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Background: Androgen deprivation therapy (ADT) improves outcomes in unfavorable-risk prostate cancer (PCa) treated with radiation therapy (RT). It was hypothesized that replacing luteinizing hormone-releasing hormone (LHRH) agonists with a 5-α-reductase inhibitor (5-ARI) would improve hormonal health-related quality of life (HRQOL) without differentially suppressing androgen-responsive (AR) gene expression., Methods: Patients with localized unfavorable-risk PCa, aged ≥70 years or Charlson Comorbidity Index score ≥2 were treated with oral ADT (oADT), consisting of 4 months of bicalutamide, a 5-ARI, and RT at 78 Gy. The primary end point was Expanded Prostate Cancer Index Composite HRQOL at 6 months ≤30%, and improvement compared with a synchronous standard of care (SOC) cohort receiving 4 months of bicalutamide and long-term LHRH agonist with RT. RNA sequencing was performed from matched pre-/post-ADT prostate tumor biopsies in a subset of men. Differential gene and pathway expressional changes were examined using gene set enrichment., Results: Between 2011 and 2018, 40 and 30 men were enrolled in the oADT and SOC cohorts, respectively. Median follow-up was 40 months. Those with ≤30% decline in hormonal HRQOL at 6 months was 97% (oADT) and 93% (SOC). The average 6-month hormonal decline was 1% (oADT) versus 12% (SOC; P = .04). The 4-year freedom from biochemical failure was 88% (oADT) versus 81% (SOC; P = .48). RNA sequencing (n = 9) showed similar numbers of downregulated and upregulated genes between the treatment groups (fold-change = 2; false-discovery rate-adjusted P ≤ .05). Both treatments comparably decreased the expression of 20 genes in canonical androgen receptor signaling., Conclusions: For men with PCa undergoing RT, oral versus standard ADT may improve 6-month QOL and appears to have a similar impact on androgen-responsive gene expression., (© 2021 American Cancer Society.)

Background: Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance., Methods: In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m 2 weekly (TC) or single-agent temsirolimus (T). The primary outcome was progression-free survival (PFS) in the TC arm versus the T arm. Response rates, overall survival, and toxicity were secondary outcomes., Results: Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms., Conclusions: The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation., (© 2020 American Cancer Society.)

Background: Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B-cell lymphomas (termed double-hit lymphoma [DHL] and double-expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Retrospective reports have suggested improved outcomes with dose-intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R) in patients with DHL and DEL., Methods: The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA-EPOCH-R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21-day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles., Results: A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose-limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow-up of 24 months., Conclusions: The combination of lenalidomide with DA-EPOCH-R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study., (© 2019 American Cancer Society.)

Background: The management of relapsed aggressive lymphomas remains problematic. Ixabepilone (BMS-247550, epothilone B analog), a potent inhibitor of tubulin disassembly, has promising preclinical and early-phase clinical activity in drug-resistant malignancies., Methods: This multicenter phase 2 clinical trial tested the activity and safety of ixabepilone in relapsed/refractory aggressive lymphoma patients with either chemosensitive (at least a partial response [PR] to most recent chemotherapy) or chemoresistant (less than PR to most recent chemotherapy) disease at 20 mg/m(2) given intravenously weekly on days 1, 8, and 15 of a 28-day cycle., Results: Fifty-one enrolled patients with a median age of 66 years received at least 1 dose of ixabepilone. Diffuse large B-cell lymphoma (n = 25; 49%), mantle cell lymphoma (n = 16; 31%), and transformed follicular lymphoma (n = 5; 10%) were the most frequent histologies. Patients were heavily pretreated, with more than one-quarter having received 4 or more prior therapies. The overall response rate was 27% (14 of 51 patients) with 12% (6 patients) experiencing complete responses and 16% (8 patients) with PRs. All responses were in patients with chemosensitive disease. The median time to response was 2 cycles with a median duration of response of 9.7 months., Conclusions: Ixabepilone was well-tolerated, with neutropenia, peripheral sensory neuropathy, fatigue, and nausea as the major toxicities. Ixabepilone has modest single-agent activity in patients with recurrent chemosensitive aggressive lymphomas., (Copyright © 2013 American Cancer Society.)

