Long-Term Outcomes of NRG Oncology/RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Anal Canal Cancer.

PURPOSE: A multi-institutional phase 2 trial assessed long-term outcomes of dose-painted intensity modulated radiation therapy (IMRT) with 5-fluorouracil (5FU) and mitomycin-C (MMC) for anal canal cancer. METHODS AND MATERIALS: T2-4N0-3M0 anal cancers received 5FU (1000 mg/m2/d, 96-hour infusion) and MMC (10 mg/m2 bolus) on days 1 and 29 of dose-painted IMRT prescribed as follows: T2N0 = 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes, 28 fractions; T3-4N0-3 = 45Gy elective nodal, 50.4 Gy ≤3 cm and 54 Gy >3cm metastatic nodal and 54 Gy anal tumor planning target volumes, 30 fractions. Local-regional failures, distant metastases, and colostomy failures were assessed using the cumulative incidence method, and disease-free survival, overall survival, and colostomy-free survival were assessed using the Kaplan-Meier method. Late effects were scored using National Cancer Institute-Common Terminology Criteria for Adverse Events v3. RESULTS: Of 52 patients, 54% were stage II, 25% were stage IIIA, and 21% were stage IIIB. Median follow-up was 7.9 years (min-max, 0.02-9.2 years). Local-regional failure, colostomy failures, distant metastases, overall survival, disease-free survival, and colostomy-free survival at 5 years are 16% (95% confidence interval [CI], 7%-27%), 10% (95% CI, 4%-20%), 16% (95% CI, 7%-27%), 76% (95% CI, 61%-86%), 70% (95% CI, 56%-81%), and 74% (95% CI, 59%-84%); and at 8 years they are 16% (95% CI, 7%-27%), 12% (95% CI, 5%-23%), 22% (95% CI, 12%-34%), 68% (95% CI, 53%-79%), 62% (95% CI, 47%-74%) and 66% (95% CI, 51%-77%), respectively. Eight patients experienced local-regional failure, with 5 patients having persistent disease at 12 weeks. No isolated nodal failures occurred in the microscopic elective nodal volumes. Six patients required colostomy-5 for local-regional salvage and 1 for a temporary ostomy for anorectal dysfunction. Rates of late adverse events included: 28 patients (55%) with grade 2, 8 patients (16%) with grade 3, 0 patients with grade 4, and 2 patients (4%) with grade 5 events (sinus bradycardia and myelodysplasia, possibly owing to chemotherapy). Only 11 patients reported grade 1 to 3 sexual dysfunction. CONCLUSIONS: Dose-painted IMRT with 5FU/MMC for the treatment of anal canal cancer yields comparable long-term efficacy as conventional radiation cohorts. Enhanced normal tissue protection lowered rates of grade 3 and higher late effects without compromising pelvic tumor control.

Precision Medicine: Genomic Profiles to Individualize Therapy.

Precision medicine is the application of genotypic and Omics biomarkers to determine the most appropriate, outcome-driven therapy for individual patients. To determine the best choice of therapy, institutions use significant information technology-enabled data from imaging, electronic medical records, sensors in the clinic/hospitals, and wearable sensors to determine treatment response. With genomic profiling, targets to affect a disease course are continuing to be developed. As clonal mutational prevalence continues to be understood, information can be communicated to patients to inform them that resistance is common, requiring collection of more genetic mutations from patients with further biopsies or blood collection.

Lay patient navigator program implementation for equal access to cancer care and clinical trials: essential steps and initial challenges.

