proton therapy patients had a lower risk of composite urinary toxicity (33% v 42% at 2 years; P < .001) and erectile dysfunction (21% v 28% at 2 years; P < .001), but a higher risk of bowel toxicity (20% v 15% at 2 years; P = .02). Mean radiation cost was

Select men benefit from androgen deprivation therapy delivered with salvage radiation therapy after prostatectomy

115,501 for proton therapy patients and