Synthesis of Substituted Indolines through Photocatalyzed Decarboxylative Radical Arylation.

We report a new photocatalyzed remote alkyl radical generation and cyclization to prepare substituted indolines in a green, metal-free procedure. This method complements the Fischer indolization, metal-catalyzed couplings, and photocatalyzed radical addition and cyclization. A wide range of functional groups is tolerated, including aryl halides, that would not be compatible with most existing methods. Electronic bias and substitution were studied to demonstrate complete regiocontrol and high chemocontrol in the indoline formation.

Association Between EGFR and ALK Mutation Status on Patient-Reported Symptoms After Palliative Radiation for Bone Pain in NSCLC.

Introduction: After palliative radiotherapy for bone metastases from NSCLC, up to 30% of patients may derive no symptomatic benefit, and there are a lack of biological predictors for this. The purpose was to investigate whether EGFR and ALK genetic rearrangements were associated with greater rates of pain response to palliative radiotherapy. Methods: Patients were identified from a prospectively collected patient-reported outcomes database for all patients with lung cancer treated with conventional palliative radiotherapy for bone metastases from 2013 to 2016 in the province of British Columbia. Patients were divided on the basis of mutational status into the following: EGFR and ALK wild type (WT), EGFR mutation present (EGFR+), or ALK mutation present (ALK+). Patient-reported outcomes of global pain severity were collected before and after radiotherapy and on an ordinal scale of 0 to 4, with 0 representing no bone pain and 4 representing the maximal possible bone pain. The primary outcome was the rate of partial pain response (any improvement in score), and the secondary outcome was the rate of complete pain response (final pain score of 0). Stepwise, multivariable logistic analysis was used to compare response rates between treatment courses for different mutational statuses. Results: The final cohort consisted of 388 treatment courses for 329 unique patients. For the WT, EGFR+, and ALK+ groups, there were 180, 63, and nine treatment courses, respectively. There were 92 patients with no ALK and EGFR testing. The most common treatment fractionations were 8 Gy in one fraction (188 of 388) and 20 Gy in five fractions (160 of 388), and use of multifraction radiotherapy did not differ between mutation status groups (p = 0.3). Partial pain response rates were as follows: WT 63%, EGFR+ 75%, and ALK+ 78%. On multivariable analysis, rates of partial response were higher for EGFR+ (OR = 5.4, p < 0.001) and for ALK+ (OR = 12.8, p = 0.008) in comparison to WT. Complete response rates were as follows: WT 20.5%, EGFR+ 35%, and ALK+ 67%. On multivariable analysis, complete response was not significantly increased in EGFR+ compared with WT (OR = 1.6, p = 0.127). ALK+ mutation status was associated with a higher rate of complete response compared with WT (OR = 5.2, p = 0.031). Conclusions: There was an association between EGFR+ and ALK+ tumors and increased rates of partial pain response to palliative radiotherapy.

After ASCENDE-RT: Biochemical and survival outcomes following combined external beam radiotherapy and low-dose-rate brachytherapy for high-risk and unfavourable intermediate-risk prostate cancer, a population-based analysis.

