Faculty Bibliography

BACKGROUND:The role of elective whole-pelvis radiotherapy (WPRT) remains controversial. Few studies have investigated it in Gleason grade group (GG) 5 prostate cancer (PCa), known to have a high risk of nodal metastases. OBJECTIVE:To assess the impact of WPRT on patients with GG 5 PCa treated with external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTING, AND PARTICIPANTS:We identified 1170 patients with biopsy-proven GG 5 PCa from 11 centers in the United States and one in Norway treated between 2000 and 2013 (734 with EBRT and 436 with EBRT+BT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS) were compared using Cox proportional hazards models with propensity score adjustment. RESULTS AND LIMITATIONS:A total of 299 EBRT patients (41%) and 320 EBRT+BT patients (73%) received WPRT. The adjusted 5-yr bRFS rates with WPRT in the EBRT and EBRT+BT groups were 66% and 88%, respectively. Without WPRT, these rates for the EBRT and EBRT+BT groups were 58% and 78%, respectively. The median follow-up was 5.6yr. WPRT was associated with improved bRFS among patients treated with EBRT+BT (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.2-0.9, p=0.02), but no evidence for improvement was found in those treated with EBRT (HR 0.8, 95% CI 0.6-1.2, p=0.4). WPRT was not significantly associated with improved DMFS or PCSS in the EBRT group (HR 1.1, 95% CI 0.7-1.7, p=0.8 for DMFS and HR 0.7, 95% CI 0.4-1.1, p=0.1 for PCSS), or in the EBRT+BT group (HR 0.6, 95% CI 0.3-1.4, p=0.2 for DMFS and HR 0.5 95% CI 0.2-1.2, p=0.1 for PCSS). CONCLUSIONS:WPRT was not associated with improved PCSS or DMFS in patients with GG 5 PCa who received either EBRT or EBRT+BT. However, WPRT was associated with a significant improvement in bRFS among patients receiving EBRT+BT. Strategies to optimize WPRT, potentially with the use of advanced imaging techniques to identify occult nodal disease, are warranted. PATIENT SUMMARY:When men with a high Gleason grade prostate cancer receive radiation with external radiation and brachytherapy, the addition of radiation to the pelvis results in a longer duration of prostate-specific antigen control. However, we did not find a difference in their survival from prostate cancer or in their survival without metastatic disease. We also did not find a benefit for radiation to the pelvis in men who received radiation without brachytherapy.

BACKGROUND:Neoadjuvant chemoradiation (nCRT) followed by esophagectomy is the standard treatment for locally advanced esophageal cancer. Older patients are often felt to be poor candidates for nCRT. Limited data is available to guide the use of nCRT in this population. METHODS:A retrospective review of patients treated at a tertiary cancer center between 2002 and 2014 was conducted grouping patients by age (≥ 65 or < 65) for evaluation of differences in toxicity and outcomes. Evaluation of pre-treatment platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) was also performed. Univariate (UVA) and multivariate analyses (MVA) determined associations between age, toxicities and outcomes. The Kaplan-Meier method (KM) assessed overall survival (OS) and relapse free survival (RFS). RESULTS:125 patients were identified for this study (67 aging <65, and 58 ≥ 65). In the UVA, advanced age was only associated with increased hematologic toxicity (p = .04). After adjusting for covariates in the MVA, there were no significant differences in toxicity between older and younger patients. There were also no differences between overall survival and relapse free survival between age groups. Increased pre-treatment NLR was strongly correlated with advanced age (p = .01), increased hospitalizations (p = .04), and decreased RFS (p = .002). CONCLUSIONS:Older patients who underwent nCRT followed by esophagectomy had similar toxicities and outcomes as younger patients suggesting that nCRT before esophagectomy is safe in select older adults with esophageal cancer. PLR and NLR may serve as prognostic markers of aging, toxicity, and outcomes. Further research is warranted to optimize the therapy of older patients with this disease.