BACKGROUND: Disparities in cancer detection, treatment, and outcomes among racial/ethnic minorities and low-income patients are well documented. One way to reduce these disparities is to use patient navigators to address barriers to care. However, little information about optimal characteristics of navigator programs or considerations for those interested in setting up such programs is available. METHODS: The design and implementation of a patient navigator program for underserved cancer patients in an urban, nonacademic community hospital setting is described. The program, which used lay navigators, was conceived as a component of the Urban Latino African American Cancer (ULAAC) Disparities Project in South Los Angeles, a National Cancer Institute (NCI)-sponsored project to improve cancer care and clinical trial access for minority and low-income patients. RESULTS: Careful initial planning, including input from a community advisory committee, was essential to smooth program implementation. Thirty-one volunteers completed navigator training in the program's first year of operation. Of 135 patients offered navigation services, 75 (56%) accepted, and preliminary feedback from patients, navigators, and providers suggests high levels of satisfaction with navigation. Standardized templates used by navigators and staff to record key information are proving helpful for monitoring quality and outcomes (such as effectiveness in addressing specific barriers to care) and continually improving the program. CONCLUSIONS: The ULAAC program represents a viable model for developing lay navigator programs in community hospitals. Preliminary assessments suggest that the program has a positive effect on minority and low-income cancer patients' experience with care and reduces barriers to care. Additional time and research are needed, however, to fully assess the impact on care and outcomes.

Optimization of MammoSite therapy.

PURPOSE: Radiation source anisotropy causes about 10% of a spherically shaped planning target volume surrounding a MammoSite balloon to receive less than the prescribed dose. The principal dose-limiting factor for MammoSite therapy is the dose to the overlying skin. Additional limiting factors potentially include the dose to portions of the heart and lung. The goal of optimization is to deliver the prescribed dose to as much of the planning target volume as possible while avoiding toxicity to adjacent organs. METHODS AND MATERIALS: An experimental CT-based high-dose-rate brachytherapy treatment planning system was used to investigate optimization strategies for MammoSite treatment. This system implements a linear optimization of high-dose-rate dwell times on the basis of constraints assigned to points of interest and a set of potential dwell positions. RESULTS: The cylindrical symmetry of the MammoSite catheter limits the optimization process to creating spherical, ellipsoidal, or egg-shaped isodose distributions whose major axis is oriented along the catheter axis. If the dose to a limiting structure, such as skin, is not an issue, the use of multiple dwell positions can compensate for source anisotropy and create a more spherical isodose surface enclosing the planning target volume compared with a single dwell position. When skin becomes a dose-limiting factor, the catheter axis orientation, source anisotropy, dwell position, and dwell weighting can be exploited to limit the skin dose while simultaneously preserving the prescribed dose to as much of the target volume as possible. CONCLUSION: Optimization of MammoSite therapy using multiple dwell positions within the balloon is both possible and practical.

MammoSite radiation therapy system.

The MammoSite Radiation Therapy System (RTS) has become the most widely used brachytherapy method used in the treatment of breast cancer, due to its ease of use, short learning curve, and requirement of only one interstitial path through the breast skin. The dosimetry is simple, one source position in the middle of the MammoSite balloon catheter. The data on long-term complications, however are not available, though developing. Trials for DCIS are being developed, as well as a comparison trial to standard external beam radiation as well as other forms of accelerated partial breast irradiation (APBI).

The use of linear programming in optimization of HDR implant dose distributions.

The introduction of high dose rate brachytherapy enabled optimization of dose distributions to be used on a routine basis. The objective of optimization is to homogenize the dose distribution within the implant while simultaneously satisfying dose constraints on certain points. This is accomplished by varying the time the source dwells at different locations. As the dose at any point is a linear function of the dwell times, a linear programming approach seems to be a natural choice. The dose constraints are inherently linear inequalities. Homogeneity requirements are linearized by minimizing the maximum deviation of the doses at points inside the implant from a prescribed dose. The revised simplex method was applied for the solution of this linear programming problem. In the homogenization process the possible source locations were chosen as optimization points. To avoid the problem of the singular value of the dose at a source location from the source itself we define the "self-contribution" as the dose at a small distance from the source. The effect of varying this distance is discussed. Test cases were optimized for planar, biplanar and cylindrical implants. A semi-irregular, fan-like implant with diverging needles was also investigated. Mean central dose calculation based on 3D Delaunay-triangulation of the source locations was used to evaluate the dose distributions. The optimization method resulted in homogeneous distributions (for brachytherapy). Additional dose constraints--when applied--were satisfied. The method is flexible enough to include other linear constraints such as the inclusion of the centroids of the Delaunay-triangulation for homogenization, or limiting the maximum allowable dwell time.

