Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204).

BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572.

BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Effect of ArginMax on sexual functioning and quality of life among female cancer survivors: results of the WFU CCOP Research Base Protocol 97106.

BACKGROUND: Problems with sexual functioning are common following therapy for breast and gynecologic cancers, although there are few effective treatments. OBJECTIVE: To assess the impact of ArginMax, a nutritional supplement comprised of extracts of L-arginine, ginseng, gingko, and damiana, as well as multivitamins and minerals, on sexual functioning and quality of life in female cancer survivors. METHODS: This was a 12-week, randomized, placebo-controlled trial of eligible patients who were 6 months or more from active treatment and reporting problems with sexual interest, satisfaction, and functioning after therapy. The participants took 3 capsules of Arginmax or placebo twice daily. Outcome measures were the Female Sexual Function Inventory (FSFI) and the Functional Assessment of Cancer Therapy - General (FACT-G). Assessments were done at baseline, 4, 8, and 12 weeks. RESULTS: 186 patients with a median age of 50 years were accrued between May 10, 2007 and March 24, 2010. 76% of the patients were non-Hispanic white. Most had breast or a gynecologic cancer (78% and 12%, respectively). At 12 weeks, there were no differences between the ArginMax group (n = 96) and placebo (n = 92) group in sexual desire, arousal, lubrication, orgasm,satisfaction or pain. However, FACT-G total scores were significantly better for participants who took ArginMax compared with those who took placebo (least squares [LS] means, 87.5 vs 82.9, respectively; P = .009). The Fact-G subscales that were most affected were Physical (25.37 vs. 23.51, P = .001) and Functional Well-Being (22.46 vs. 20.72, P = .007). Toxicities were similar for both groups. LIMITATIONS: Study results are limited by a lack of data on the participants' psychological and physical symptoms and sexual partner variables. CONCLUSIONS: ArginMax had no significant impact on sexual functioning, but patient quality of life was significantly better at 12 weeks in participants who received ArginMax.

Hot flashes severity, complementary and alternative medicine use, and self-rated health in women with breast cancer.

CONTEXT: Hot flashes (HF) are a common distressing symptom in women with breast cancer (BC). Current pharmacologic options are moderately effective and are associated with bothersome side effects. Complementary and alternative medicine is commonly used by cancer patients. However, information on the association of hot flashes severity with such use and self-rated health is lacking. OBJECTIVE: To examine the hot flashes severity in women with breast cancer and its association with complementary and alternative medicine use and self-rated health (SRH). DESIGN: Longitudinal multicenter study to assess information needs of cancer outpatients. PARTICIPANTS: Patients with a diagnosis of breast cancer who were scheduled to undergo chemotherapy and/or radiotherapy. OUTCOME MEASURES: Hot flashes severity (0 = not present and 10 = as bad as you can imagine), use of complementary and alternative medicine (yes/no), and self-rating of health (SRH) status post-treatment and six-months thereafter (1-5, higher score = better SRH). RESULTS: The majority of women with HF (mean age = 54.4 years) were Caucasian and married, with higher education, and 93% had received surgical treatment for BC. At the end of treatment, 79% women reported experiencing HF [mean severity = 5.87, standard deviation (SD) = 2.9]; significantly more severe HF were reported by younger women with poor SRH, poor performance status, and those reporting doing spiritual practices. At follow-up, 73% had HF (mean severity = 4.86, SD = 3.0), and more severe HF were reported by younger women with poor self-rated health who had undergone chemotherapy plus radiotherapy, used vitamins, and did not exercise. CONCLUSIONS: A high percentage of women experienced hot flashes at the end of treatment and at six-month follow-up. A significant association of hot flashes severity with spiritual practice, increased vitamin use, and reduced exercise emphasize the need for future studies to confirm the results. This can facilitate safe use of complementary and alternative medicine and favorable outcomes while managing cancer-related hot flashes.

Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial.

PURPOSE: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity. EXPERIMENTAL DESIGN: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1-5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B). RESULTS: Fifty-four patients were enrolled: 19 patients in group A and 35 in group B. Objective response rate was 18.5% with median duration of 6.7 months (range 0.5-24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7-8.2]; outcome was similar between the two dose groups. We identified SNPs in the VEGF and VEGFR2 promoter regions, which were associated with PFS6 (P<0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell-derived factor-1 was associated with PFS6 success (P=0.04). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P=0.022). Imaging analysis showed a trend associating ADC-L with poor outcome. CONCLUSIONS: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation.

Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients.