PURPOSE:Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity. METHODS AND MATERIALS:The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n = 38) between 2000 and 2013. Propensity scores were included as covariates for comparative analysis. Overall survival, prostate cancer-specific survival, and distant metastasis-free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding. RESULTS:test), though the durations were similar (median, 24 months vs 22.5 months). Of the RP patients, 34% received postoperative EBRT, and 35% received neoadjuvant systemic therapy. The propensity score-adjusted 5-year overall survival rate was 80% for the RP group, 73% for the EBRT group, and 83% for the EBRT-BT group. The corresponding adjusted 5-year prostate cancer-specific survival rates were 87%, 75%, and 94%, respectively. The EBRT-BT group trended toward superior DMFS when compared with the RP group (hazard ratio, 0.3; 95% confidence interval 0.1-1.06; P = .06) and had superior DMFS when compared with the EBRT group (hazard ratio, 0.4; 95% confidence interval 0.1-0.99; P = .048). CONCLUSIONS:To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5 years after treatment.

IMPORTANCE/OBJECTIVE:Mismatch repair (MMR) deficiency of DNA has been observed in up to 15% of sporadic colorectal cancers (CRCs) and is a characteristic feature of Lynch syndrome, which has a higher incidence in young adults (age, <50 years) with CRC. Mismatch repair deficiency can be due to germline mutations or epigenetic inactivation, affects prognosis and response to systemic therapy, and results in unrepaired repetitive DNA sequences, which increases the risk of multiple malignant tumors. OBJECTIVE:To evaluate the utilization of MMR deficiency testing in adults with CRC and analyze nonadherence to long-standing testing guidelines in younger adults using a contemporary national data set to help identify potential risk factors for nonadherence to newly implemented universal testing guidelines. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Adult (age, <30 to ≥70 years) and, of these, younger adult (<30 to 49 years) patients with invasive colorectal adenocarcinoma diagnosed between 2010 and 2012 and known MMR deficiency testing status were identified using the National Cancer Database. The study was conducted from March 16, 2016, to March 1, 2017. EXPOSURES/METHODS:Patient sociodemographic, facility, tumor, and treatment characteristics. MAIN OUTCOMES AND MEASURES/METHODS:The primary outcome of interest was receipt of MMR deficiency testing. Multivariable logistic regression was used to identify independent predictors of testing in adult and/or young adult patients. RESULTS:A total of 152 993 adults with CRC were included in the study (78 579 [51.4%] men; mean [SD] age, 66.9 [13.9] years). Of these patients, only 43 143 (28.2%) underwent MMR deficiency testing; the proportion of patients tested increased between 2010 and 2012 (22.3% vs 33.1%; P<.001). Among 17 218 younger adult patients with CRC, only 7422 (43.1%) underwent MMR deficiency testing; the proportion tested increased between 2010 and 2012 (36.1% vs 48.0%; P < .001). Irrespective of age, higher educational level (OR, 1.38; 95% CI, 1.15-1.66), later diagnosis year (OR, 1.81; 95% CI, 1.65-1.98), early stage disease (OR, 1.24; 95% CI, 1.18-1.30), and number of regional lymph nodes examined (≥12) (OR, 1.44; 95% CI, 1.34-1.55) were independently associated with MMR deficiency testing, whereas older age (OR, 0.31; 95% CI, 0.26-0.37); Medicare (OR, 0.89; 95% CI, 0.84-0.95), Medicaid (OR, 0.83; 95% CI, 0.73-0.93), or uninsured (OR, 0.78; 95% CI, 0.66-0.92) status; nonacademic vs academic/research facility type (OR, 0.44; 95% CI, 0.34-0.56); rectosigmoid or rectal tumor location (OR, 0.76; 95% CI, 0.68-0.86); unknown grade (OR, 0.61; 95% CI, 0.53-0.69); and nonreceipt of definitive surgery (OR, 0.33; 95% CI, 0.30-0.37) were associated with underuse of MMR deficiency testing. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Despite recent endorsement of universal use of MMR deficiency testing in patients with CRC and well-established guidelines aimed at high-risk populations, overall utilization of testing is poor and significant underuse of testing among young adults persists. Interventions tailored to groups at risk for nonadherence to guidelines may be warranted in the current era of universal testing.