PURPOSE: To evaluate the outcomes of unfavorable intermediate-risk (UIR) and high-risk (HR) prostate cancer patients treated with combined external beam radiation therapy (EBRT) and low-dose-rate prostate brachytherapy (LDR-PB). METHODS AND MATERIALS: A population-based cohort of 568 prostate cancer patients treated with combined EBRT and LDR-PB from 2010 to 2016 was analyzed. All patients received EBRT followed by LDR-PB boost. Outcomes were compared with the results for the brachytherapy arm of the ASCENDE-RT trial. RESULTS: The median followup was 4.5 years. Sixty-nine percent (N = 391) had HR disease. Ninety-four percent of the HR and 57% of UIR were treated with androgen deprivation therapy (ADT) with a median duration of 12 months. The 5-year K-M biochemical progression-free survival (b-PFS), metastasis-free survival (MFS), and overall survival (OS) were 84 ± 2%, 90 ± 2%, and 88 ± 2%, similar to 89 ± 5%, 94 ± 4%, and 92 ± 4% for the ASCENDE-RT LDR-PB arm. The likelihood of achieving a PSA ≤0.2 ng/mL at 4 years was 88%, similar to 86% in the ASCENDE-RT LDR-PB arm. Thirty-three men (5.8%) would have been ineligible for ASCENDE-RT due to high-risk features. The 5-year K-M b-PFS, MFS and OS estimates were 86 ± 2%, 92 ± 1% and 89 ± 2% for the ASCENDE-RT eligible versus 56 ± 10% (p < 0.001), 73 ± 8% (p < 0.001), and 77 ± 9% (p = 0.098) for the ineligible patients. CONCLUSIONS: In this population-based cohort, combining LDR-PB with pelvic EBRT (+/- ADT) achieves very favorable b-PFS that compares to the LDR-PB arm of the ASCENDE-RT, supporting the generalizability of those results. Men ineligible for ASCENDE-RT, based on prognostic features, have a much higher risk of biochemical recurrence and metastatic relapse.

Using a Weekly Patient-Reported Outcome Questionnaire to Track Acute Toxicity in Patients Undergoing Pelvic Radiotherapy for Gynecologic Cancers.

There are limited patient-reported outcome (PRO) data tracking changes in toxicity in patients actively undergoing radiotherapy. Between 2015−2019, acute toxicity was prospectively measured in 698 patients undergoing a 5-week course of pelvic radiotherapy for gynecologic cancers using a weekly PRO questionnaire. Our questionnaire was able detect a pattern of onset and resolution of acute gastrointestinal (GI) and genitourinary (GU) toxicity in 27 out of 32 questions. Logistic regression analysis showed that increasing GI and GU toxicity at week 2 could predict for severe toxicity at week 5. However, due to a low number of severe events, univariate results could not be productively added to a multivariate model. We observed a >70% response rate for all sections of the questionnaire, except for questions on sexual and vaginal health, which had a 13% average response rate. By demonstrating that PRO data can be used to track acute toxicity during radiotherapy, there is a need to further examine how this tool may be implemented in the clinic to provide complex, adaptive care, such as early side effect management, and modifying radiation delivery in real-time.

Evaluation of Patient-Reported Outcome Differences by Radiotherapy Techniques for Bone Metastases in A Population-Based Healthcare System.

We assessed whether advanced RT techniques were associated with differences in patient-reported outcomes (PROs). Patients with bone metastases who completed the brief pain inventory (BPI) before and after RT were identified, and RT technique was categorized as simple (e.g., parallel opposed pair) or advanced (e.g., 3D-conformal RT (3DCRT), intensity-modulated RT (IMRT), or stereotactic ablative RT (SABR)). Pain response and patient-reported interference on quality of life secondary to pain was compared. A total of 1712 patients completed the BPI. From 2017−2021, the rate of advanced RT technique increased significantly (p < 0.001; 2.4%, 2.4%, 9.7%, 5.5%, 9.3%), with most advanced techniques consisting of IMRT, and only 7% of advanced techniques were SABR. Comparing simple vs. advanced technique, neither the complete pain response (12.3% vs. 11.4%; p = 0.99) nor the partial pain response (50.0% vs. 51.8%; p = 0.42) was significantly different. There was no significant patient-reported difference in pain interfering with general activity, mood, walking ability, normal work, relationships, sleep, or enjoyment of life. Given that there is increasing utilization of advanced RT techniques, there is further need for randomized trials to assess their benefits given the increased cost and inconvenience to patients.

Patient-reported outcomes and complications during head and neck cancer radiotherapy before versus during the COVID-19 pandemic.

