Alliance A151945: Accrual and characteristics of adolescent and young adult patients in Alliance trials from 2000 to 2017.

BACKGROUND: Identifying patient- and disease-specific characteristics associated with clinical trial enrollment of adolescents and young adults (AYAs) with cancer may target efforts to improve accrual. METHODS: Alliance for Clinical Trials in Oncology (Alliance) trials opened from January 1, 2000, and closed before January 1, 2018, for common AYA cancers were identified. Proportions of AYAs (aged 18-39 years old) versus non-AYAs (aged ≥40 years old) enrolled by cancer type were summarized by descriptive statistics. Among studies with ≥20 AYAs enrolled, demographic and disease characteristics of AYAs versus non-AYAs were compared with χ2 and Kruskal-Wallis tests. A qualitative review was also conducted of therapeutic trials included in analysis in PubMed through December 31, 2021, that reported AYA-specific survival. RESULTS: Among 188 trials enrolling 40,396 patients, AYAs represented 11% (4468 of 40,396) of accrual. AYA accrual varied by cancer type (leukemia, 23.6%; breast, 9.9%; lymphoma, 14.8%; colorectal, 6.2%; central nervous system, 8.1%; melanoma, 11.8%; sarcoma, 12%). Across ages, the proportion of Black and Hispanic patients enrolled was 1%-10%. Compared to non-AYAs, AYAs in breast and colorectal cancer trials were less likely to be White and more likely to be Hispanic. Disease characteristics differed by age for selected trials. Two trials reported AYA-specific survival, with no significant differences observed by age. CONCLUSIONS: AYA accrual to Alliance trials was comparable to or exceeded population-based, age-specific prevalence estimates for most cancer types. Greater proportional representation of Hispanic and non-White patients among AYAs reflects US demographic trends. The small number of minority patients enrolled across ages underscores the persistent challenge of ensuring equitable access to trials, including for AYAs.

A pilot randomized, placebo-controlled, double-blind study of omega-3 fatty acids to prevent paclitaxel-associated acute pain syndrome in breast cancer patients: Alliance A22_Pilot2.

PURPOSE: Paclitaxel is associated with an acute pain syndrome (P-APS- and chronic chemotherapy-induced peripheral neuropathy (CIPN). P-APS is associated with higher risk of CIPN. Omega-3 fatty acids have well-established anti-inflammatory and neuroprotective properties. The primary purpose of this pilot study was to assess whether omega-3 fatty acids could decrease P-APS and thus CIPN. METHODS: Patients scheduled to receive weekly paclitaxel for breast cancer were randomized to receive 4 g of omega-3 acid ethyl esters (Lovaza) or placebo, beginning 1 week prior and continued until paclitaxel was stopped. Patients completed acute pain questionnaires at baseline, daily after each treatment, and 1 month after completion of therapy. RESULTS: Sixty patients (49 evaluable) were randomized to treatment versus placebo. Seventeen (68.0%) patients receiving the omega-3 fatty acids intervention experienced P-APS, compared to 15 (62.5%) of those receiving placebo during the first week of treatment (p = 0.77). Over the full 12-week study, 21 (84.0%) patients receiving the omega-3 fatty acid intervention experienced P-APS, compared to 21 (87.5%) of those receiving placebo (p = 1.0). Secondary outcomes suggested that those in the intervention arm used more over-the-counter analgesics (OR: 1.65, 95% CI: 0.72-3.78, p = 0.23), used more opiates (OR: 2.06, 95% CI: 0.55-7.75, p = 0.28), and experienced higher levels of CIPN (12.8, 95% CI: 7.6-19.4 vs. 8.4, 95% CI: 4.6-13.2, p = 0.21). CONCLUSIONS: The results of this pilot study do not support further study of the use of omega-3 fatty acids for the prevention of the P-APS and CIPN. TRIAL REGISTRATION: Number: NCT01821833.

Cisplatin-associated neuropathy characteristics compared with those associated with other neurotoxic chemotherapy agents (Alliance A151724).