IMPORTANCE:The optimal treatment for Gleason score 9-10 prostate cancer is unknown. OBJECTIVE:To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. DESIGN, SETTING, AND PARTICIPANTS:Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. EXPOSURES:Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. MAIN OUTCOMES AND MEASURES:The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. RESULTS:Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). CONCLUSIONS AND RELEVANCE:Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

OBJECTIVES:Freedom from biochemical failure (FFBF) is a common primary outcome of randomized-controlled trials of prostate cancer (PCa). We aimed to determine how increasing the PCa biologically equivalent dose (BED) of external radiation therapy (RT) is correlated with FFBF and overall patient outcomes: overall survival (OS), distant metastasis (DM), and cancer-specific mortality (CSM); as well as genitourinary (GU), and gastrointestinal toxicities. MATERIALS AND METHODS:We performed a meta-analysis of 6884 PCa patients from 12 randomized-controlled trials of external beam RT. Mixed effects regression models were used to estimate weighted linear relationships between BED and observed percentages of 5- and 10-year outcomes. For toxicities, a subset analysis of using 3-dimensional conformal RT (3D-CRT) versus intensity-modulated RT (IMRT) was performed. RESULTS:Increasing BED correlated with improved FFBF: 10-year absolute improvement of 9.6% and 7.2% for low-risk and intermediate-risk patients, respectively (P<0.05); but not with improvement of OS, DM, or CSM at either time point. BED escalation was not correlated with increased acute toxicities; it was correlated with increased late gastrointestinal toxicities in patients treated with 3D-CRT (1.5% increase over BED range, P<0.01). IMRT patients had significantly fewer late toxicities, despite being treated at higher BED. CONCLUSIONS:RT BED escalation has resulted in significantly improved PCa FFBF at up to 10 years; but not with improvement in OS, DM, or CSM. Thus, FFBF is a poor surrogate of overall patient outcomes for trials of RT. Late toxicities were less frequent with IMRT than with 3D-CRT, even at higher BED.

OBJECTIVES/OBJECTIVE:Intensity-modulated radiation therapy (IMRT) has been shown to decrease abdominal toxicity in patients undergoing chemoradiation (CRT) for pancreatic cancer. We evaluated whether IMRT impacts the rates of hematologic toxicity and chemotherapy dose intensity in patients undergoing CRT. METHODS:We retrospectively reviewed patients with borderline resectable or locally advanced pancreatic cancer undergoing CRT between 2006 and 2012. Exclusion criteria included receipt of non-gemcitabine therapy, chemotherapy before CRT, or abnormal baseline hematologic indices. Endpoints included total gemcitabine dose received, dose intensity, unplanned dose reductions, and hematologic toxicity (WBC, ANC, platelet, and hemoglobin). Patient/treatment factors were evaluated for their relationship to the above endpoints during CRT and within the first 3 months post-CRT. Statistical analysis was performed using the Fisher exact test and regression models. Because of the multiple comparisons in the presented analysis, a false discovery rate adjustment was performed at the 5% false discovery rate level. RESULTS:Eighty-five patients met the inclusion criteria. Fifty-eight (68.2%) patients received treatment with IMRT, and 27 (31.8%) patients were treated with 3D-conformal radiation. During CRT, there was no relationship between radiation technique and gemcitabine dose received, dose intensity, or hematologic grade 3+ toxicity. Post-CRT, there was no relationship between radiation technique and total gemcitabine dose received, dose intensity, or dose reduction. Patients receiving IMRT were more likely to have ANC grade 3+ toxicity (P=0.007) post-CRT, although this was no longer statistically significant after correction. There were no other relationships between treatment technique and hematologic toxicity. CONCLUSIONS:IMRT technique may be associated with higher hematologic toxicity in patients undergoing CRT for pancreatic cancer. Given the expanding use of CRT, additional study is needed to identify the impact of IMRT on myelosuppression in these patients.

PURPOSE/OBJECTIVE:To evaluate the impact of rheumatoid arthritis (RA) on toxicity and cosmesis in women undergoing radiotherapy for breast cancer. METHODS:We queried an institutional database for women with RA treated with external beam radiotherapy for breast cancer between 1981 and 2016. Matching each patient to three controls without RA was attempted. Radiation toxicity was graded using CTCAE 4.0. Cosmesis was graded using the Global Harris Scoring System of Excellent, Good, Fair, or Poor. Grade 2+ (G2+) acute and late toxicities were compared between women with RA and their matched pairs using a generalized estimating equation (GEE). Wilcoxon test and mixed effects model were used to compare the cosmesis between two groups. RESULTS:Forty women with RA at time of radiation were matched to 117 controls. The median radiation dose was 60 Gy (50-66 Gy) and the median follow-up was 94 months (1-354 months). When comparing the women with RA to their matched pairs, there was no significant difference in the rates of G2+ acute toxicity (25.0 vs. 13.7%, O 2.1, CI 0.91-4.9) or G2+ late toxicity (7.5 vs. 4.3%, OR 1.8, CI 0.48-6.8). Mean cosmesis was between Good and Excellent for both groups of patients, although women with RA were less likely to get Excellent cosmesis compared to their matched pairs (OR 0.35, CI 0.15-0.84). CONCLUSIONS:Among women with RA, radiation for breast cancer was well tolerated without significantly increased toxicity. Their cosmesis was generally Good to Excellent, although they might be less likely to get Excellent cosmesis compared to their matched pairs.

Lung cancer is the leading cause of cancer death worldwide. Majority of newly diagnosed lung cancers are non-small cell lung cancer (NSCLC), of which up to half are considered locally advanced at the time of diagnosis. Patients with locally advanced stage III NSCLC consists of a heterogeneous population, making management for these patients complex. Surgery has long been the preferred local treatment for patients with resectable disease. For select patients, multi-modality therapy involving systemic and radiation therapies in addition to surgery improves treatment outcomes compared to surgery alone. For patients with unresectable disease, concurrent chemoradiation is the preferred treatment. More recently, research into different chemotherapy agents, targeted therapies, radiation fractionation schedules, intensity-modulated radiotherapy, and proton therapy have shown promise to improve treatment outcomes and quality of life. The array of treatment approaches for locally advanced NSCLC is large and constantly evolving. An updated review of past and current literature for the roles of surgery, chemotherapeutic agents, radiation therapy, and targeted therapy for stage III NSCLC patients are presented.

BACKGROUND:The purpose of the study was to determine the effect of type 2 diabetes mellitus (T2DM) on outcomes and toxicities among men with localized prostate cancer receiving definitive radiation therapy. PATIENTS AND METHODS:We performed a retrospective review of 3217 patients, from 1998 to 2013, subdivided into 5 subgroups: (I) no T2DM; (II) T2DM receiving oral antihyperglycemic agent that contains metformin, no insulin; (III) T2DM receiving nonmetformin oral agent alone, no insulin; (IV) T2DM receiving any insulin; and (V) T2DM not receiving medication. Outcome measures were overall survival, freedom from biochemical failure (BF), freedom from distant metastasis, cancer-specific survival, and toxicities. Kaplan-Meier analysis, log rank tests, Fine and Gray competing risk regression (to adjust for patient and lifestyle factors), Cox models, and subdistribution hazard ratios (sHRs) were used. RESULTS:Of the 3217 patients, 1295 (40%) were low-risk, 1192 (37%) were intermediate-risk, and 652 (20%) were high risk. The group I to V distribution was 81%, 8%, 5%, 3%, and 4%. The median dose was 78 Gy, and the median follow-up time was 50 (range, 1-190) months. Group V had increased mortality (sHR, 2.1; 95% confidence interval [CI], 0.66-1.54), BF (sHR, 2.14; 0.88-1.83), and cause-specific mortality (sHR, 3.87; 95% CI, 1.31-11). Acute toxicities were higher in group IV versus group I (genitourinary: 38% vs. 26%; P = .01; gastrointestinal: 21% vs. 5%; P = 001). Late toxicities were higher in groups IV and V versus group I (12%-14% vs. 2%-6%; P < .01). CONCLUSION:Men with T2DM not receiving medication and men with T2DM receiving insulin had worse outcomes and toxicities compared to other patients.