PURPOSE: This study compares patient-reported outcomes and treatment-related complications during radiotherapy before (August 2019-January 2020) versus during (March-Sept 2020) the COVID-19 pandemic. MATERIALS AND METHODS: The MD Anderson Symptom Inventory-head and neck module was used to assess curative intent in H&N cancer patients' symptoms during radiotherapy. RESULTS: There were 158 patients in the pre-pandemic cohort and 137 patients in the pandemic cohort. There was no significant difference in enteral feeding requirements between the cohorts (21% versus 30%, p = 0.07). Weight loss was higher during the pandemic (mean - 5.6% versus 6.8%, p = 0.03). On multivariate analysis, treatment during the pandemic was associated with higher symptom scores for coughing/choking while eating (2.7 versus 2.1, p = 0.013). CONCLUSIONS: Complication rates during H&N radiotherapy during the COVID-19 pandemic were similar at our institution relative to the pre-pandemic era, although weight loss was greater and patients reported more severe choking/coughing while eating.

Functionalized Polyhydroquinolines from Amino Acids Using a Key One-Pot Cyclization Cascade and Application to the Synthesis of (±)-Δ7-Mesembrenone.

Substituted polyhydroquinolines are ubiquitous skeletal cores found in drugs and bioactive natural products. As a new route to access this motif, we successfully developed a one-pot cyclization cascade with high chemocontrol and diastereoselectivity. The sequence generates two cycles, three carbon-carbon bonds, and an all-carbon quaternary center in a highly convergent process. Functionalized polyhydroquinolines and congeners can be accessed from commercially available amino acids. This versatile and robust strategy was applied to the synthesis of (±)-Δ7-mesembrenone.

Patient-reported outcome measures in patients undergoing radiotherapy for head and neck cancer.

OBJECTIVES: Head and neck (H&N) cancer patients experience significant acute side effects from treatment. This study evaluates prospectively collected patient-reported outcomes (PROs) in H&N patients undergoing radiotherapy (RT) to assess feasibility of electronically collecting PROs and to objectively document symptom acuity and trajectory during RT. MATERIALS AND METHODS: H&N patients undergoing radical RT at our multicentre institution completed a 12-item partial survey of the Vanderbilt Head & Neck Symptom Survey 2.0 prior to RT and weekly on RT. Between October 2016 and October 2018, 318 of 333 patients completed a baseline survey and at least one weekly survey. RESULTS: The average number of weekly questionnaires completed was 5 (range 1-8). The mean maximum symptom scores were highest for dysgeusia (5.8/10), pain (5.4/10), mucositis (4.8/10), weight loss due to swallowing (4.5/10) and mucus causing choking/gagging (4.3/10). On multivariate analysis, female gender, sinonasal, nasopharynx and oropharynx primaries were associated with a greater risk of moderate-severe pain (p < 0.05). Sinonasal, nasopharynx, oral cavity, oropharynx and thyroid primaries were associated with a greater risk of moderate-severe mucositis during radiation (p < 0.0001). Salivary gland, sinonasal, nasopharynx and oropharynx primaries and higher radiation dose were associated with a greater risk of moderate-severe dysgeusia (all p < 0.05). CONCLUSIONS: Electronic PRO collection during H&N cancer RT is feasible. H&N cancer patients experience significant symptoms during RT, and the most severe symptoms reported were dysgeusia, pain and mucositis. Oropharynx cancer patients reported the highest symptom scores during RT.

Pain response in a population-based study of radium-223 (Ra223) for metastatic castration-resistant prostate cancer.

INTRODUCTION: Clinical trials have shown that radium-223 (Ra223) can prolong survival and improve quality of life in patients with metastatic castration-resistant prostate cancer (mCRPC). The objectives of this study were to evaluate pain responses with Ra223 at a population-based level and to determine if there is an association between pain response and alkaline phosphatase (ALP) response. METHODS: All patients from the Vancouver and Kelowna Cancer Centers (CC) in British Columbia who were treated with Ra223 between June 2015 and December 2016 were identified. Patients completed the Brief Pain Inventory (BPI) just prior to each Ra223 injection. Pain response was defined as a two or more point improvement in worst pain relative to baseline, without an increase in pain medication level. ALP was determined at each visit, with a response threshold defined as a 30% decrease from baseline, consistent with the definition of response used in the ALSYMPCA trial. RESULTS: A total of 65 patients in Vancouver and Kelowna CC received Ra223 during the study period and 56 patients had at least one BPI record, of which 44 (79%) patients were assessable for change in worst pain. Of the assessable patients, 23 (52%, 95% confidence interval [CI] 38-67) had a pain response, although the use of concurrent external beam radiotherapy was a confounder in four cases. Of the 44 patients assessable for change in worst pain, 59% had ALP responses greater than 30%. An ALP response was seen in 56% of pain-responders vs. 43% of non-pain-responders. There was no association between pain response and ALP response (Phi =-0.05; p=0.77). CONCLUSIONS: Ra223 administration was associated with a meaningful pain response rate in this cohort. There was no correlation between pain response and ALP response.