Breast-conserving therapy for ductal carcinoma in situ: a 20-year experience with excision plus radiation therapy.

BACKGROUND: Breast conservation therapy is a practical alternative to mastectomy for the treatment of ductal carcinoma in situ (DCIS). The role of radiation therapy after excision for DCIS has been debated, however, its value in reducing recurrence has been proven by multiple prospective randomized trials and is well accepted. METHODS: We examined a prospective database of 260 patients treated for DCIS with excision and radiation from 1979 to 2002. Two different treatment regimens were examined for local recurrence-free survival. Patients treated with radiation therapy 4 days per week were compared with patients treated 5 days per week. The total doses were similar for both groups; boost types differed. Local recurrence as a function of other factors, including nuclear grade, comedonecrosis, and margin width was evaluated. RESULTS: The median time to local recurrence was 61 months for patients treated 4 days per week compared with 52 months for patients treated 5 days per week (P = not significant). There was no statistical difference in the Kaplan-Meier detailing the probability of local recurrence-free survival for patients treated 4 days per week versus patients treated 5 days per week. Overall, cosmetic results between the two groups were equivalent. CONCLUSIONS: The comparison of two different radiation treatment regimens shows no difference in local disease-free survival or cosmetic result.

Postoperative radiotherapy in 423 patients with pT3N0 prostate cancer.

PURPOSE: To evaluate the treatment outcome in pT3N0 patients with adenocarcinoma of the prostate treated with an elective course of postoperative irradiation (RT). METHODS AND MATERIALS: During a 22-year period, a total of 423 pT3N0 prostate cancer patients were treated at a single medical center with prostatic fossa RT, which was the only adjuvant therapy given. The patient characteristics were as follows: median age 66 years; Stage pT3aN0 in 296 (70%) and pT3bN0 in 127 (30%); Gleason score 2-4 in 12 (2.8%), 5-6 in 157 (37.1%), 7 in 151 (35.7%), and 8-10 in 100 (23.6%); and the median and mean preoperative prostate-specific antigen (PSA) level was 10 and 15.9 ng/mL, respectively. Radiotherapy consisted of a median dose of 48 Gy delivered to the prostatic fossa and its immediate vicinity. The median follow-up was 7 years. RESULTS: The 5- and 10-year actuarial survival rate was 92% and 73%, respectively, and the 5- and 10-year disease-free survival rate (PSA <0.05 ng/mL) was 69% and 51%, respectively. In multivariate analysis, the Gleason score was the most important predictor for survival (p = 0.00005), and pathologic stage and Gleason score were independently predictive of disease-free survival (p = 0.00007 and 0.0003, respectively). The worst prognostic category was represented by pT3bN0, Gleason score 7-10 patients who had a 5.3 times greater risk of tumor recurrence than those with pT3aN0, Gleason score 2-6. A high (>25 ng/mL) preoperative PSA level was also a predictor of tumor recurrence (p = 0.03). A total of 43 patients (10.2%) developed clinical recurrence. This included 30 patients (7%) with distant metastases alone and 13 (3%) with local recurrence, which included 2 patients who also had distant disease. An additional 88 patients (20%) had PSA elevation (>0.05 ng/mL). This treatment program was well tolerated, with acute toxicity common (62%) but of no clinical significance. No late or severe toxicity was recorded. CONCLUSION: Adjuvant radiotherapy, as given in this study, appears to substantially reduce the expected incidence of local tumor recurrence in pT3N0 prostate cancer patients. The treatment outcome was poor in pT3bN0 and Gleason score 7-10 patients, with >80% showing evidence of clinical or PSA recurrence at 10 years after therapy. This group should be the target of a prospective trial of systemic therapy.