Clinical Utility of Genomic Recurrence Risk Stratification in Early, Hormone-Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Real-World Experience.

BACKGROUND: RNA-based genomic risk assessment estimates chemotherapy benefit in patients with hormone-receptor positive (HR+)/Human Epidermal Growth Factor 2-negative (ERBB2-) breast cancer (BC). It is virtually used in all patients with early HR+/ERBB2- BC regardless of clinical recurrence risk. PATIENTS AND METHODS: We conducted a retrospective chart review of adult patients with early-stage (T1-3; N0; M0) HR+/ERBB2- BC who underwent genomic testing using the Oncotype DX (Exact Sciences) 21-genes assay. Clinicopathologic features were collected to assess the clinical recurrence risk, in terms of clinical risk score (CRS) and using a composite risk score of distant recurrence Regan Risk Score (RRS). CRS and RRS were compared to the genomic risk of recurrence (GRS). RESULTS: Between January 2015 and December 2020, 517 patients with early-stage disease underwent genomic testing, and clinical data was available for 501 of them. There was statistically significant concordance between the 3 prognostication methods (P < 0.01). Within patients with low CRS (n = 349), 9.17% had a high GRS, compared to 8.93% in patients with low RRS (n = 280). In patients with grade 1 histology (n = 130), 3.85% had a high GRS and 68.46% had tumors > 1 cm, of whom only 4.49% had a high GRS. Tumor size > 1cm did not associate with a high GRS. CONCLUSION: Genomic testing for patients with grade 1 tumors may be safely omitted, irrespective of size. Our finds call for a better understanding of the need for routine genomic testing in patients with low grade/low clinical risk of recurrence.

Liquid Biopsy-based Precision Therapy in Patients with Advanced Solid Tumors: A Real-world Experience from a Community-based Oncology Practice.

BACKGROUND: Liquid biopsy testing offers a significant potential in selecting signal-matched therapies for advanced solid malignancies. The feasibility of liquid biopsy testing in a community-based oncology practice, and its actual impact on selecting signal-matched therapies, and subsequent survival effects have not previously been reported. PATIENTS AND METHODS: A retrospective chart review was conducted on adult patients with advanced solid cancer tested with a liquid-biopsy assay between December 2018 and 2019, in a community oncology practice. The impact of testing on treatment assignment and survival was assessed at 1-year follow-up. RESULTS: A total of 178 patients underwent testing. A positive test was reported in 140/178 patients (78.7%), of whom 75% had an actionable mutation. The actual overall signal-based matching rate was 17.8%. While 85.7% of patients with no actionable mutation had a signal-based clinical trial opportunity, only 10% were referred to a trial. Survival analysis of lung, breast, and colorectal cancer patients with actionable mutations who received any therapy (n = 66) revealed a survival advantage for target-matched (n = 22) compared to unmatched therapy (n = 44): patients who received matched therapy had significantly longer progression-free survival (PFS) (mPFS: 12 months; 95%CI, 10.6-13.4 vs. 5.0 months; 95%CI, 3.4-6.6; P = .029), with a tendency towards longer overall survival (OS) (mOS: 15 months; 95%CI, 13.5-16.5 vs. 13 months; 95%CI: 11.3-14.7; P = .087). CONCLUSIONS: Implementation of liquid biopsy testing is feasible in a US community practice and impacts therapeutic choices in patients with advanced malignancies. Receipt of liquid biopsy-generated signal-matched therapies conferred added survival benefits.

Autologous and allogeneic hematopoietic cell transplantation for diffuse large B-cell lymphoma-type Richter syndrome.