Provincial development of a patient-reported outcome initiative to guide patient care, quality improvement, and research.

The BC Cancer Agency Radiotherapy (RT) program started the Prospective Outcomes and Support Initiative (POSI) at all six centres to utilize patient-reported outcomes for immediate clinical care, quality improvement, and research. Patient-reported outcomes were collected at time of computed tomography simulation via tablet and 2 to 4 weeks post-RT via either tablet or over the phone by a registered nurse. From 2013 to 2016, patients were approached on 20,150 attempts by POSI for patients treated with RT for bone metastases (52%), brain metastases (11%), lung cancer (17%), gynecological cancer (16%), head and neck cancer (2%), and other pilots (2%). The accrual rate for all encounters was 85% (n = 17,101), with the accrual rate varying between the lowest and the highest accruing centre from 78% to 89% ( P < .001) and varying by tumour site ( P < .001). Using the POSI database, we have performed research and quality improvement initiatives that have changed practice.

Comparison of patient-reported outcomes with single versus multiple fraction palliative radiotherapy for bone metastasis in a population-based cohort.

BACKGROUND: Despite randomized control trials showing equivalent efficacy between single-fraction (SF) and multiple-fraction (MF) radiation therapy (RT) for bone metastases (BoM), considerable variation in fractionation exists. We compared patient-reported outcomes (PROs) following SF versus MF RT in a population-based cohort. METHODS: PROs were chosen to assess patients' perception of pain, function, and symptom frustration. Total score was the sum of the 3 questions. RESULTS: 968 patients completed pre and post-RT PROs, 35% (335) had complicated BoM. Overall, there were no differences in total score improvement (79% vs. 83%; p=0.13), nor for complicated BoM (77% vs. 84%; p=0.12), SFRT and MFRT respectively. On multivariate analysis no differences in improvement in total score were observed between SFRT and MFRT overall (OR=0.71; 95% CI 0.49-1.02; p=0.06), nor for complicated BoM (OR=0.74; 95% CI 0.39-1.39; p=0.35). In the complicated BoM subset, pain complete response (CR) (19% vs. 33%; p=0.01) and functional improvement occurred more commonly in the MFRT group (69% vs. 81%; p=0.04). CONCLUSION: Improvements in PROs for pain, function and symptom frustration were similar between SFRT and MFRT supporting the use of hypofractionated regimens. Using a simple, 3-question, telephone-based questionnaire to assess response to palliative RT is a feasible strategy to collect PROs.

Effect of aging and long-term erectile function after iodine-125 prostate brachytherapy.