PURPOSE: The current project was developed to obtain natural history information regarding cisplatin-induced peripheral neuropathy in males with testicular/germ cell cancers and to compare such neuropathy data with similarly obtained data in patients receiving other chemotherapy drugs in similarly conducted clinical trials. METHODS: Patients without baseline neuropathy symptoms, who were initiating cisplatin-based chemotherapy, completed the EORTC CIPN 20 patient-reported instrument to evaluate chemotherapy-induced peripheral neuropathy (CIPN). Results were compared with EORTC CIPN 20 data obtained from independent study sets regarding patients receiving (1) paclitaxel, (2) combined paclitaxel and carboplatin, (3) oxaliplatin, or (4) a combination of doxorubicin and cyclophosphamide (AC). The last study set of patients on AC was selected to evaluate the use of EORTC CIPN 20 data in patients receiving chemotherapy not known to cause CIPN. RESULTS: Cisplatin-induced neuropathy was more similar to neuropathy in patients receiving oxaliplatin than in those receiving paclitaxel. The cisplatin and oxaliplatin groups exhibited the coasting phenomenon and more prominent upper extremity symptoms than lower extremity symptoms during chemotherapy administration weeks. In contrast, paclitaxel-treated patients did not, on average, exhibit the coasting phenomenon; additionally, lower extremity symptoms were more prominent during the weeks when paclitaxel was administered. Cisplatin-induced neuropathy was less severe than was seen in patients in the other two groups, potentially because the cisplatin-receiving patients were younger. Patients receiving AC did not report substantial EORTC CIPN 20 changes. CONCLUSION: Understanding neuropathy similarities and differences with various chemotherapy agents may help elucidate CIPN processes and facilitate means to prevent and/or treat established CIPN. TRIAL REGISTRATION: NCT02677727.

A randomized, double-blind, placebo-controlled trial of testosterone for treatment of postmenopausal women with aromatase inhibitor-induced arthralgias: Alliance study A221102.

PURPOSE: To evaluate the efficacy of testosterone supplementation for improving aromatase inhibitor musculoskeletal symptoms (AIMSS). METHODS: Postmenopausal women experiencing moderate-to-severe arthralgias while taking adjuvant aromatase inhibitors for breast cancer were enrolled in this trial. Initially, patients were randomly allocated to receive either a subcutaneous testosterone pellet versus a placebo pellet. Due to slow accrual, the protocol was modified such that additional participants were randomized to receive either a topical testosterone gel or a placebo gel. Changes in patient-reported joint pain were compared between patients receiving testosterone and those receiving placebo using a two-sample t test. Changes in hot flashes and other vasomotor symptoms were also analyzed. Further analyses were conducted to evaluate whether 27 single nucleotide polymorphisms (SNPs) in 14 genes previously associated with AIMSS were associated with testosterone supplementation benefit. RESULTS: While 64% of patients reported an improvement in joint pain at 3 months, there were no significant differences in average pain or joint stiffness at 3 or 6 months between testosterone and placebo arms. Patients receiving testosterone did report improvements in strength, lack of energy, urinary frequency, and stress incontinence (p < 0.05). The subset of patients receiving subcutaneous testosterone also experienced improvements in hot flashes and mood swings. An inherited variant (rs7984870 CC genotype) in TNFSF11 was more likely to be associated with improvements in hot flashes in patients receiving testosterone. CONCLUSION: The doses of testosterone supplementation used in this study did not significantly improve AIMSS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01573442.

Age and the Risk of Paclitaxel-Induced Neuropathy in Women with Early-Stage Breast Cancer (Alliance A151411): Results from 1,881 Patients from Cancer and Leukemia Group B (CALGB) 40101.