PURPOSE: Despite the widespread use of antiemetics, nausea continues to be reported by over 70% of patients receiving chemotherapy. METHODS: In this double blind, multicenter trial, we randomly assigned 744 cancer patients to four arms: 1) placebo, 2) 0.5 g ginger, 3) 1.0 g ginger, or 4) 1.5 g ginger. Nausea occurrence and severity were assessed at a baseline cycle and the two following cycles during which patients were taking their assigned study medication. All patients received a 5-HT(3) receptor antagonist antiemetic on Day 1 of all cycles. Patients took three capsules of ginger (250 mg) or placebo twice daily for 6 days starting 3 days before the first day of chemotherapy. Patients reported the severity of nausea on a 7-point rating scale ("1" = "Not at all Nauseated" and "7" = "Extremely Nauseated") for Days 1-4 of each cycle. The primary outcomes were to determine the dose and efficacy of ginger at reducing the severity of chemotherapy-induced nausea on Day 1 of chemotherapy. RESULTS: A total of 576 patients were included in final analysis (91% female, mean age = 53). Mixed model analyses demonstrated that all doses of ginger significantly reduced acute nausea severity compared to placebo on Day 1 of chemotherapy (p = 0.003). The largest reduction in nausea intensity occurred with 0.5 g and 1.0 g of ginger (p = 0.017 and p = 0.036, respectively). Anticipatory nausea was a key factor in acute chemotherapy-induced nausea (p < 0.0001). CONCLUSIONS: Ginger supplementation at a daily dose of 0.5 g-1.0 g significantly aids in reduction of the severity of acute chemotherapy-induced nausea in adult cancer patients.

Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336.

PURPOSE: We conducted a cooperative group phase II study to assess antitumor activity and toxicity of sorafenib in patients with metastatic breast cancer (MBC) who had received prior treatment for their disease. PATIENT AND METHODS: Patients were eligible if they had measurable disease and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. The primary end point of the study was tumor response per Response Evaluation Criteria in Solid Tumors (RECIST). The study was designed in two stages. Sorafenib was administered as 400 mg twice daily on days 1 through 28 of each 4-week cycle. RESULTS: Twenty-three patients were enrolled with a median age of 54 years (range, 37 to 70 years). Twenty-two (96%) had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range, one to 15 cycles) with a median follow-up of 2.4 years (range, 2.2 to 2.6 years). There were no grade 4 toxicities and few grade 3 toxicities. Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST criteria. Thus, the trial stopped at the end of the first stage per study design. Two patients (10%; 90% CI, 1.8% to 28.3%) achieved stable disease lasting longer than 6 months. CONCLUSION: Sorafenib as a single agent, although well tolerated, did not exhibit activity when measured by tumor shrinkage in patients with MBC who had received prior treatment. Further research should focus on combinations with standard therapy and end points more sensitive to effects of targeted agents, such as disease stabilization.

Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07.

PURPOSE: This phase III clinical trial evaluated the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin as surgical adjuvant therapy for stage II and III colon cancer. PATIENTS AND METHODS: Patients who had undergone a potentially curative resection were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). RESULTS: A total of 2,407 patients (96.6%) of the 2,492 patients randomly assigned were eligible. Median follow-up for patients still alive is 42.5 months. The hazard ratio (FLOX v FULV) is 0.80 (95% CI, 0.69 to 0.93), a 20% risk reduction in favor of FLOX (P < .004). The 3- and 4-year disease-free survival (DFS) rates were 71.8% and 67.0% for FULV and 76.1% and 73.2% for FLOX, respectively. Grade 3 neurosensory toxicity was noted in 8.2% of patients receiving FLOX and in 0.7% of those receiving FULV (P < .001). Hospitalization for diarrhea associated with bowel wall thickening occurred in 5.5% of the patients receiving FLOX and in 3.0% of the patients receiving FULV (P < .01). A total of 1.2% of patients died as a result of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens. CONCLUSION: The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.

Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma.

PURPOSE: Protein kinase C beta (PKCbeta) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCbeta, enzastaurin, in patients with relapsed or refractory DLBCL. PATIENTS AND METHODS: Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for > or= two cycles (one cycle = 28 days), objective response, and toxicity. RESULTS: Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for two cycles, and eight patients remained free from progression for four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry. CONCLUSION: Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.

A tomato-based, lycopene-containing intervention for androgen-independent prostate cancer: results of a Phase II study from the North Central Cancer Treatment Group.

OBJECTIVES: Tomatoes are rich in lycopene. This study explored the efficacy of a lycopene-rich tomato product in androgen-independent prostate cancer and the reasons patients participated in an "alternative medicine" study. METHODS: This Phase II study evaluated 46 patients with androgen-independent prostate cancer. All were asymptomatic and had serum prostate-specific antigen elevation despite hormonal manipulation. All patients completed a questionnaire on their motivations for enrolling in an "alternative medicine" study. Patients were prescribed a lycopene-rich tomato supplement at a lycopene dose of 15 mg twice daily. RESULTS: One patient manifested a tumor response with a 50% or greater confirmed decline in serum prostate-specific antigen level, yielding a response rate of 2%. Lycopene was well tolerated, but 1 patient died of a cancer-related hemorrhage, and 1 had grade 4 diarrhea. Grade 1 or 2 events included diarrhea in 18, nausea in 12, abdominal distension in 8, flatulence in 2, vomiting in 2, anorexia in 1, and dyspepsia in 1. The reasons for entering the trial are discussed and were overall positive. CONCLUSIONS: Lycopene, as prescribed in our study, did not appear effective for androgen-independent prostate cancer. The patients' reasons for enrolling in this trial were positive and realistic.

Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1.

PURPOSE: Hot flashes can cause significant morbidity in postmenopausal women undergoing or finished with breast cancer treatment. Black cohosh has been used to treat hot flashes, but definitive clinical data about efficacy have been equivocal. METHODS: A double-blind, randomized, cross-over clinical trial with two 4-week periods, was used to study the efficacy of black cohosh (1 capsule, Cimicifuga racemosa 20 mg BID) for the treatment of hot flashes in women. Participants kept a daily hot flash diary during a baseline week and then during two 4-week crossover treatment periods. Hot flash scores were measured by assigning points (1 to 4 for mild to very severe) to each hot flash based on severity and then adding the points for a given time period. RESULTS: Between October 31, 2003, to March 4, 2004, 132 patients were randomly assigned. Toxicity was minimal and not different by treatment group. Patients receiving black cohosh reported a mean decrease in hot flash score of 20% (comparing the fourth treatment week to the baseline week) compared with a 27% decrease for patients on placebo (P = .53). Mean hot flash frequency was reduced 17% on black cohosh and 26% on placebo (P = .36). Patient treatment preferences were measured after completion of both treatment periods by ascertaining which treatment period, if any, the patient preferred. Thirty-four percent of patients preferred the black cohosh treatment, 38% preferred the placebo, and 28% did not prefer either treatment. CONCLUSION: This trial failed to provide any evidence that black cohosh reduced hot flashes more than the placebo.

The efficacy of acupressure and acustimulation wrist bands for the relief of chemotherapy-induced nausea and vomiting. A University of Rochester Cancer Center Community Clinical Oncology Program multicenter study.

As an adjunct to standard antiemetics for the relief of chemotherapy-induced nausea and vomiting (NV), 739 patients were randomly assigned to either: 1) acupressure bands, 2) an acustimulation band, or 3) a no band control condition. Patients in the acupressure condition experienced less nausea on the day of treatment compared to controls (P<0.05). There were no significant differences in delayed nausea or vomiting among the three treatment conditions. Additional analyses revealed pronounced gender differences. Men in the acustimulation condition, but not the acupressure condition, had less NV compared to controls (P<0.05). No significant differences among the three treatment conditions were observed in women, although the reduction in nausea on the day of treatment in the acupressure, compared to the no band condition, closely approached statistical significance (P=0.052). Expected efficacy of the bands was related to outcomes for the acupressure but not the acustimulation conditions.

A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma.

BACKGROUND: Recent laboratory and epidemiologic studies have suggested that green tea has antitumor effects in patients with prostate carcinoma. This Phase II trial explored green tea's antineoplastic effects in patients with androgen independent prostate carcinoma. METHODS: This study, which was conducted by the North Central Cancer Treatment Group, evaluated 42 patients who were asymptomatic and had manifested, progressive prostate specific antigen (PSA) elevation with hormone therapy. Continued use of luteinizing hormone-releasing hormone agonist was permitted; however, patients were ineligible if they had received other treatments for their disease in the preceding 4 weeks or if they had received a long-acting antiandrogen therapy in the preceding 6 weeks. Patients were instructed to take 6 grams of green tea per day orally in 6 divided doses. Each dose contained 100 calories and 46 mg of caffeine. Patients were monitored monthly for response and toxicity. RESULTS: Tumor response, defined as a decline >/= 50% in the baseline PSA value, occurred in a single patient, or 2% of the cohort (95% confidence interval, 1-14%). This one response was not sustained beyond 2 months. At the end of the first month, the median change in the PSA value from baseline for the cohort increased by 43%. Green tea toxicity, usually Grade 1 or 2, occurred in 69% of patients and included nausea, emesis, insomnia, fatigue, diarrhea, abdominal pain, and confusion. However, six episodes of Grade 3 toxicity and one episode of Grade 4 toxicity also occurred, with the latter manifesting as severe confusion. CONCLUSIONS: Green tea carries limited antineoplastic activity, as defined by a decline in PSA levels, among patients with androgen independent prostate carcinoma.