PURPOSE: To evaluate long-term erectile function (EF) in men treated with iodine-125 prostate brachytherapy (PB) and to determine factors predictive for erectile dysfunction (ED), including natural decline because of aging. METHODS: Two thousand nine hundred twenty-nine patients (implanted July 1989-June 2012) with baseline EF and greater than 10-month followup (FU) are included. About 78.9% had full and 7.9% had partial EF at baseline. EF was assessed on a physician-reported three-point scale. Poisson regression with generalized estimating equations was used to assess predictors of ED and Kaplan-Meier curves time to ED. The effect of aging was calculated from the declining rate of baseline EF seen in sequential 5-year age cohorts and from the Massachusetts Male Aging Study. RESULTS: The median age was 66 years and median FU 3.5 years (maximum 14 years). About 1142 patients had more than 5 years of FU, and 43% had received 6 months of androgen deprivation therapy (ADT). Significant drop in EF was seen at 6 weeks after PB, with gradual decline thereafter. EF preservation at 5 years for age younger than 55, 56-59, 60-64, 65-69, and 70 year and older was 82%, 73%, 58%, 39%, and 23%, respectively. Comparisons of the 5-year age-related and treatment-related EF decline show that 50% of the long-term EF decline is related to aging. On univariate and multivariate analyses, age at implant, length of FU, hypertension, diabetes, and use of ADT (all p < 0.01) were significant predictors of ED. CONCLUSION: More than 80% of young men have EF preserved 5 years after PB. Age, ADT, history of hypertension, and the natural decline in EF have negative impact on long-term EF after PB.

Knowledge, attitudes and beliefs about chronic noncancer pain in primary care: a Canadian survey of physicians and pharmacists.

BACKGROUND: Primary care providers' knowledge, attitudes and beliefs (KAB) regarding chronic noncancer pain (CNCP) are a barrier to optimal management. OBJECTIVES: To evaluate and identify the determinants of the KAB of primary care physicians and pharmacists, and to document clinician preferences regarding the content and format of a continuing education program (CEP). METHOD: Physicians and pharmacists of 486 CNCP patients participated. Physicians completed the original version of the KnowPain-50 questionnaire. Pharmacists completed a modified version. A multivariate linear regression model was developed to identify the determinants of their KAB. RESULTS: A total of 137 of 387 (35.4%) physicians and 110 of 278 (39.5%) pharmacists completed the survey. Compared with the physicians, the pharmacists surveyed included more women (64% versus 38%) and had less clinical experience (15 years versus 26 years). The mean KnowPain-50 score was 69.3% (95% CI 68.0% to 70.5%) for physicians and 63.8% (95% CI 62.5% to 65.1%) for pharmacists. Low scores were observed on all aspects of pain management: initial assessment (physicians, 68.3%; pharmacists, 65.4%); definition of treatment goals and expectations (76.1%; 61.6%); development of a treatment plan (66.4%; 59.0%); and reassessment and management of longitudinal care (64.3%; 53.1%). Ten hours of reported CEP sessions increased the KAB score by 0.3 points. All clinicians considered a CEP for CNCP to be essential. Physicians preferred an interactive format, while pharmacists had no clear preferences. CONCLUSION: A CEP to improve primary care providers' knowledge and competency in managing CNCP, and to reduce false beliefs and inappropriate attitudes regarding CNCP is relevant and perceived as necessary by clinicians.

Late urinary side effects 10 years after low-dose-rate prostate brachytherapy: population-based results from a multiphysician practice treating with a standardized protocol and uniform dosimetric goals.