Richter syndrome (RS) represents a transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), which is associated with a dismal prognosis. Patients with DLBCL-RS have poor outcomes with DLBCL-directed therapy; thus, consolidation with hematopoietic cell transplantation (HCT) has been used, with durable remissions observed. Studies reporting HCT outcomes in patients with DLBCL-RS have been small, have not evaluated the prognostic impact of cytogenetic risk factors, and were conducted prior to the era of novel targeted therapy of CLL/SLL. We performed a Center for International Blood and Transplant Research registry study evaluating outcomes after autologous HCT (auto-HCT; n = 53) and allogeneic HCT (allo-HCT; n = 118) in patients with DLBCL-RS treated in the modern era. More auto-HCT recipients were in complete response (CR) at HCT relative to allo-HCT recipients (66% vs 34%), whereas a higher proportion of allo-HCT recipients had 17p deletion (33% vs 7%) and had previously received novel agents (39% vs 10%). In the auto-HCT cohort, the 3-year relapse incidence, progression-free survival (PFS), and overall survival (OS) were 37%, 48%, and 57%, respectively. Among allo-HCT recipients, the 3-year relapse incidence, PFS, and OS were 30%, 43%, and 52%, respectively. In the allo-HCT cohort, deeper response at HCT was associated with outcomes (3-year PFS/OS, 66%/77% CR vs 43%/57% partial response vs 5%/15% resistant; P < .0001 for both), whereas cytogenetic abnormalities and prior novel therapy did not impact outcomes. In our study, HCT resulted in durable remissions in therapy-sensitive patients with DLBCL-RS treated in the era of targeted CLL/SLL therapy, including patients with high-risk features.

Induction versus no induction chemotherapy before neoadjuvant chemoradiotherapy and surgery in oesophageal adenocarcinoma: a multicentre randomised phase II trial (NCCTG N0849 [Alliance]).

AIM: report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. METHODS: In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). RESULTS: Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). CONCLUSIONS: Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.

Patient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03).

PURPOSE: Aromatase inhibitors are the most commonly prescribed adjuvant endocrine therapy for hormone-dependent early breast cancer in postmenopausal women. Among Canadian Cancer Trials Group MA.27 participants, anastrozole and exemestane had comparable 5-year event-free survival. This companion study examined differences in patient-reported treatment-related symptoms (TRS) and health-related quality of life (HRQL) among postmenopausal women randomized to anastrozole or exemestane. METHODS: MA.27 participants (N = 686, of 7576) randomized to 5 years of anastrozole (1 mg/day, n = 371, Arm A) or exemestane (25 mg/day, n = 315, Arm E) completed the 56-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire to assess TRS and HRQL. The FACT-ES was completed at baseline, 3, 6, 12, and 24 months. RESULTS: No significant differences in FACT-ES median scores measuring TRS and HRQL were observed between treatment arms at any time point. Change in TRS from baseline was statistically significant at 3, 6, 12, and 24 months. HRQL was stable over time in both arms. Greater TRS burden was associated with poorer HRQL (coefficient = 0.57, p < 0.001). Twenty percent of patients discontinued AI therapy by month 24 and 32% discontinued AIs at 4 years. In both arms, patients reporting more side effect bother prior to initiating study treatment had a higher risk of discontinuing treatment before completing protocol therapy (hazard ratio [HR] 1.29, 95% CI 1.08-1.55, p = 0.01). CONCLUSIONS: TRS and HRQL were comparable between anastrozole and exemestane. TRS negatively affect HRQL. Women who report being bothered by treatment side effects prior to initiating an AI are at increased risk for early treatment discontinuation.

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.

Safety and Pharmacokinetics of Bendamustine Rapid-Infusion Formulation.

Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution. Both formulations are administered as a 500 mL admixture with a recommended infusion time of 30 or 60 minutes for chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma, respectively. A newer liquid BDM formulation (rapid BDM) is a ready-to-dilute solution not requiring reconstitution that dilutes into an admixture of only 50 mL and can be safely administered in a shorter infusion time (10 minutes). Rapid BDM admixture also has longer stability at room temperature than both lyophilized and liquid BDM formulations (6 vs 2 to 3 hours). This phase 1, open-label, randomized, crossover (3-period, partially replicated) study, conducted in "end-of-life" cancer patients at 10 oncology centers in the United States, demonstrates that rapid BDM is bioequivalent to original BDM as determined by area under the curve. Expected differences in maximum plasma concentration and time to maximum plasma concentration were observed between study treatments, given the substantially shorter infusion time of rapid BDM. No clinically relevant differences in other evaluated pharmacokinetic parameters were found. Rapid BDM infusions were safe and tolerable for cancer patients in this study. The overall safety profiles of the 2 BDM formulations were comparable, with no new safety signals identified and no differences in infusion-related adverse events.

Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518.

Purpose Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs. Patients and Methods Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. Results A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). Conclusion No significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.

A randomized comparison of once weekly epoetin alfa to extended schedule epoetin or darbepoetin in chemotherapy-associated anemia.

Erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients with cancer chemotherapy-associated anemia (CAA). Extended-interval ESA dosing (administration less than once weekly) is common with DA, but previous studies suggested that EA might also be administered less often than weekly. In this multicenter prospective trial, 239 CAA patients with Hb <10.5 g/dL were randomized to receive EA 40,000 U subcutaneously once weekly ("40K" arm), EA 80,000 U every 3 weeks ("80K"), EA 120,000 U every 3 weeks ("120K" arm), or DA 500 mcg every 3 weeks ("DA"), for 15 weeks. The primary endpoint was the proportion of patients achieving Hb ≥ 11.5 g/dL or increment of Hb > 2.0 g/dL from baseline without transfusion. Secondary endpoints included transfusion requirements, adverse events (AEs), and patient-reported outcomes (PROs). There were no significant differences between treatment arms in the proportion of patients achieving Hb response (68.9% for 40K, 61.7% for 80K, 65.5% for 120K, and 66.7% for DA; P > 0.41 for all comparisons) or requiring RBC transfusion, but the median Hb increment from baseline was higher in the 40K and DA arms compared to the two extended dosing EA arms, and Hb response was achieved soonest in the weekly EA arm. There were no differences in PROs or AEs. The FDA-approved schedules tested-weekly EA 40,000 U, and every 3 week DA 500 mcg-are reasonable standards for CAA therapy.

A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for non-small-cell lung cancer: North Central Cancer Treatment Group (NCCTG)-N0321.

INTRODUCTION: Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III non-small-cell lung cancer was evaluated in this phase I/II study. METHODS: Patients with histologic or cytologic confirmed stage III nonmetastatic non-small-cell lung cancer who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel, and carboplatin concomitantly with thoracic radiation (60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A one-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a 0.09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival, progression-free survival, and the confirmed response rate. RESULTS: Thirty-one patients enrolled during the phase I portion of the trial, of which four cancelled before receiving treatment, leaving 27 evaluable patients. Of these 27 patients, two dose-limiting toxicities were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m, paclitaxel at 150 mg/m, and carboplatin at area under the curve of 5) and one (grade 4 neutropenia lasting ≥8 days) at dose level 6 (bortezomib 1.2 mg/m, paclitaxel 175 mg/m, and carboplatin at area under the curve of 6). During the phase I portion, the most common grade 3 of 4 AEs were leukopenia (44%), neutropenia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be the recommended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% confidence interval [CI], 70-98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6-phase I RP2D; 21-phase II). Of these 27 patients, the 12MS was 73% (95% CI, 58-92%), the median overall survival was 25.0 months (95% CI, 15.6-35.8), and the median progression-free survival was 8.4 months (95% CI, 4.1-10.5). The confirmed response rate was 26% (seven of 27; 95% CI, 11-46%), consisting of four partial responses and three complete responses. Grade 3+ and grade 4+ AEs occurred in 82% and 56% of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively. CONCLUSIONS: The addition of bortezomib to concurrent carboplatin/paclitaxel and radiation seemed to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen.

A Phase II trial of docetaxel and carboplatin administered every 2 weeks as preoperative therapy for stage II or III breast cancer: NCCTG study N0338.