PURPOSE: A few previous studies report a direct relationship between older age and chemotherapy-induced neuropathy. This study further evaluated this adverse event's age-based risk. METHODS: CALGB 40101 investigated adjuvant paclitaxel (80 mg/m2 once per week or 175 mg/m2 every 2 weeks) in patients with breast cancer and served as a platform for the current study that investigated age-based differences in neuropathy. Grade 2 or worse neuropathy, as per Common Terminology Criteria for Adverse Events version 4, was the primary endpoint; patients were assessed at baseline, every 6 months for 2 years, and then annually for 15 years. RESULTS: Among these 1,881 patients, 230 were 65 years of age or older, 556 were 55-64 years, and 1,095 were younger than 55; 1,226 neuropathy events (commonly grade 1 or 2) were reported in 65% of the cohort. The number of grade 2 or worse events was 63 (27%), 155 (28%), and 266 (24%) within respective age groups (p = .14). In univariate analysis, only motor neuropathy had a higher age-based incidence: 19 (8%), 43 (8%), and 60 (5%), respectively (p = .04); in multivariate analyses, this association was no longer statistically significant. Other endpoints, such as time to onset of neuropathy (time from trial enrollment to neuropathy development) and time to improvement (time from maximal grade sensory neuropathy to a one-category improvement), showed no statistically significant age-based differences. In contrast, obesity was associated with neuropathy, and every 2-week paclitaxel was associated with trends toward neuropathy. CONCLUSION: Although paclitaxel-induced neuropathy is common, older age is not an independent risk factor. Clinical trial identification number. NCT00041119 (CALGB 40101). IMPLICATIONS FOR PRACTICE: Age alone is not an independent risk factor for paclitaxel-induced neuropathy.

Older-Patient-Specific Cancer Trials: A Pooled Analysis of 2,277 Patients (A151715).

BACKGROUND: Less than 3% of older patients with cancer are enrolled in clinical trials. To reverse this underrepresentation, we compared older patients enrolled with older-patient-specific trials, defined as those designed for older patients with cancer, with those enrolled in age-unspecified trials. MATERIALS AND METHODS: We focused on individual patient data from those ≥65 years (younger patients excluded) and included all Alliance phase III adjuvant breast cancer trials from 1985-2012. RESULTS: Among 2,277 patients, 1,014 had been enrolled to older-patient-specific and 1,263 to age-unspecified trials. The median age (range) in the older-patient-specific trials was 72 (65-89) years compared with 68 (65-84) years in the cohort of older patients in age-unspecified trials; p < .0001. A greater percentage of patients 75 years or older had enrolled in older-patient-specific trials compared with the cohort of age-unspecified trials: 26% versus 6% (p < .0001). Median overall survival (OS) was 12.8 years (95% confidence interval [CI], 11.9-13.7) and 13.5 years (95% CI, 12.9-14.1) for older-patient-specific and age-unspecified trials, respectively. OS was comparable (hazard ratio [HR], 1.08; 95% CI, 0.92-1.28; p = .34; referent: age-unspecified trials), after adjusting for age, estrogen receptor status, tumor size, and lymph node status. Similar findings were reached for recurrence-free survival. A lower rate of grade 3-5 adverse events (hematologic and nonhematologic) was reported in older-patient-specific trials (43% vs. 58%; p < .0001). Sensitivity analysis with chemotherapy only trials and subset analysis, adjusted for performance score, yielded similar OS results. CONCLUSION: Older-patient-specific trials appear to address this underrepresentation of older patients with ostensibly comparable outcomes. Clinical trial identification numbers. NCT00003088 (CALGB 9741); NCT00024102 (CALGB 49907); NCT00068601 (CALGB 40401); NCT00005970 (NCCTG N9831) IMPLICATIONS FOR PRACTICE: This work underscores the importance of clinical trials that focus on the recruitment of older patients with cancer.

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting.