PURPOSE: To determine late urinary toxicity (>12 months) in a large cohort of uniformly treated low-dose-rate prostate brachytherapy patients. METHODS AND MATERIALS: From 1998 to 2009, 2709 patients with National Comprehensive Cancer Network-defined low-risk and low-tier intermediate-risk prostate cancer were treated with Iodine 125 ((125)I) low-dose-rate prostate brachytherapy; 2011 patients with a minimum of 25 months of follow-up were included in the study. Baseline patients, treatment, implant factors, and late urinary toxicity (Radiation Therapy Oncology Group [RTOG] grading system and International Prostate Symptom Score [IPSS]) were recorded prospectively. Time to IPSS resolution, late RTOG genitourinary toxicity was examined with Kaplan-Meier and log-rank tests. Cox proportional hazards regression was done for individual covariates and multivariable models. RESULTS: Median follow-up was 54.5 months (range, 2-13 years). Actuarial toxicity rates reached 27% and 10% (RTOG ≥2 and ≥3, respectively) at 9-13 years. Symptoms resolved quickly in the majority of patients (88% in 6-12 months). The prevalence of RTOG 0, 1, 2, 3, and 4 toxicity with a minimum of 7 years' follow-up was 70%, 21%, 6.4%, 2.3%, and 0.08%, respectively. Patients with a larger prostate volume, higher baseline IPSS, higher D90, acute toxicity, and age >70 years had more late RTOG ≥2 toxicity (all P≤.02). The IPSS resolved slower in patients with lower baseline IPSS and larger ultrasound prostate volume, those not receiving androgen deprivation therapy, and those with higher D90. The crude rate of RTOG 3 toxicity was 6%. Overall the rate of transurethral resection of the prostate was 1.9%; strictures, 2%; incontinence, 1.3%; severe symptoms, 1.8%; late catheterization, 1.3%; and hematuria, 0.8%. The majority (80%) resolved their symptoms in 6-12 months. CONCLUSION: Long-term urinary toxicity after brachytherapy is low. Although actuarial rates increase with longer follow-up (27% RTOG 2 and 10% RTOG 3 at 13 years), symptoms resolve relatively quickly; between 5 and 13 years' follow-up, >90% of patients have minimal urinary toxicity. Refining patient selection criteria, planning, and treatment delivery may further reduce toxicity.

Decline in acute urinary toxicity: a long-term study in 2011 patients with prostate brachytherapy within a provincial institution.

PURPOSE: To determine whether acute urinary toxicity rates improve with the overall experience of a large prostate brachytherapy program. METHODS AND MATERIALS: From 1998 to 2009, 2937 patients were treated with prostate brachytherapy at the British Columbia Cancer Agency. Baseline patient, treatment, and implant factors were recorded prospectively. Acute urinary toxicity data were prospectively recorded at baseline and each follow-up visit. Patients with ≥2 years of follow-up data were grouped into cohorts of 500 for analysis. RESULTS: Two thousand eleven patients met the above criteria. Acute urinary retention (AUR) in the acute period (within 6 months of implant) occurred in 9.1% of patients overall and was prolonged (catheterization >20 days) in 3.4%. Both overall AUR and prolonged AUR decreased across implant cohorts (p ≤ 0.001 in both cases). Overall acute Radiation Therapy Oncology Group (RTOG) Grades 0 and 1 urinary toxicity rate was 57.5% and RTOG Grades 2 and 3 urinary toxicity rates were 34.3% and 8.1%, respectively. Acute toxicity improved over time for both RTOG Grades ≥2 and ≥3 toxicity (p < 0.0001). International prostate symptom score resolution to baseline was achieved in 80.5% of patients with a median time of 12.2 months. CONCLUSIONS: Acute AUR and RTOG urinary toxicity rates continue to decline with the increasing experience of our provincial prostate brachytherapy program, despite its expansion to new centers and addition of members. This is likely due to better patient selection, refinement in treatment planning and implantation technique, and mentorship and training process.

Prostate-specific antigen at 4 to 5 years after low-dose-rate prostate brachytherapy is a strong predictor of disease-free survival.

