A randomized phase II trial evaluating two non-pharmacologic interventions in cancer survivors for the treatment of sleep-wake disturbances: NCCTG N07C4 (Alliance).

PURPOSE: Sleep disturbance is a prevalent problem for cancer survivors and effective behavioral treatments are not widely used for this population. This study evaluated home-based sleep interventions based on cognitive behavioral therapy for insomnia (CBT-I). METHODS: This phase II randomized controlled trial evaluated two manualized interventions over 7 weeks. The intervention group received sleep hygiene information, stimulus control, sleep restriction, and a bedtime imagery audio recording. The control group was similar, but without sleep restriction and used audio recordings of bedtime short stories instead of imagery. Eligibility included adult cancer survivors who had trouble falling asleep or falling back to sleep on 3 of 7 days. Patients with diagnoses of sleep or mental health disorders were excluded. The primary endpoint was change in time to fall asleep or falling back to sleep after awakening, from baseline to week 7. Two-sample T tests evaluated differences between arms for this endpoint. RESULTS: Ninety-three of 168 planned participants were enrolled from 20 institutions. The study closed early for poor accrual. Baseline time to sleep was 45 min and 52 min for the intervention and control group, respectively. At 7 weeks, both groups improved, the intervention group to 26 min and control group to 30 min, a non-significant difference between groups (p = 0.85). Secondary outcomes improved in both groups with no significant differences between arms. CONCLUSIONS: Improvement in sleep outcomes in both arms was consistent with other CBT-I interventions delivered through alternative approaches to provider-delivered therapy. More research on optimal scalable delivery of CBT-I is needed. CLINICAL RELEVANCE: This study supports the effectiveness of CBT-I based behavioral interventions for sleep but also the need for better delivery methods to improve uptake and effect size. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00993928.

Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).

PURPOSE: Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS: Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS: There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION: Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

Associations between self-reported diet during treatment and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221).

BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment. METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900). RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05). CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.

Supplement Use and Chemotherapy-Induced Peripheral Neuropathy in a Cooperative Group Trial (S0221): The DELCaP Study.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) can interfere with daily function and quality of life, and there are no known preventive approaches. In a cohort of breast cancer patients receiving paclitaxel as part of a clinical trial (SWOG 0221), we examined the use of dietary supplements both before diagnosis and during treatment in relation to CIPN. Methods: At registration to S0221, 1225 breast cancer patients completed questionnaires regarding the use of multivitamins and supplements before and at diagnosis. A second questionnaire at six months queried use during treatment. Supplement use was evaluated in relation to CIPN, assessed via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v. 3.0) and the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed with logistic regression for the CTCAE analyses and ordinal regression for the FACT/GOG-Ntx analyses. Results: Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE-adjusted OR = 0.60, 95% CI = 0.42 to 0.87; FACT/GOG-Ntx-adjusted OR = 0.78, 95% CI = 0.61 to 1.00). Use during treatment was marginally inversely associated with CIPN (CTCAE-adjusted OR = 0.73, 95% CI = 0.49 to 1.08; FACT/GOG-Ntx-adjusted OR = 0.77, 95% CI = 0.60 to 0.99). Other supplement use, either before diagnosis or during treatment, was not statistically significantly associated with CIPN. Conclusions: Multivitamin use may be associated with reduced risk of CIPN, although individual dietary supplement use did not appreciably affect risk. Multivitamin use could be a surrogate for other related behaviors that are the actual drivers of the association with reduced CIPN. Without prospective randomized trials of vitamin supplementation, recommendations for use or changes to clinical practice are clearly not warranted.

Supplement use during an intergroup clinical trial for breast cancer (S0221).

The use of supplements during chemotherapy is controversial, partly due to the potential effect of antioxidants on reduced efficacy of chemotherapy-related cytotoxicity. We examined supplement use among breast cancer patients registered to a clinical trial (SWOG 0221) before diagnosis and during treatment. Patients (n = 1,467) completed questionnaires regarding multivitamin and supplement use at trial registration (baseline) to capture use before diagnosis. Of these patients, 1,249 completed a 6-month followup questionnaire to capture use during treatment. We examined the use of vitamins C, D, E, B6, B12, folic acid, and calcium at these timepoints, as well as physician recommendations regarding supplement use. The use of vitamins C, E, folic acid, and calcium decreased during treatment, while the use of vitamin B6 increased. Five hundred seventy four patients (51 %) received no physician recommendations regarding supplement use. Among the remaining 49, 10 % were advised not to take multivitamins and/or supplements, 7 % were advised to use only multivitamins, and 32 % received recommendations to use multivitamins and/or supplements. Among patients who took vitamin C before diagnosis, those who were advised not to take supplements were >5 times more likely not to use of vitamin C during treatment than those not advised to stop use (OR = 5.27, 95 % CI 1.13-24.6). Previous non-users who were advised to take a multivitamin were nearly 5 times more likely to use multivitamins during treatment compared to those who received no recommendation (OR = 4.66, 95 % CI 2.10-10.3). In this clinical trial for high-risk breast cancer, supplement use generally decreased during treatment. Upon followup from the clinical trial, findings regarding supplement use and survival outcomes will better inform physician recommendations for patients on adjuvant chemotherapy.