BACKGROUND: We examined the efficacy of olanzapine for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy. METHODS: In a randomized, double-blind, phase 3 trial, we compared olanzapine with placebo, in combination with dexamethasone, aprepitant or fosaprepitant, and a 5-hydroxytryptamine type 3-receptor antagonist, in patients with no previous chemotherapy who were receiving cisplatin (≥70 mg per square meter of body-surface area) or cyclophosphamide-doxorubicin. The doses of the three concomitant drugs administered before and after chemotherapy were similar in the two groups. The two groups received either 10 mg of olanzapine orally or matching placebo daily on days 1 through 4. Nausea prevention was the primary end point; a complete response (no emesis and no use of rescue medication) was a secondary end point. RESULTS: In the analysis, we included 380 patients who could be evaluated (192 assigned to olanzapine, and 188 to placebo). The proportion of patients with no chemotherapy-induced nausea was significantly greater with olanzapine than with placebo in the first 24 hours after chemotherapy (74% vs. 45%, P=0.002), the period from 25 to 120 hours after chemotherapy (42% vs. 25%, P=0.002), and the overall 120-hour period (37% vs. 22%, P=0.002). The complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Although there were no grade 5 toxic effects, some patients receiving olanzapine had increased sedation (severe in 5%) on day 2. CONCLUSIONS: Olanzapine, as compared with placebo, significantly improved nausea prevention, as well as the complete-response rate, among previously untreated patients who were receiving highly emetogenic chemotherapy. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02116530.).

Promoting Accrual of Older Patients with Cancer to Clinical Trials: An Alliance for Clinical Trials in Oncology Member Survey (A171602).

BACKGROUND: There are multiple known individual- and practice-level barriers to enrollment of older patients with cancer to clinical trials, but little is known about how the clinical research workforce feels about potential higher-level strategy changes aimed to promote increased enrollment of older patients. SUBJECTS, MATERIALS, AND METHODS: We invited all 11,351 Alliance for Clinical Trials in Oncology ("Alliance") members to participate in an anonymous, web-based survey to examine awareness of current accrual patterns for older patients to clinical trials, to ascertain consensus on how to tackle enrollment challenges, and to provide the impetus for high-level changes to improve clinical trial accrual of older patients with cancer. RESULTS: During the period from February 28, 2017, to June 16, 2017, 1,146 Alliance members participated (response rate = 10%), including a national diverse sample of physicians, nurses, administrative/clinical research staff, and patient advocates with representation from community, academic, and rural sites. Overall, one third felt that >50% of clinical trial enrollees should be age ≥65, and 64.9% felt the Alliance could improve upon enrollment of older patients. The four most commonly ranked strategies to improve enrollment of older patients were creating more dedicated trials for this population (36.3%), minimizing exclusion criteria focused on comorbidity (35.5%), developing independent strategies for those aged ≥65 and for those aged ≥70 (33.2%), and requiring that most/all Alliance trials have a specific expansion cohort of older patients (30.0%). CONCLUSION: We anticipate that the recommendations from >1,000 Alliance members will continue to propel important strategy changes aimed to improve accrual of older patients with cancer to clinical trials. IMPLICATIONS FOR PRACTICE: This survey of the Alliance for Clinical Trials membership sought opinions on potential, large-scale, national strategies to improve accrual of older adults with cancer. Consensus was found around multiple strategies, including creating more dedicated trials for older patients, developing less stringent eligibility criteria, and mandating expansion cohorts of older patients within broader Alliance trials. It is anticipated that the recommendations from >1,000 Alliance members will continue to propel important strategy changes aimed to improve accrual of older patients with cancer to clinical trials.

Identification of risk factors for toxicity in patients with hormone receptor-positive advanced breast cancer treated with bevacizumab plus letrozole: a CALGB 40503 (alliance) correlative study.