PURPOSE: To determine (1) the prognostic utility of prostate-specific antigen (PSA) concentration at 45 to 60 months (48mPSA) after low-dose-rate prostate brachytherapy (LDR-PB); (2) the predictors of 48mPSA; and (3) the prognostic utility of directional trends between PSA levels at 24, 36, and 48 months after LDR-PB. METHODS AND MATERIALS: Between 1998 and 2008, 2223 patients with low- and intermediate-risk prostate cancer received LDR-PB monotherapy. A cohort of 1434 of these patients was identified with a documented 48mPSA and no evidence of disease relapse prior to the 48mPSA. In addition, a subset of this cohort (n=585) was identified with ≥72 months of follow-up and documented PSA values at both 24 and 36 months after implantation. RESULTS: Median follow-up time was 76 months. Eight-year Kaplan-Meier disease-free survival (DFS) rates were 100% vs 73.4% for patients with 48mPSA≤0.2 vs those with >0.2 ng/mL; 99.1% versus 53.8% for a 48mPSA threshold of ≤0.4 versus >0.4 ng/mL, respectively; and 97.3% versus 0% for a threshold of ≤1.0 versus >1.0 ng/mL, respectively. On multivariate analysis, the only factor predictive of DFS was 48mPSA (P<.0001). On subset analysis (n=585), 29 patients had a PSA rise (defined as >0.2 ng/mL) between 24 and 36 months, 24 patients had a rise between 36 and 48 months, and 11 patients had rises over both intervals. Failure rates in these patients were 52%, 79%, and 100%, respectively. On multivariate analysis, initial PSA, androgen deprivation therapy, and dose to 90% of the prostate significantly correlated with 48mPSA but together accounted for only ∼5% of its total variance. CONCLUSIONS: The 48mPSA after LDR-PB is highly predictive of long-term DFS. Patients with 48mPSA≤0.4 ng/mL had a <1% risk of disease relapse at 8 years, whereas all patients with 48mPSA>1.0 ng/mL relapsed. Consecutive PSA rises of >0.2 ng/mL from 24 to 36 months and from 36 to 48 months were also highly predictive of subsequent failure.

Biological consequences of MLC calibration errors in IMRT delivery and QA.

PURPOSE: The purpose of this work is threefold: (1) to explore biological consequences of the multileaf collimator (MLC) calibration errors in intensity modulated radiotherapy (IMRT) of prostate and head and neck cancers, (2) to determine levels of planning target volume (PTV) and normal tissue under- or overdose flagged with clinically used QA action limits, and (3) to provide biologically based input for MLC QA and IMRT QA action limits. METHODS: Ten consecutive prostate IMRT cases and ten consecutive head and neck IMRT cases were used. Systematic MLC offsets (i.e., calibration error) were introduced for each control point of the plan separately for X1 and X2 leaf banks. Offsets were from - 2 to 2 mm with a 0.5 mm increment. The modified files were imported into the planning system for forward dose recalculation. The original plan served as the reference. The generalized equivalent uniform dose (gEUD) was used as the biological index for the targets, rectum, parotid glands, brainstem, and spinal cord. Each plan was recalculated on a CT scan of a 27 cm diameter cylindrical phantom with a contoured 0.6 cc ion chamber. Dose to ion chamber and 3D gamma analysis were compared to the reference plan. QA pass criteria: (1) at least 95% of voxels with a dose cutoff of 50% of maximum dose have to pass at 3 mm/3% and (2) dose to chamber within 2% of the reference dose. RESULTS: For prostate cases, differences in PTV and rectum gEUD greater than 2% were identified. However, a larger proportion of plans leading to greater than 2% difference in prostate PTV gEUD passed the ion chamber QA but not 3D gamma QA. A similar trend was found for the rectum gEUD. For head and neck IMRT, the QA pass criteria flagged plans leading to greater than 4% differences in PTV gEUD and greater than 5% differences in the maximum dose to brainstem. If pass criteria were relaxed to 90% for gamma and 3% for ion chamber QA, plans leading to a 5% difference in PTV gEUD and a 5%-8% difference in brainstem maximum dose would likely pass IMRT QA. A larger proportion of head and neck plans with greater than 2% PTV gEUD difference passed 3D gamma QA compared to ion chamber QA. CONCLUSIONS: For low modulation plans, there is a better chance to catch MLC calibration errors with 3D gamma QA rather than ion chamber QA. Conversely, for high modulation plans, there is a better chance to catch MLC calibration errors with ion chamber QA rather than with 3D gamma QA. Ion chamber and 3D gamma analysis IMRT QA can detect greater than 2% change in gEUD for PTVs and critical structures for low modulation treatment plans. For high modulation treatment plans, ion chamber and 3D gamma analysis can detect greater than 2% change in gEUD for PTVs and a 5% change in critical structure gEUD since either QA methods passes the QA criteria. For gEUD changes less than those listed above, either QA method has the same proportion of passing rate.

Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: a population-based cohort study.