Cytokeratin-19 and mammaglobin gene expression in circulating tumor cells from metastatic breast cancer patients enrolled in North Central Cancer Treatment Group trials, N0234/336/436/437.

PURPOSE: To investigate the associations between baseline and posttreatment circulating tumor cell (CTC) gene expression and outcome of patients enrolled in four North Central Cancer Treatment Group metastatic breast cancer (MBC) trials in which specimens were shipped (at 4°C) from community-based sites to a reference laboratory (Mayo Clinic, Rochester, MN). EXPERIMENTAL DESIGN: Blood was collected at treating sites from MBC patients before (baseline), during, and at the end of treatment with erlotinib + gemcitabine (N0234), sorafenib (N0336), irinotecan + cetuximab (N0436), or paclitaxel-poliglumex + capecitabine (N0437). CTCs from 10 mL of EDTA blood were enriched with CD45 depletion, 24 to 30 hours postblood collection. Reverse transcription/quantitative PCR was used to determine cytokeratin-19 (CK19) and mammaglobin (MGB1) mRNA levels in CTCs from up to 13 (N0234), 16 (N0336), 18 (N0436), and 39 (N0437) patients. The gene expressions were normalized to ß(2)-microglobulin and calibrated to healthy blood using the 2(-ΔΔCq) algorithm; positivity was defined as 2 or more. RESULTS: CK19+mRNA cells were detected in 56% to 75% and MGB1+mRNA cells in 23% to 38% of 86 patients at baseline. CK19+mRNA cells were detected in 30% to 67% and MGB1+mRNA cells in 14% to 64% of 110 postbaseline serial samples. The presence of baseline CK19+mRNA cells (P = 0.01) but not MGB1+mRNA cells (P = 0.14) was significantly associated with shorter overall survival. A decrease in MGB1+mRNA levels (baseline-week 8) seemed to be associated with clinical response (P = 0.05). CONCLUSIONS: CTC gene expression analysis conducted by a reference laboratory is feasible when blood is collected from treating sites and processed 24 to 30 hours postcollection. The presence of baseline CK19+mRNA CTCs was associated with poor prognosis; a decrease in MGB1+mRNA CTCs may help predict response to therapy of MBC patients.

An overview of approaches to adjuvant therapy for colorectal cancer in the United States.

Adjuvant chemotherapy for colon cancer and combined chemotherapy and radiation therapy (RT) for rectal cancer increases the proportion of patients cured of their disease. Adjuvant chemotherapy is indicated for stage III colon cancer, and although controversial for stage II disease, there is evidence to suggest that these patients may benefit as well. Adjuvant chemotherapy and RT is recommended for patients with stage II/III rectal cancer. Studies incorporating oral fluoropyrimidines as well as combination chemotherapy have been completed, with results demonstrating the value of these approaches. A new generation of studies will evaluate the biologic agents bevacizumab and cetuximab in the adjuvant therapy of colorectal cancer. For rectal cancer, optimal outcomes are dependent not only on the systemic therapy, but also on the expertise of the surgeon and the timing of RT, with improved local control and toxicity seen with preoperative therapy.

Adjuvant therapy of colon cancer: a review.

Colon cancer is a common cause of cancer-related mortality. Complete surgical resection of the primary tumor and/or select metastatic lesions can be curative in many patients. The risk of recurrence after resection can be predicted by pathologic staging. Large prospective randomized trials over the past 2 decades have clearly shown an increased overall survival for patients with resected stage III colon cancer who are treated with adjuvant 5-fluorouracil-based chemotherapy. The benefit of adjuvant chemotherapy for patients with stage II disease remains controversial. There is indirect evidence to support adjuvant chemotherapy after resection of metastatic disease. Locoregional approaches such as radiation, hepatic arterial infusion, or portal vein chemotherapy remain investigational. Adjuvant immunotherapy with monoclonal antibodies is emerging as a therapeutic option that might complement chemotherapy. Future challenges include improving adjuvant chemotherapy with the addition and/or substitution of new agents, resolving which subset of patients with stage II and resected stage IV colon cancer might benefit from therapy, validating the benefit of immunotherapy, and investigating locoregional therapies compared with systemic therapy.