BACKGROUND: In hormone receptor-positive advanced breast cancer, a progression-free survival benefit was reported with addition of bevacizumab to first-line letrozole. However, increased toxicity was observed. We hypothesized that functional age measures could be used to identify patients at risk for toxicity while receiving letrozole plus bevacizumab for hormone receptor-positive advanced breast cancer. METHODS: CALGB 40503 was a phase III trial that enrolled patients with hormone receptor-positive advanced breast cancer randomized to letrozole with or without bevacizumab. Patients randomized to bevacizumab were approached to complete a validated assessment tool evaluating physical function, comorbidity, cognition, psychological state, social support, and nutritional status. The relationship between pretreatment assessment measures and the incidence of grade ≥ 3 (National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0) adverse events was determined. RESULTS: One hundred thirteen (58%) of 195 patients treated with letrozole plus bevacizumab completed the pretreatment assessment questionnaire. One patient was excluded due to missing adverse event data. The median age of patients was 56. Frequently reported grade ≥ 3 adverse events were hypertension (26%), pain (20%), and proteinuria (7%). Two hemorrhagic events (one grade 5) and 1 thrombosis event occurred. Age ≥ 65 years (p < 0.01), decreased vision (p = 0.04), and poorer pretreatment physical function measures (p < 0.05) were found on univariate analysis to be significantly associated with increased incidence of grade ≥ 3 adverse events. Upon multivariate analysis, age ≥ 65 years (p = 0.01) and decreased vision (p = 0.04) remained significant. Univariable and multivariable logistic regression models demonstrated associations between age, vision, the ability to walk up flights of stairs, and grade ≥ 3 adverse events. CONCLUSIONS: Age (≥ 65 years), decreased vision, and impairments in physical function correlated with increased incidence of toxicity in patients receiving first-line letrozole plus bevacizumab. When evaluating therapy likely to increase toxicity, functional assessment measures can identify patients at increased risk for side effects who may benefit from closer monitoring.

Evaluating the efficacy of vaginal dehydroepiandosterone for vaginal symptoms in postmenopausal cancer survivors: NCCTG N10C1 (Alliance).

BACKGROUND: Women with estrogen deficiencies can suffer from vaginal symptoms that negatively impact sexual health. This study evaluated vaginal dehydroepiandrosterone (DHEA) for alleviation of vaginal symptoms. METHODS: This three-arm randomized, controlled trial evaluated DHEA 3.25 mg and DHEA 6.5 mg, each compared to a plain moisturizer (PM) over 12 weeks, to improve the severity of vaginal dryness or dyspareunia, measured with an ordinal scale, and overall sexual health using the Female Sexual Function Index (FSFI). Postmenopausal women with a history of breast or gynecologic cancer who had completed primary treatment, had no evidence of disease, and reported at least moderate vaginal symptoms were eligible. The mean change from baseline to week 12 in the severity of vaginal dryness or dyspareunia for each DHEA dose was compared to PM and analyzed by two independent t tests using a Bonferroni correction. RESULTS: Four hundred sixty-four women were randomized. All arms reported improvement in either dryness or dyspareunia. Neither DHEA dose was statistically significantly different from PM at 12 weeks (6.25 mg, p = .08; 3.25 mg, p = 0.48), although a significant difference at 8 weeks for 6.5 mg DHEA was observed (p = 0.005). Women on the 6.5 mg arm of DHEA reported significantly better sexual health on the FSFI (p < 0.001). There were no significant differences in provider-graded toxicities and few significant differences in self-reported side effects. CONCLUSION: PM and DHEA improved vaginal symptoms at 12 weeks. However, vaginal DHEA, 6.5 mg, significantly improved sexual health. Vaginal DHEA warrants further investigation in women with a history of cancer.

Systemic and local effects of vaginal dehydroepiandrosterone (DHEA): NCCTG N10C1 (Alliance).

BACKGROUND: Dehydroepiandrosterone (DHEA) is helpful for treating vaginal symptoms. This secondary analysis evaluated the impact of vaginal DHEA on hormone concentrations, bone turnover, and vaginal cytology in women with a cancer history. METHODS: Postmenopausal women, diagnosed with breast or gynecologic cancer, were eligible if they reported at least moderate vaginal symptoms. Participants could be on tamoxifen or aromatase inhibitors (AIs). Women were randomized to 3.25 versus 6.5 mg/day of DHEA versus a plain moisturizer (PM) control. Sex steroid hormone levels, biomarkers of bone formation, vaginal pH, and maturation index were collected at baseline and 12 weeks. Analysis included independent t tests and Wilcoxon rank tests, comparing each DHEA arm with the control. RESULTS: Three hundred forty-five women contributed evaluable blood and 46 contributed evaluable cytology and pH values. Circulating DHEA-S and testosterone levels were significantly increased in those on vaginal DHEA in a dose-dependent manner compared to PM. Estradiol was significantly increased in those on 6.5 mg/day DHEA but not in those on 3.25 mg/day DHEA (p < 0.05 and p = 0.05, respectively), and not in those on AIs. Biomarkers of bone formation were unchanged in all arms. Maturation of vaginal cells was 100% (3.25 mg/day), 86% (6.5 mg/day), and 64% (PM); pH decreased more in DHEA arms. CONCLUSION: DHEA resulted in increased hormone concentrations, though still in the lowest half or quartile of the postmenopausal range, and provided more favorable effects on vaginal cytology, compared to PM. Estrogen concentrations in women on AIs were not changed. Further research on the benefit of vaginal DHEA is warranted in hormone-dependent cancers.