To improve future drug development efficiency in renal cell carcinoma (RCC), a disease-progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best-fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib; the model incorporated baseline tumor size, a linear disease-progression component, and an exponential drug effect (DE) parameter. With the model-estimated effect of sorafenib on RCC growth, we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater DE than sorafenib would have 82% power (one-sided α = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with computed tomography (CT) imaging offers a scaffold on which to develop new, more efficient, phase II trial end points and analytic strategies for RCC.

Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid-induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple-dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral-cecal transit time from a pretreatment baseline value of 101.3 +/- 29.4 min (mean +/- SD) to 82.5 +/- 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 +/- 237 and 675 +/- 180 ng/mL after doses 1 and 2, respectively. Based on 6-hour sampling periods, the plasma half-life, 2.5 +/- 0.5 and 2.9 +/- 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid-naive volunteers suggests that endogenous opioids modulate human gut motility.

Background: The goal of the current study was to determine the prostate-specific antigen (PSA) and objective response rates and the pharmacokinetics associated with a monthly x 3 one-hour infusion of suramin in 58 patients with hormone-refractory prostate carcinoma., Methods: A PSA response was defined as a > 50% reduction in the PSA level from baseline for at least 3 consecutive evaluations over a minimum of 6 weeks. The suramin dose was 2400 mg/m(2) taken intravenously on Day 1, 1620 mg/m(2) on Day 29, and 1292 mg/m(2) on Day 57. All patients received 0.5 mg dexamethasone twice daily., Results: Among 56 evaluable patients (median entry PSA level, 229.5 ng/mL), there were 21 PSA responders (37.5%). Among 27 patients with measurable disease, there were 5 responders (4 partial and 1 complete). The median overall survival time was 15.3 months. Grade III fatigue (14.1%) was the predominant toxicity observed. Suramin plasma levels remained high even 3 months after treatment was discontinued. Among the 12 evaluable patients who previously had received chemotherapy, the PSA response rate was 42%; one response was observed among 4 patients with measurable disease, and the median survival was 12 months., Conclusions: Monthly bolus suramin was well tolerated, reduced PSA levels, and induced objective responses, even in patients who previously had received chemotherapy., (Copyright 2003 American Cancer Society.)

Background: Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time., Methods: This trial consisted of two studies: a pilot study and a controlled study. The lactulose hydrogen breath test was used to measure the oral-cecal transit time., Results: In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric-coated methylnaltrexone effectively reversed the effects of morphine, producing transit times shorter than baseline levels. Subsequently, in the controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the lower dose (3.2 mg/kg) of enteric-coated methylnaltrexone completely prevented the morphine-induced change in oral-cecal transit time in all nine subjects. Morphine significantly increased oral-cecal transit time from baseline level of 96.7 +/- 54.1 minutes (mean +/- SD) to 155.0 +/- 53.6 minutes (P = .014). After enteric-coated methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 +/- 56.0 minutes; P = .55 compared with placebo). Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric-coated methylnaltrexone were substantially lower compared with those after 6.4 mg/kg of the uncoated formulation., Conclusion: Our results suggest that there is a prevailing direct and local luminal effect of enteric-coated methylnaltrexone and that the enteric-coated formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation.

Objectives: To determine the frequency of potentially inappropriate medication selection for older persons presenting to the ED, the most common problematic drugs, risk factors for suboptimal medication selection, and whether use of these medications is associated with worse outcomes., Methods: The authors performed a prospective cohort study of 898 patients 65 years or older who presented to an urban academic ED in 1995 and 1996. Seventy-nine percent of the patients were African-American and 43% did not graduate from high school. Potentially inappropriate medications and adverse drug-disease interactions were identified using the 1997 Beers explicit criteria for elders. During the three months after the initial visit, revisits to the ED or hospital, death, and changes in health-related quality of life were analyzed as measured by validated questions adapted from the Medical Outcomes Study., Results: Upon presentation, 10.6% of the patients were taking a potentially inappropriate medication, 3.6% were given one in the ED, and 5.6% were prescribed one upon discharge from the ED. The most frequently prescribed potentially inappropriate medications in the ED were diphenhydramine, indomethacin, meperidine, and cyclobenzaprine. Emergency physicians added potentially inappropriate medications most often to patients with discharge diagnoses of musculoskeletal disorder, back pain, gout, and allergy or urticaria. Potentially adverse drug-disease interactions were relatively uncommon at presentation (5.2%), in the ED (0.6%), and on discharge from the ED (1.2%). Potentially inappropriate medications and adverse drug-disease interactions prescribed in the ED were not associated with higher rates of revisit to the ED, hospitalization, or death, but were correlated with worse physical function and pain. However, confidence intervals were wide for analyses of revisits and death., Conclusions: Suboptimal medication selection was fairly common and was associated with worse patient-reported health-related quality of life.