BACKGROUND AND PURPOSE: To evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency. MATERIALS AND METHODS: Between 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6 months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ≤ 6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence. RESULTS: Median follow-up was 60 months. Estimated 5 year bNED was 97% for patients with Gleason score ≤ 6 and 94% for patients with Gleason 7 disease (p=0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p=0.791). There was no difference in bNED between implants achieving D90 ≥ versus

The effect of loose versus stranded seeds on biochemical no evidence of disease in patients with carcinoma of the prostate treated with iodine-125 brachytherapy.

PURPOSE: The British Columbia Cancer Agency has been performing iodine-125 prostate brachytherapy since 1998, initially using loose seeds and phasing into the exclusive use of RAPIDStrand (RS) (Oncura Inc., Plymouth Meeting, PA) by November 2000. The aim of this study was to investigate rates of biochemical no evidence of disease (bNED) in patients treated with loose seeds compared with RS from this population-based cohort. METHODS AND MATERIALS: Between July 1998 and February 2006, 1500 implants were performed (327 loose and 1173 RS). Biochemical failure is reported using the Phoenix definition and prostate-specific antigen (PSA) >0.4ng/mL at ≥48 months postimplant. Actuarial estimates were calculated by the Kaplan-Meier method. Analysis was repeated with the first 100 loose and stranded implants excluded to assess the learning curve effect. Log-rank test was used to evaluate differences in bNED. Variables showing association with bNED were included in a multivariate model. RESULTS: There was no difference between loose and stranded seeds. Estimated rate of bNED was 93.5% (95% confidence interval [CI], 90.6-96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8-96.2) for patients treated with RS according to Phoenix definition (p=0.846). Using the PSA >0.4ng/mL definition, estimated rates were 91.3% (95% CI, 88.0-94.6) and 91.9% (95% CI, 89.7-94.1) for loose and stranded seeds, respectively (p=0.871). Exclusion of the first 100 loose and stranded implants also revealed no difference in bNED. CONCLUSION: This study of 1500 patients treated with iodine-125 brachytherapy demonstrates no difference in bNED between loose and stranded seeds, using either Phoenix or PSA >0.4ng/mL definitions of biochemical failure.

Evaluating the Phoenix definition of biochemical failure after (125)I prostate brachytherapy: Can PSA kinetics distinguish PSA failures from PSA bounces?

PURPOSE: To evaluate the prostate-specific antigen (PSA) kinetics of PSA failure (PSAf) and PSA bounce (PSAb) after permanent (125)I prostate brachytherapy (PB). METHODS AND MATERIALS: The study included 1,006 consecutive low and "low tier" intermediate-risk patients treated with (125)I PB, with a potential minimum follow-up of 4 years. Patients who met the Phoenix definition of biochemical failure (nadir + 2 ng/mL(-1)) were identified. If the PSA subsequently fell to ≤0.5 ng/mL(-1)without intervention, this was considered a PSAb. All others were scored as true PSAf. Patient, tumor and dosimetric characteristics were compared between groups using the chi-square test and analysis of variance to evaluate factors associated with PSAf or PSAb. RESULTS: Median follow-up was 54 months. Of the 1,006 men, 57 patients triggered the Phoenix definition of PSA failure, 32 (56%) were true PSAf, and 25 PSAb (44%). The median time to trigger nadir + 2 was 20.6 months (range, 6-36) vs. 49 mo (range, 12-83) for PSAb vs. PSAf groups (p < 0.001). The PSAb patients were significantly younger (p < 0.0001), had shorter time to reach the nadir (median 6 vs. 11.5 months, p = 0.001) and had a shorter PSA doubling time (p = 0.05). Men younger than age 70 who trigger nadir +2 PSA failure within 38 months of implant have an 80% likelihood of having PSAb and 20% chance of PSAf. CONCLUSIONS: With adequate follow-up, 44% of PSA failures by the Phoenix definition in our cohort were found to be benign PSA bounces. Our study reinforces the need for adequate follow-up when reporting PB PSA outcomes, to ensure accurate estimates of treatment efficacy and to avoid unnecessary secondary interventions.