Comparative "nocebo effects" in older patients enrolled in cancer therapeutic trials: Observations from a 446-patient cohort.

BACKGROUND: A nocebo is an inert substance associated with adverse events. Although previous studies have examined the positive (placebo) effects of such inert substances, few have examined negative (nocebo) adverse event profiles, particularly in older patients who have higher morbidity and can experience frequent and severe adverse events from cancer therapy. METHODS: This study focused on placebo/nocebo-exposed patients who participated in 2 double-blind, placebo-controlled, cancer therapeutic studies, namely, North Central Cancer Therapy Group trial NCCTG 97-24-51 and American College of Surgeons Oncology Group trial Z9001, with the goal of reporting the comparative, age-based adverse event rates, as reported during the conduct of these trials. RESULTS: Among the 446 patients who received only placebo/nocebo and who were the focus of the current report, 161 were aged ≥65 years at the time of respective trial entry, and 5234 adverse events occurred. Unadjusted adverse event rates did not differ significantly between patients aged ≥65 years and younger patients (rate ratio, 1.01; 99% confidence interval, 0.47-2.02), and the findings were similar findings for grade 2 or worse adverse events and for all symptom-driven adverse events (for example, pain, loss of appetite, anxiety). Adjustment for sex, ethnicity, baseline performance score, and individual trial resulted in no significant age-based differences in adverse event rates. Similar findings were observed with an age threshold of 70 years. CONCLUSIONS: Adverse events are equally common in older and younger cancer patients who are exposed to nocebo and thus require the same degree of clinical consideration regardless of age. Cancer 2017;123:4193-4198. © 2017 American Cancer Society.

Lymphedema, musculoskeletal events and arm function in older patients receiving adjuvant chemotherapy for breast cancer (Alliance A171302).

PURPOSE: Musculoskeletal events (MEs) resulting from breast cancer treatment can significantly interfere with the quality of life (QOL) of older adults. We evaluated the incidence of MEs in women 65 years and older who had surgery and adjuvant chemotherapy for breast cancer, and the impact of treatment on MEs and arm function. PATIENTS AND METHODS: Patient-reported data in Alliance/CALGB 49907 were collected using the EORTC QLQ-BR23 and physician-reported adverse events to characterize self-reported MEs and incidence of lymphedema. EORTC QLQ-BR23 items related to musculoskeletal events were analyzed in this study and data collected at study entry (post-operative) and 12 and 24 months post-entry. RESULTS: Lymphedema, arm function, and ME data were available for 321 patients. One or more MEs were reported by 87% (median number = 3) and 64% (median number = 1) of patients post-operatively and at 24 months. At 24 months 2% had persistence of six MEs. Seventy-four percent experienced at least ≥3/6 types of MEs over the 24-month period. Detection of lymphedema at any time during the study was noted in 7.5% of the patients and appeared to be associated with the type of chemotherapy given: CMF 16.4%, capecitabine 5.8%, and AC 4%. Mastectomy and axillary node dissection were associated with the most MEs. LROM correlated with poorer arm function at all time periods. CONCLUSION: Potentially debilitating MEs occur in three-fourths of elderly women undergoing standard therapy for breast cancer. Emphasis should be placed on prevention, identification, and treatment of these MEs to improve QOL.