The cold-pressor test is a widely used pain-induction model in humans. This method has been shown to be a sensitive measure for detecting opioid analgesia. However, nonsteroidal anti-inflammatory drugs have not produced consistent analgesic effects with use of this model. The analgesic effect of acetaminophen (INN, paracetamol) on cold pressor-induced pain has not been reported by other investigators. In this study, a double-blind, randomized, placebo-controlled design was used to evaluate the dose-related effects of oral acetaminophen on cold pressor-induced pain in 18 normal healthy human subjects. We observed dose-related analgesic activity of oral acetaminophen using the cold pressor-induced pain model in these subjects. There were statistically significant main effects of both dose and time (pain and bothersomeness ratings decreased with increasing drug dose and increased over time). In pairwise comparisons only the contrast between the highest dose of acetaminophen (1000 mg) and placebo reached statistical significance. Results from our study suggest that the cold-pressor method may have clinical value in evaluating nonopioid analgesic agents.

Brookmeyer and Crowley derived a non-parametric confidence interval for the median survival time of a homogeneous population by inverting a generalization of the sign test for censored data. The 1-alpha confidence interval for the median is essentially the set of all values t such that the Kaplan--Meier estimate of the survival function at time t does not differ significantly from one-half at significance level alpha. Here I extend the method to incorporate covariates into the analysis by assuming an underlying piecewise exponential model with proportional hazards covariate effects. Maximum likelihood estimates of the model parameters are obtained via iterative techniques, from which the estimated (log) survival curve is easily constructed. The delta method provides asymptotic standard errors. Following Brookmeyer and Crowley, I find the confidence interval for the median survival time at a specified value of the covariate vector by inverting the sign test. I illustrate the methods using data from a clinical trial conducted by the Radiation Therapy Oncology Group in cancer of the mouth and throat. It is seen that the piecewise exponential model provides considerable flexibility in accommodating to the shape of the underlying survival curve and thus offers advantages to other, more restrictive, parametric models. Simulation studies indicate that the method provides reasonably accurate coverage probabilities.

Brookmeyer and Crowley derived a non-parametric confidence interval for the median survival time of a homogeneous population by inverting a generalization of the sign test for censored data. The 1 - alpha confidence interval for the median is essentially the set of all values t such that the Kaplan-Meier estimate of the survival curve at time t does not differ significantly from one-half at the two-sided alpha level. Su and Wei extended this approach to the two-sample problem and derived a confidence interval for the difference in median survival times based on the Kaplan-Meier estimates of the individual survival curves and a 'minimum dispersion' test statistic. Here, I incorporate covariates into the analysis by assuming a proportional hazards model for the covariate effects, while leaving the two underlying survival curves virtually unconstrained. I generate a simultaneous confidence region for the two median survival times, adjusted to any selected value, z, of the covariate vector using a test-based approach analogous to Brookmeyer and Crowley's for the one-sample case. This region is, in turn, used to derive a confidence interval for the difference in median survival times between the two treatment groups at the selected value of z. Employment of a procedure suggested by Aitchison sets the level of the simultaneous region to a value that should yield, at least approximately, the desired confidence coefficient for the difference in medians. Simulation studies indicate that the method provides reasonably accurate coverage probabilities.

The authors report the findings in 107 women who are known to have survived 25 years from among a population of 746 consecutive patients who underwent radical mastectomy for breast carcinoma at the University of Chicago Hospitals and Clinics from 1929 to 1955. Of these patients, 103 had invasive carcinomas, two had intraductal carcinomas, and two had subareolar papillomatosis. Six patients had to be excluded because of inadequate pathologic material. The pathologic findings in 93 cases were compared with those in an equal number of control cases dying within a comparatively short period (median, 3.4 years; range 0.9-9.9 years) after radical mastectomy. These were matched for age, tumor size, and number of positive nodes. Only two of our patients suffered recurrences, and none died of her original tumor; however, 12 developed second primaries in the opposite breast, and four died from them. Compared with all patients who underwent radical mastectomy in this period, the 25-year survivors were younger (69 versus 43% were younger than age 50 years), had smaller tumors (39 versus 26% less than 2 cm in diameter), and a larger number (60 versus 39%) had negative nodes. Nonetheless, 12% of the survivors had tumors larger than 5 cm in diameter and 11% had four or more positive nodes. Histologically, 19% of the 25-year survivors had medullary, mucoid, infiltrating lobular, tubular or lipid rich carcinomas, whereas there was only one lobular and one apocrine carcinoma in the control group. Compared with controls, the survivors had a higher percentage of Grade I tumors and a lower incidence of lymphatic and vascular invasion in the breast. Only one 25-year survivor compared with 16 controls had blood vessel invasion. A surprising 63% of the 25-year survivors had lymphatic or vascular invasion within the tumor, or lymph node metastases compared with 82% of controls. While our studies confirm the importance of these well-known prognostic indicators, it also shows that some patients with pathologically unfavorable lesions, i.e., large tumors of high grade with extensive lymphatic invasion and many positive nodes, treated by radical mastectomy may survive for 25 years. However, we could not accurately predict, among the cases we studied, who would be expected to survive 25 years or who would die within four years.

One hundred twenty-three women younger than 70 years of age and at clinical Stages I or II were enrolled in a randomized clinical trial of radical versus extended radical mastectomy. The 5-year survival rates in the radical and extended radical groups were 75 +/- 6.7% and 80 +/- 6.7%, respectively. (Cox P value for comparison of survival curves = 0.32.) Of the total series, 112 were treated by the same surgeon and confirmed pathologically as having invasive mammary carcinoma. In this more homogeneous subgroup, the 5-year survival rates for the radical and extended radical groups were 71 +/- 7.6% and 85 +/- 6.2%, respectively (P = 0.09). For patients from this subgroup with central or medial tumors, the 5-year survival rates were 66 +/- 10% and 88 +/- 8.2%, respectively (P = 0.06). For patients with lateral tumors, the 5-year survival rates were nearly equal: 79 +/- 11% and 81 +/- 9.7%, respectively. The findings in a nonrandomized series of similar patients were comparable. The results are not definitive, but suggest an advantage of extended radical mastectomy over radical mastectomy for patients with central or medial tumors. Continued follow-up of the randomized series may lead to more conclusive results.

Cell proliferation was assessed in 33 invasive breast carcinomas by an immunoperoxidase procedure using the monoclonal antibody, Ki-67, which reacts with a nuclear antigen in proliferating cells. The antibody labeled a variable proportion of tumor cells ranging from 3% to 60%. High numbers of Ki-67-positive cells were found in tumors with high mitotic rates, high nuclear grade, high histologic grade, and in premenopausal women. Tumors with low and intermediate Ki-67 labeling rates often had high estrogen receptor content, whereas tumors with high Ki-67 labeling rates were usually estrogen receptor negative. These correlations are similar to those previously reported for other measurements of cell cycle kinetics such as thymidine labeling index and suggest that immunohistochemical staining of invasive breast carcinoma for the Ki-67 epitope may provide cell cycle information not otherwise readily available to the clinician and may be useful in assessing prognosis in carcinoma of the breast.

In view of increasing debate over possible benefit of more complete surgery compared to conservative procedures, a randomized controlled trial contrasting the then standard Halsted radical (RDL) operation with the more complete extended radical (EXT) mastectomy was initiated in 1973. Between November 1973 and July 1982, 123 women younger than 70 years of age and at clinical Stages I and II were enrolled. Of the total series, 112 were treated by the same surgeon and confirmed pathologically as having invasive mammary carcinoma. In this more homogeneous subgroup, the 10-year survival rates (and standard errors) were for RDL, 60% (+/- 7%) and for EXT, 74% (+/- 6%) (P value for comparison of survival curves = 0.13). In patients from this subgroup with central-medial tumors, comprising 62% of the total, survival after RDL at 10 years was 60% (+/- 8%), and after EXT 86% (+/- 6%) (P = 0.025). In the remaining patients with lateral tumors, survival rates were unaffected by treatment: 58% (+/- 13%) and 56% (+/- 11%), respectively (P = 0.62). Comparison of a nonrandomized series of 266 RDL and 124 EXT patients treated between 1960 and 1978 found differences consistent with those of the randomized study, although not statistically significant.