OBJECTIVE: We conducted a multicenter phase II trial to assess the efficacy and toxicity of docetaxel and carboplatin combination as neoadjuvant therapy for stage II or III breast cancer (BC). METHODS: Patients received 75 mg/m of docetaxel and AUC 6 of carboplatin on day 1 followed by pegfilgrastim on day 2, every 14 days for 4 cycles, followed by definitive breast surgery. The primary endpoint was the proportion of patients achieving pathologic complete remission (pCR), defined as disappearance of all invasive and in situ tumors in the breast and axilla after chemotherapy. RESULTS: A total of 57 women (median age, 53 y) were enrolled. Thirty-eight (67%) had ER+, 31 (54%) PR+, and 6 (11%) HER2+ disease; 9 had triple negative BC (TNBC). Forty-three (75%; 95% confidence interval, 62%-86%) of 57 eligible patients had clinical response (15 clinical complete response, 28 clinical partial response). Nine (16%; 90% confidence interval, 10%-28%) patients achieved pCR. Four of 9 (44%) patients with TNBC achieved pCR. Thrombocytopenia (5%) was the only grade 4 adverse event. The most common grade 3 adverse events were thrombocytopenia (19%), fatigue (12%), and anemia (9%). CONCLUSIONS: Four cycles of 2-weekly Docetaxel and Carboplatin are feasible with acceptable toxicity and a pCR rate of 16%. This regimen can be considered for neoadjuvant therapy of BC, particularly for patients not eligible for anthracycline therapy. A high pCR rate of 44% noted in a subset of patients with TNBC is encouraging and needs to be validated in large prospective trials.

Cardiac angiosarcoma presenting with tamponade.

Primary cardiac angiosarcoma is extremely rare, but it is the most common primary malignant cardiac tumor. We herein present the case of a 51-year-old man who presented with symptoms of acute right heart failure, secondary to pericardial tamponade. Pericardiocentesis showed bloody fluid with negative pathology. Repeat 2-D echocardiography and a trans-esophageal echocardiogram showed a right atrial mass. The patient underwent surgery and adjuvant chemotherapy, but died seven months after the diagnosis. Despite being rare, cardiac angiosarcoma should be included in the differential diagnosis of bloody pericardial effusions, even with negative early investigations. The prognosis of the disease is usually poor. Treatment is mainly surgical resection if the cancer is localized, and can include neadjuvant and adjuvant chemotherapy, radiation treatment, and immunotherapy.

The relationship between numbness, tingling, and shooting/burning pain in patients with chemotherapy-induced peripheral neuropathy (CIPN) as measured by the EORTC QLQ-CIPN20 instrument, N06CA.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is characterized by numbness, tingling, and shooting/burning pain. This analysis was performed to describe the relationship between numbness, tingling, and shooting/burning pain in patients with CIPN, as reported using the EORTC QLQ-CIPN20 (CIPN20). METHODS: Baseline CIPN20 data were provided for all patients on a prospective trial designed to treat patients with bothersome CIPN. Baseline frequencies for the items on the CIPN20 are primarily described by descriptive statistics and histograms, with correlational analyses between individual items. RESULTS: A majority of the 199 patients accrued to this study reported "quite a bit" to "very much" numbness (57%) or tingling (63%) in the hands compared to "a little" or "not at all" (numbness (43%), tingling (38%)). Fewer patients reported "quite a bit" to "very much" shooting/burning pain in the hands (18%). Numbness and tingling in the hands were highly correlated (r = 0.69), while neither were highly correlated with shooting/burning pain. Similar results were observed in the feet. More severe ratings for tingling and shooting/burning pain were ascribed to the lower extremities, as opposed to the upper extremities. CONCLUSIONS: In patients with CIPN, severe sensory neuropathy symptoms (numbness, tingling) commonly exist without severe neuropathic pain symptoms (shooting/burning pain), while the reverse is not common. Symptoms in the feet should be evaluated distinctly from those in the hands as the experience of symptoms is not identical, for individual patients, in upper versus lower extremities.

A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group Study, N057E(1).

BACKGROUND: There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). ABI-007 is an albumin-bound formulation of paclitaxel that has demonstrated single-agent activity against metastatic melanoma. METHODS: A parallel phase II trial was conducted in patients with unresectable stage IV melanoma who were either chemotherapy naive (CN) or previously treated (PT). The treatment regimen consisted of ABI-007 (100 mg/m(2) ) and carboplatin area under the curve (AUC2) administered on days 1, 8, and 15 every 28 days. The primary aim of this study was objective response rate (RECIST). RESULTS: Seventy-six patients (41 CN and 35 PT) were enrolled between November 2006 and July 2007. Three patients withdrew consent prior to starting treatment. The median number of treatment cycles was 4. There were 10 (25.6%) responses (1 complete response [CR] and 9 partial responses [PRs]) in the CN cohort (90% CI, 16.7%-42.3%) and 3 (8.8%) responses (3 PRs) in the PT cohort (90% CI, 2.5%-21.3%). Median progression-free survival was 4.5 months in the CN cohort and 4.1 months in the PT cohort. Median overall survival (OS) was 11.1 months in the CN group and 10.9 months in the PT group. Severe toxicities in both groups (Common Terminology Criteria for Adverse Effects v.3.0 ≥grade 3) included neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting. CONCLUSIONS: The weekly combination of ABI-007 and carboplatin appears to be moderately well tolerated, with promising clinical activity as therapy in patients who are chemotherapy naive and with modest antitumor activity in those previously treated.

The use of Valeriana officinalis (Valerian) in improving sleep in patients who are undergoing treatment for cancer: a phase III randomized, placebo-controlled, double-blind study (NCCTG Trial, N01C5).

Sleep disorders are a substantial problem for cancer survivors, with prevalence estimates ranging from 23% to 61%. Although numerous prescription hypnotics are available, few are approved for long-term use or have demonstrated benefit in this circumstance. Hypnotics may have unwanted side effects and are costly, and cancer survivors often wish to avoid prescription drugs. New options with limited side effects are needed. The purpose of this trial was to evaluate the efficacy of a Valerian officinalis supplement for sleep in people with cancer who were undergoing cancer treatment. Participants were randomized to receive 450 mg of valerian-or placebo orally 1 hour before bedtime for 8 weeks. The primary end point was area under the curve (AUC) of the overall Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included the Functional Outcomes of Sleep Questionnaire, the Brief Fatigue Inventory (BFI), and the Profile of Mood States (POMS). Toxicity was evaluated with both self-reported numeric analogue scale questions and the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Questionnaires were completed at baseline and at 4 and 8 weeks. A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007, with 119 being evaluable for the primary end point. The AUC over the 8 weeks for valerian was 51.4 (SD = 16), while that for placebo was 49.7 (SD = 15), with a P value of 0.6957. A supplemental, exploratory analysis revealed that several fatigue end points, as measured by the BFI and POMS, were significantly better for those taking valerian over placebo. Participants also reported less trouble with sleep and less drowsiness on valerian than placebo. There were no significant differences in toxicities as measured by self-report or the CTCAE except for mild alkaline phosphatase increases, which were slightly more common in the placebo group. This study failed to provide data to support the hypothesis that valerian, 450 mg, at bedtime could improve sleep as measured by the PSQI. However, exploratory analyses revealed improvement in some secondary outcomes, such as fatigue. Further research with valerian exploring physiologic effects in oncology symptom management may be warranted.

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. METHODS: Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. RESULTS: Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. CONCLUSION: Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

Does sunscreen prevent epidermal growth factor receptor (EGFR) inhibitor-induced rash? Results of a placebo-controlled trial from the North Central Cancer Treatment Group (N05C4).

PURPOSE: Rash occurs in >50% of patients prescribed epidermal growth factor receptor (EGFR) inhibitors. This study was undertaken to determine whether sunscreen prevents or mitigates these rashes. METHODS: This placebo-controlled, double-blinded trial enrolled rash-free patients starting an EGFR inhibitor. Patients were randomly assigned to sunscreen with a sun protection factor of 60 applied twice a day for 28 days versus placebo. They were then monitored for rash and quality of life (Skindex-16) during the 4-week intervention and for an additional 4 weeks. RESULTS: Fifty-four patients received sunscreen, and 56 received placebo; the arms were balanced at baseline. During the 4-week intervention, physician-reported rash occurred in 38 (78%) and 39 (80%) sunscreen-treated and placebo-exposed patients, respectively (p = 1.00); no significant differences in rash rates emerged over the additional 4 weeks. There were no significant differences in rash severity, and patient-reported outcomes of rash yielded similar conclusions. Adjustment for sun intensity by geographical zone, season, and use of photosensitivity medications did not yield a significant difference in rash across study arms (p = .20). Quality of life scores declined but remained comparable between arms. CONCLUSIONS: Sunscreen, as prescribed in this trial, did not prevent or attenuate EGFR inhibitor-induced rash.

Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy.

BACKGROUND: Postmenopausal women with osteoporosis/osteopenia are at increased risk of fracture. Aromatase inhibitors further increase bone loss in these patients. This study evaluates whether zoledronic acid prevents the bone loss expected when these patients initiate letrozole. PATIENTS AND METHODS: Postmenopausal women with estrogen and/or progesterone receptor-positive breast cancer and a bone mineral density (BMD) T-score <-2.0 were given letrozole 2.5mg/vitamin D 400 international units daily, calcium 500mg twice daily, and 4mg zoledronic acid every 6 months. The BMD was assessed at baseline and 1 year. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year. RESULTS: Forty-six patients completed 1 year of treatment. LS BMD increased by 2.66% (p=0.01), femoral neck (FN) by 4.81% (p=0.01), and any measured endpoint by 4.55% (p=0.0052). CONCLUSIONS: Zoledronic acid prevents bone loss in postmenopausal women with osteoporosis/osteopenia starting letrozole and is associated with improvements in BMD.

Phase II trial of oral topotecan and intravenous carboplatin with G-CSF support in previously untreated patients with extensive stage small cell lung cancer: A North Central Cancer Treatment Group Study.

OBJECTIVES: The objective of this study was to evaluate the response rate and toxicities of the combination of oral topotecan and carboplatin in patients with untreated extensive stage small cell lung cancer (ES-SCLC). Previous studies have suggested improved outcomes with a topoisomerase I inhibitor in combination with a platinum agent. METHODS: Twenty-six patients with previously untreated, ES-SCLC were evaluable in this phase II trial. All patients received oral topotecan 2.0 mg/m per day on days 1 through 5 and carboplatin at an area under curve of 5 on day 5. Treatment was repeated every 21 days up to a total of 6 cycles. All patients received G-CSF. RESULTS: There were no complete responses and 16 partial responses, for an overall response rate of 62% (95% CI: 41-80). Median time to progression was 6.0 months (95% CI: 4-8), with a median overall survival of 12 months (95% CI: 8-16). This study was closed to accrual early with 26 of a planned 39 patients enrolled because of grade 5 adverse events in 4 (15%) patients (3 neutropenic infections, 1 sudden cardiac death). Eighty-five percent of patients experienced grade 3 or higher hematologic events. The most common severe nonhematologic events included diarrhea, vomiting, dyspnea, hypoxia, and hypotension. CONCLUSIONS: Although this drug regimen has activity as first-line therapy in ES-SCLC, it is associated with excessive hematologic toxicity, which occurred in spite of growth factor support. Despite promising survival estimates, this particular combination and dose level of oral topotecan and carboplatin cannot be recommended.

A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9).

PURPOSE: This study tested whether infliximab, a chimeric IgG1kappa monoclonal antibody that blocks tumor necrosis factor (TNF) alpha, improves/stabilizes weight loss in elderly and/or poor performance status patients with metastatic non-small cell lung cancer (NSCLC). METHODS: This double-blind trial randomly assigned patients to infliximab/docetaxel (n=32) versus placebo/docetaxel (n=29). The primary endpoint was > or = 10% weight gain. RESULTS: Groups were balanced with respect to age, number of prior chemotherapy regimens, baseline weight loss, and performance status. No patient gained > or = 10% baseline weight, and early evidence of the lack of efficacy prompted early trial closure. Appetite improvement was negligible in both arms. However, infliximab-/docetaxel-treated patients developed greater fatigue and worse global quality of life scores. Other outcomes, such as tumor response rate (<10% in both groups) and overall survival, were not statistically different between groups. There were no statistically significant differences in adverse events, although one death was attributed to infliximab. Genotyping for the TNF alpha -238 and -308 polymorphisms revealed no clinical significance of these genotypes, as relevant to the loss of weight or appetite. CONCLUSIONS: This trial closed early because infliximab did not prevent or palliate cancer-associated weight loss. Infliximab was associated with increased fatigue and inferior global quality of life.