Using ePrognosis to estimate 2-year all-cause mortality in older women with breast cancer: Cancer and Leukemia Group B (CALGB) 49907 and 369901 (Alliance A151503).

PURPOSE: Tools to estimate survival, such as ePrognosis ( http://eprognosis.ucsf.edu/carey2.php ), were developed for general, not cancer, populations. In older patients with breast cancer, accurate overall survival estimates would facilitate discussions about adjuvant therapies. METHODS: Secondary analyses were performed of data from two parallel breast cancer studies (CALGB/Alliance 49907/NCT000224102 and CALGB/Alliance 369901/NCT00068328). We included patients (n = 971) who were age 70 years and older with complete baseline quality of life data (194 from 49907; 777 from 369901). Estimated versus observed all-cause two-year mortality rates were compared. ePrognosis score was calculated based on age, sex, and daily function (derived from EORTC QLQ-C30). ePrognosis scores range from 0 to 10, with higher scores indicating worse prognosis based on mortality of community-dwelling elders and were categorized into three groups (0-2, 3-6, 7-10). Observed mortality rates were estimated using Kaplan-Meier methods. RESULTS: Patient mean age was 75.8 years (range 70-91) and 73% had stage I-IIA disease. Most patients were classified by ePrognosis as good prognosis (n = 562, 58% 0-2) and few (n = 18, 2% 7-10) poor prognosis. Two-year observed mortality rates were significantly lower than ePrognosis estimates for patients scoring 0-2 (2% vs 5%, p = 0.001) and 3-6 (8% vs 12%, p = 0.01). The same trend was seen with scores of 7-10 (23% vs 36%, p = 0.25). CONCLUSIONS: ePrognosis tool only modestly overestimates mortality rate in older breast cancer patients enrolled in two cooperative group studies. This tool, which estimates non-cancer mortality risk based on readily available clinical information may inform adjuvant therapy decisions but should be validated in non-clinical trial populations.

A pilot study of minocycline for the prevention of paclitaxel-associated neuropathy: ACCRU study RU221408I.

PURPOSE: Paclitaxel is associated with both an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Given that extensive animal data suggest that minocycline may prevent chemotherapy-induced neurotoxicity, the purpose of this pilot study was to investigate the efficacy of minocycline for the prevention of CIPN and the P-APS. METHODS: Patients with breast cancer were enrolled prior to initiating neoadjuvant or adjuvant weekly paclitaxel for 12 weeks and were randomized to receive minocycline 200 mg on day 1 followed by 100 mg twice daily or a matching placebo. Patients completed (1) an acute pain syndrome questionnaire daily during chemotherapy to measure P-APS and (2) the EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose of paclitaxel, and monthly for 6 months post treatment, to measure CIPN. RESULTS: Forty-seven patients were randomized. There were no remarkable differences noted between the minocycline and placebo groups for the overall sensory neuropathy score of the EORTC QLQ-CIPN20 or its individual components, which evaluate tingling, numbness and shooting/burning pain in hands and feet. However, patients taking minocycline had a significant reduction in the daily average pain score attributed to P-APS (p = 0.02). Not only were no increased toxicities reported with minocycline, but there was a significant reduction in fatigue (p = 0.02). CONCLUSIONS: Results of this pilot study do not support the use of minocycline to prevent CIPN, but suggest that it may reduce P-APS and decrease fatigue; further study of the impact of this agent on those endpoints may be warranted.

MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy.

PURPOSE: Previous pilot data suggested that venlafaxine could prevent acute and chronic oxaliplatin-related neuropathy. The purpose of this randomized, placebo-controlled, double-blinded pilot study was to obtain additional data to support conducting a phase III trial to test the use of venlafaxine to prevent oxaliplatin neurotoxicity. METHODS: Fifty patients, scheduled to undergo oxaliplatin-based therapy (FOLFOX) for stages II-III (67%) or stage IV (33%) colon cancer, were randomized to receive venlafaxine extended release (37.5 mg) or placebo, twice daily, through their last dose of oxaliplatin and then titrated off. Neurotoxicity was evaluated via several patient- and physician-reported measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) instrument. RESULTS: Baseline patient characteristics were equivalent for the two arms, with a median age of 60 years. There was a trend toward benefit for the venlafaxine arm, when evaluated by the oxaliplatin-specific neuropathy scale and by acute neuropathy measures of throat discomfort and discomfort swallowing cold liquids, the latter only for the first two oxaliplatin doses. These trends were outweighed by a lack of any such trends in all other measurements including the following: (1) the CIPN20 sensory subscale (P = 0.55, primary endpoint), physician-completed NCI CTCAE assessment, or cumulative administered oxaliplatin doses (median 716 vs 631 mg for placebo and venlafaxine, respectively, P = 0.34). CONCLUSIONS: The present study neither supports the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice nor the initiation of a phase III trial to investigate venlafaxine in this setting.

Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up.

PURPOSE: This study was designed to explore whether zoledronic acid could prevent expected loss of bone mineral density (BMD) in postmenopausal women with pre-existing osteopenia or osteoporosis who were initiating adjuvant letrozole therapy for primary breast cancer. METHODS: Between June 2006 and July 2007, 60 postmenopausal women with estrogen and/or progesterone receptor-positive breast cancer and a BMD T-score ≤-2.0 were enrolled. Participants received letrozole 2.5 mg and vitamin D 400 IU daily, calcium 500 mg twice daily, and zoledronic acid 4 mg every 6 months for a maximum of 5 years or until disease progression. BMD at the lumbar spine and femoral neck was recorded at the start of the study and annually for 5 years. Patients were evaluated for fractures every 6 months for the duration of the trial. RESULTS: After 5 years, mean BMD increased significantly by 11.6% (p = 0.01) at the lumbar spine and by 8.8% (p = 0.01) at combined sites. Femoral neck BMD increased by 4.2%, although this was not significant (p = 0.23). At the end of the trial, BMDs were consistent with osteoporosis in 7 % and osteopenia in 36% of the patients. A total of six fractures were reported after 417 individual assessments. CONCLUSIONS: Zoledronic acid appears to prevent further bone loss in postmenopausal breast cancer patients with osteopenia and osteoporosis starting treatment with letrozole. These findings were maintained at 5 years and support concurrent initiation of bisphosphonate and aromatase inhibitor therapy in this high-risk population.

Comparison of oxaliplatin and paclitaxel-induced neuropathy (Alliance A151505).

PURPOSE: Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and differences of these clinical syndromes. METHODS: Neuropathy data were pooled from patients receiving adjuvant oxaliplatin and weekly paclitaxel or every 3 weeks of paclitaxel. Patients completed daily questionnaires after each chemotherapy dose and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy before each chemotherapy cycle and for 12 months post-treatment. RESULTS: Acute neuropathy symptoms from both drugs peaked around day 3. Acute symptoms experienced in cycle 1 predicted occurrence in subsequent cycles. Paclitaxel-induced acute symptoms were similar in intensity in each cycle and largely resolved between cycles. Oxaliplatin-induced acute symptoms were about half as severe in the first cycle as in later cycles and did not resolve completely between cycles. Both drugs caused a predominantly sensory chronic neuropathy (with numbness and tingling being more common than pain). Oxaliplatin-induced neuropathy worsened after the completion of treatment and began to improve 3 months post-treatment. In contrast, paclitaxel-induced neuropathy began improving immediately after chemotherapy cessation. During treatment, the incidence of paclitaxel sensory symptoms was similar in the hands and feet; with oxaliplatin, the hands were affected more than the feet. Both paclitaxel- and oxaliplatin-induced acute neurotoxicity appeared to predict the severity of chronic neuropathy, more prominently with oxaliplatin. CONCLUSIONS: Knowledge of the similarities and differences between neuropathy syndromes may provide insight into their underlying pathophysiology and inform future research to identify preventative treatment approaches.

5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial.

BACKGROUND: Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. METHODS: A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of <-2.0 or fracture. RESULTS: The incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm. CONCLUSIONS: Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms.