A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment.

BACKGROUND: Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. METHODS: A phase 1b, dose escalation study was performed to assess maximum tolerated dose, safety/toxicity, clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab. RESULTS: The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months. DISCUSSION: This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.

Phenotypic Plasticity in Circulating Tumor Cells Is Associated with Poor Response to Therapy in Metastatic Breast Cancer Patients.

Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 timepoints at 3-month intervals. CTCs were analyzed in parallel samples from the same blood draw by imaging and by gene expression profiling to capture CTC phenotypic plasticity. Enumeration of CTCs by image analysis relying primarily on epithelial markers from samples obtained before therapy or at 3-month follow-up identified the patients at the highest risk of progression. CTC counts decreased with therapy, and progressors had higher CTC counts than non-progressors. CTC count was prognostic primarily at the start of therapy in univariate and multivariate analyses but had less prognostic utility at 6 months to 1 year later. In contrast, gene expression, including both epithelial and mesenchymal markers, identified high-risk patients after 6-9 months of treatment, and progressors had a shift towards mesenchymal CTC gene expression on therapy. Cross-sectional analysis showed higher CTC-related gene expression in progressors 6-15 months after baseline. Furthermore, patients with higher CTC counts and CTC gene expression experienced more progression events. Longitudinal time-dependent multivariate analysis indicated that CTC count, triple-negative status, and CTC expression of FGFR1 significantly correlated with inferior progression-free survival while CTC count and triple-negative status correlated with inferior overall survival. This highlights the utility of protein-agnostic CTC enrichment and multimodality analysis to capture the heterogeneity of CTCs.

Triple-negative subtype predicts poor overall survival and high locoregional relapse in inflammatory breast cancer.

BACKGROUND: Numerous studies have demonstrated that expression of estrogen/progesterone receptor (ER/PR) and human epidermal growth factor receptor (HER)-2 is important for predicting overall survival (OS), distant relapse (DR), and locoregional relapse (LRR) in early and advanced breast cancer patients. However, these findings have not been confirmed for inflammatory breast cancer (IBC), which has different biological features than non-IBC. METHODS: We retrospectively analyzed the records of 316 women who presented to MD Anderson Cancer Center in 1989-2008 with newly diagnosed IBC without distant metastases. Most patients received neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. Patients were grouped according to receptor status: ER(+) (ER(+)/PR(+) and HER-2-; n = 105), ER(+)HER-2(+) (ER(+)/PR(+) and HER-2(+); n = 37), HER-2(+) (ER(-)/PR(-) and HER-2(+); n = 83), or triple-negative (TN) (ER(-)PR(-)HER-2(-); n = 91). Kaplan-Meier and Cox proportional hazards methods were used to assess LRR, DR, and OS rates and their associations with prognostic factors. RESULTS: The median age was 50 years (range, 24-83 years). The median follow-up time and median OS time for all patients were both 33 months. The 5-year actuarial OS rates were 58.7% for the entire cohort, 69.7% for ER(+) patients, 73.5% for ER(+)HER-2(+) patients, 54.0% for HER=2(+) patients, and 42.7% for TN patients (p < .0001); 5-year LRR rates were 20.3%, 8.0%, 12.6%, 22.6%, and 38.6%, respectively, for the four subgroups (p < .0001); and 5-year DR rates were 45.5%, 28.8%, 50.1%, 52.1%, and 56.7%, respectively (p < .001). OS and LRR rates were worse for TN patients than for any other subgroup (p < .0001-.03). CONCLUSIONS: TN disease is associated with worse OS, DR, and LRR outcomes in IBC patients, indicating the need for developing new locoregional and systemic treatment strategies for patients with this aggressive subtype.

Expressive writing in patients receiving palliative care: a feasibility study.

BACKGROUND: Patients with advanced cancer receiving palliative care often experience severe physical and psychosocial symptoms. However, there are limited resources for psychological and emotional support. Expressive writing has shown decreased anxiety level in young and healthy people suffering from a number of stressors. OBJECTIVE: The purpose of this study was to determine the feasibility of expressive writing in patients receiving palliative care and the most suitable outcomes of expressive writing in this patient population. DESIGN: In this pilot study, patients were randomly assigned to either the expressive writing group (EW) or the neutral writing group (NW). Anxiety level before and after the writing session was compared between the two groups. Writing materials were content analyzed using standard qualitative research methods. RESULTS: A total of 24 patients (12 in EW and 12 in NW) were enrolled in the study between October 2006 and January 2007. Although the majority of patients (83%-100%) were able to complete all baseline assessments, poor adherence was observed during the follow-ups. Only 8% of patients completed the 2-week study. There was no significant difference in the State-Trait Anxiety Inventory (STAI) State-Anxiety scores at baseline, before and after each writing session between the EW and NW groups. DISCUSSION: Our rapid accrual suggests that palliative care patients are interested in participating in studies such as expressive writing. The high level of adherence to the baseline assessments indicates that these assessments were not particularly difficult for our patients to complete. Future studies may need to include patients with better performance status, better patient education, means of emotional expression (i.e., audio recording, telephone interview) and improved adherence. CONCLUSION: We conclude that clinical trials of expressive writing in the palliative care setting are not feasible unless they undergo major modification in methods compared to those previous reported in other patient population. Our findings will hopefully assist researchers considering similar studies.

Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole.

BACKGROUND: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. RESULTS: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. CONCLUSIONS: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

Distinct epidemiological profiles associated with inflammatory breast cancer (IBC): A comprehensive analysis of the IBC registry at The University of Texas MD Anderson Cancer Center.

BACKGROUND: To date, studies on inflammatory breast cancer (IBC) lack comprehensive epidemiological data. We analyzed detailed prospectively collected clinical and epidemiological data from the IBC Registry at The University of Texas MD Anderson Cancer Center. METHODS: Patients with IBC (n = 248) were consecutively diagnosed and prospectively enrolled between November 2006 and April 2013. All patients were newly diagnosed and at least 18 years old. Secondary IBC was excluded. Overall 160 variables were collected and evaluated including sociodemographics, anthropometrics, tobacco and alcohol consumption, reproductive variables, and family history data. RESULTS: Mean age at diagnosis was 51.6 (±11.5 SD) years, and the majority of patients were White (77.8%). A mean BMI ≥ 25 kg/m2, irrespective of menopausal status, was observed in 80.2% of all patients, with 82.6% of African Americans being obese. Approximately 42.2% of patients were ever smokers, and 91% reported ever being pregnant. A history of breastfeeding was reported in 54% of patients, with significant differences between ethnic groups in favor of White women (P<0.0001). Other reproductive factors such as use of birth control pills & hormone replacement therapy were also more frequently associated with White women compare to other ethnic groups (P < 0.05). In the multivariate Cox proportional hazard analysis, African American or Hispanic ethnicity, not having breastfed, higher clinical stage, and TNBC subtype were associated with shorter survival. CONCLUSION: Our data suggest that IBC is associated with distinct epidemiological profiles. This information could assist in targeting patients with specific preventive strategies based on their modifiable behavioral patterns.

Safety and Efficacy of Panitumumab Plus Neoadjuvant Chemotherapy in Patients With Primary HER2-Negative Inflammatory Breast Cancer.

Importance: Combining conventional chemotherapy with targeted therapy has been proposed to improve the pathologic complete response (pCR) rate in patients with inflammatory breast cancer (IBC). Epidermal growth factor receptor (EGFR) expression is an independent predictor of low overall survival in patients with IBC. Objective: To evaluate the safety and efficacy of the anti-EGFR antibody panitumumab plus neoadjuvant chemotherapy in patients with primary human epidermal growth factor receptor 2 (HER2)-negative IBC. Design, Setting, and Participants: Women with primary HER2-negative IBC were enrolled from 2010 to 2015 and received panitumumab plus neoadjuvant chemotherapy. Median follow-up time was 19.3 months. Tumor tissues collected before and after the first dose of panitumumab were subjected to immunohistochemical staining and RNA sequencing analysis to identify biomarkers predictive of pCR. Intervention: Patients received 1 dose of panitumumab (2.5 mg/kg) followed by 4 cycles of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin weekly and then 4 cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks. Main Outcomes and Measures: The primary end point was pCR rate; the secondary end point was safety. The exploratory objective was to identify biomarkers predictive of pCR. Results: Forty-seven patients were accrued; 7 were ineligible. The 40 enrolled women had a median age of 57 (range, 23-68) years; 29 (72%) were postmenopausal. Three patients did not complete therapy because of toxic effects (n = 2) or distant metastasis (n = 1). Nineteen patients had triple-negative and 21 had hormone receptor-positive IBC. The pCR and pCR rates were overall, 11 of 40 (28%; 95% CI, 15%-44%); triple-negative IBC, 8 of 19 (42%; 95% CI, 20%-66%); and hormone receptor-positive/HER2-negative IBC, 3 of 21 (14%; 95% CI, 3%-36%). During treatment with panitumumab, nab-paclitaxel, and carboplatin, 10 patients were hospitalized for treatment-related toxic effects, including 5 with neutropenia-related events. There were no treatment-related deaths. The most frequent nonhematologic adverse event was skin rash. Several potential predictors of pCR were identified, including pEGFR expression and COX-2 expression. Conclusions and Relevance: This combination of panitumumab and chemotherapy showed the highest pCR rate ever reported in triple-negative IBC. A randomized phase 2 study is ongoing to determine the role of panitumumab in patients with triple-negative IBC and to further validate predictive biomarkers. Trial Registration: ClinicalTrials.gov Identifier: NCT01036087.

Effects of parenteral hydration in terminally ill cancer patients: a preliminary study.

PURPOSE: Most patients with cancer develop decreased oral intake and dehydration before death. This study aimed to determine the effect of parenteral hydration on overall symptom control in terminally ill cancer patients with dehydration. PATIENTS AND METHODS: Patients with clinical evidence of mild to moderate dehydration and a liquid oral intake less than 1,000 mL/day were randomly assigned to receive either parenteral hydration with 1,000 mL (treatment group) or placebo with 100 mL normal saline administered over 4 hours for 2 days. Patients were evaluated for target symptoms (hallucinations, myoclonus, fatigue, and sedation), global well-being, and overall benefit. RESULTS: Twenty-seven patients randomly assigned to the treatment group had improvement in 53 (73%) of their 73 target symptoms versus 33 (49%) of 67 target symptoms in the placebo group (n=22; P = .005). Fifteen (83%) of 18 and 15 (83%) of 18 patients had improved myoclonus and sedation after hydration versus eight (47%) of 17 and five (33%) of 15 patients after placebo (P = .035 and P = .005, respectively). There were no significant differences of improvement in hallucinations or fatigue between groups. When blinded to treatment, patients (17 [63%] of 77) and investigators (20 [74%] of 27) perceived hydration as effective compared with placebo in nine (41%) of 22 patients (P = .78) and 12 (54%) of 22 investigators (P = .15), respectively. The intensity of pain and swelling at the injection site were not significantly different between groups. CONCLUSION: Parenteral hydration decreased symptoms of dehydration in terminally ill cancer patients who had decreased fluid intake. Hydration was well tolerated, and a placebo effect was observed. Studies with larger samples and a longer follow-up period are justified.

The Edmonton Symptom Assessment System as a screening tool for depression and anxiety.

PURPOSE: Mood disorders are among the most important psychiatric problems in patients with cancer. However, they are frequently underdiagnosed and therefore undertreated. This may lead to difficulties with symptom control, social withdrawal, and poor quality of life. This study was conducted to evaluate the screening performance of the Edmonton Symptom Assessment System (ESAS) for depression and anxiety, compared to Hospital Anxiety and Depression Scale (HADS). METHODS: We retrospectively reviewed and analyzed ESAS and HADS data collected from three previous clinical trials conducted by our group. The diagnosis of depression and/or anxiety, and moderate/severe depression and/or anxiety made when patients scored 8 or more, and 11 or more in HADS questionnaire, respectively. The sensitivity, specificity, positive, and negative predictive values for ESAS were calculated. RESULTS: Of 216 patients analyzed, the median (range) score for depression was 2 (0-10) and anxiety 3 (0-10) using ESAS, and 6 (0-16) and 7 (0-19) using HADS, respectively. A cut off of 2 out of 10 or more in the ESAS gave a sensitivity of 77% and 83% with a specificity of 55% and 47% for depression and moderate/severe depression, respectively. A cutoff of 2 out of 10 or more in the ESAS gave a sensitivity of 86% and 97%, and a specificity of 56% and 43% for anxiety and moderate/severe anxiety, respectively. CONCLUSION: Our data suggest that the ideal cutoff point of ESAS for the screening of depression and anxiety in palliative care is 2 out of 10 or more. More research is needed to define the ideal cutoff point for screening of severe depression and anxiety.

Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report.

PURPOSE: To assess the effects of patient-controlled methylphenidate for cancer-related fatigue. PATIENTS AND METHODS: In this prospective open study, 31 patients with advanced cancer and fatigue who scored >/= 4 on a scale of 0 to 10 received methylphenidate 5 mg by mouth every 2 hours as needed for 7 days (maximum, 20 mg/d). Multiple symptoms were assessed daily; the primary end point, fatigue, was measured using the 0 to 10 scale, and the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F) was performed at baseline, day 7, and day 28. RESULTS: The following mean (+/- standard deviation) scores for 30 assessable patients improved significantly between baseline and day 7: fatigue (0 to 10 scale), 7.2 +/- 1.6 v 3.0 +/- 1.9 (P <.001); overall well-being (0 to 10 scale), 4.5 +/- 2.2 v 2.8 +/- 2.1 (P <.001); fatigue (FACIT-F) subscore, 17.5 +/- 11.3 v 34.7 +/- 10.0 (P <.001); functional well-being, 14.4 +/- 5.9 v 18.3 +/- 6.6 (P <.001); and physical well-being, 13.5 +/- 6.4 v 21.4 +/- 5.0 (P <.001). Anxiety, appetite, pain, nausea, depression, and drowsiness all improved significantly (P <.05). All patients took afternoon or evening doses, and 28 patients (93%) took three or more doses daily. All patients chose to continue taking methylphenidate after 7 days of treatment. No serious side effects were reported. CONCLUSION: These preliminary results suggest that patient-controlled methylphenidate administration rapidly improved fatigue and other symptoms. Randomized controlled trials are justified.

Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study.

PURPOSE: To determine whether high doses of fish oil, administered over 2 weeks, improve symptoms in patients with advanced cancer and decreased weight and appetite. PATIENTS AND METHODS: Sixty patients were randomly assigned to fish oil capsules or placebo. Appetite, tiredness, nausea, well-being, caloric intake, nutritional status, and function were prospectively assessed at days 1 and 14. RESULTS: The baseline weight loss was 16 +/- 11 and 16 +/- 8 kg in the fish oil (n = 30) and placebo (n = 30) group respectively, whereas the baseline appetite (0 mm = best and 10 mm = worst) was 58 +/- 24 mm and 67 +/- 19 mm, respectively (P = not significant). The mean daily dose was 10 +/- 4 (fish oil group) and 9 +/- 3 (placebo group) capsules, which provided 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid in the fish oil group. No significant differences in symptomatic or nutritional parameters were found (P <.05), and there was no correlation between changes in different variables between days 1 and 14 and the fish oil doses. Finally, the majority of the patients were not able to swallow more than 10 fish oil capsules per day, mainly because of burping and aftertaste. CONCLUSION: Fish oil did not significantly influence appetite, tiredness, nausea, well-being, caloric intake, nutritional status, or function after 2 weeks compared with placebo in patients with advanced cancer and loss of both weight and appetite.

Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study.

PURPOSE: To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. PATIENTS AND METHODS: Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks. RESULTS: A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P =.019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. CONCLUSION: Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain.

Somatic symptoms in patients with chronic non-cancer-related and cancer-related pain.

This study describes and compares patients' reports of somatic symptoms and physicians' ratings of the same symptoms in patients with chronic non-cancer-related and cancer-related pain. Ninety-seven patients with chronic non-cancer-related pain and 100 patients with chronic cancer-related pain reported somatic symptoms using a newly developed checklist of somatic symptoms. Patients also completed the Brief Symptom Inventory-18, Courtland Emotional Control Inventory, Catastrophizing scale, two items from the Coping Strategies Questionnaire (one about efficacy to control and another about ability to decrease pain), and a numeric rating of average pain. After they completed medical histories and physical examinations on patients, physicians rated the degree to which the patients' reported somatic symptoms on the checklist were medically unexplainable. Over 80% of patients in both groups reported somatic symptoms that their physicians rated as not fully explainable. Strong associations existed between patient-reported somatic symptoms and negative mood states. For the majority of patients, results supported a concept of combined illness- and affect-related pathology rather than one of pure somatoform disorder. Assessing patients' reports of somatic symptoms and negative mood states and incorporating physicians' ratings of level of medically unexplainable somatic symptoms were useful for distinguishing these diagnoses.

Nebulized versus subcutaneous morphine for patients with cancer dyspnea: a preliminary study.

This study compared the effects of nebulized versus subcutaneous morphine on the intensity of dyspnea in cancer patients. Patients with a resting dyspnea intensity > or =3 on a 0-10 scale (0=no dyspnea, 10=worst possible dyspnea) who received regular oral or parenteral opioids were included. On day 1, patients received either subcutaneous (SC) morphine plus nebulized placebo or nebulized morphine plus SC placebo. On day 2, a crossover was made. Dyspnea intensity, side effects, and blinded preference of treatment were assessed. Eleven patients completed the study. Dyspnea decreased from a median of 5 (range, 3-8) to 3 (range, 0-7) after SC morphine (P=0.025) and from 4 (range, 3-9) to 2 (range, 0-9) after nebulized morphine (P=0.007). There was no significant difference in dyspnea intensity between nebulized and subcutaneous morphine at 60 minutes. Unfortunately, due to limited sample size, there was insufficient power to rule out a significant difference between both routes of administration. Nebulized morphine offered dyspnea relief similar to that of SC morphine. Larger randomized controlled trials in patients with both continuous dyspnea and earlier stages of dyspnea are justified.

Impact of physician sitting versus standing during inpatient oncology consultations: patients' preference and perception of compassion and duration. A randomized controlled trial.

The purpose of this study was to determine the impact of physician sitting versus standing on the patient's preference of physician communication style, and perception of compassion and consult duration. Sixty-nine patients were randomized to watch one of two videos in which the physician was standing and then sitting (video A) or sitting and then standing (video B) during an inpatient consultation. Both video sequences lasted 9.5 minutes. Thirty-five patients (51%) blindly preferred the sitting physician, 16 (23%) preferred the standing, and 18 (26%) had no preference. Patients perceived that their preferred physician was more compassionate and spent more time with the patient when compared with the other physician. There was a strong period effect favoring the second sequence within the video. The patients blinded choice of preference (P = 0.003), perception of compassion (P = 0.0016), and other attributes favored the second sequence seen in the video. The significant period effect suggests that patients prefer the second option presented, notwithstanding a stated preference for a sitting posture (55/68, 81%). Physicians should ask patients for their preference regarding physician sitting or standing as a way to enhance communication.

Subcutaneous administration of cefepime.

Management of symptomatic infections can aid in palliation. We investigated the pharmacokinetics and tolerability of cefepime given as a subcutaneous infusion. This novel route of administration is proposed as an alternative to intravenous and intramuscular administration for patients treated outside an institutional setting, such as home hospice. Ten healthy adult volunteers received a single dose of 1g cefepime infused subcutaneously over 30 minutes. Serial serum samples (0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours) were obtained after the end of infusion, and cefepime concentrations were determined by high performance liquid chromatography (HPLC). All serum concentration profiles were modeled by a population pharmacokinetic analysis using the Non-Parametric Adaptive Grid (NPAG) program. Acceptability of administration was evaluated using subjective sensation grading, observation of the subcutaneous site, and a final global evaluation. The mean (median) Cmax, beta-t1/2, AUC0-oo and total clearance were found to be 36.1 (30.9) mg/L, 2.34 (2.56) hours, 134.8 (125.3) h*mg/L, and 7.42 (7.98) L/h, respectively. All infusions were completed without difficulty or discomfort. No drug side effects occurred. The global acceptability was "strongly agreeable" with all the subjects. Subcutaneous infusion of cefepime appeared to result in a pharmacokinetic profile similar to that of an intramuscular injection. Our evaluations showed excellent tolerability and acceptability. These favorable results warrant further clinical evaluation.

The association between anemia and fatigue in patients with advanced cancer receiving palliative care.

BACKGROUND: Fatigue has been reported to be associated with anemia in patients receiving cancer treatment. Treatment of anemia such as erythropoietin has been reported to decrease fatigue in these patients. OBJECTIVE: To investigate the correlation between anemia and fatigue intensity in patients with advanced cancer receiving palliative care. METHODS: We reviewed medical charts of 177 consecutive outpatients seen by our palliative care specialists. Information of fatigue intensity and hemoglobin level was collected. RESULTS: Among 147 (83%) evaluable patients, the median hemoglobin level was 11.6 g/dL (range, 7.5-16.1). Eighty-two (56%) patients had a hemoglobin level 12 g/dL or less, whereas 125 (85%) had 10 g/dL or more. The median fatigue score in patients with a hemoglobin level 10 g/dL or more and 10 g/dL or less was 6 (range, 4-8) and 7 (range, 5-8), respectively (p = 0.048). The median fatigue score in patients with a hemoglobin level 12 g/dL or more and 12 g/dL or less was 6 (range, 4-7) and 6 (range, 4-8), respectively (p > 0.5). Spearman's rank correlation coefficient showed a significant association only between the hemoglobin level and the albumin level (r = 0.52, p < 0.0001). Hemoglobin level did not show a significant correlation with fatigue although there was a trend (p = 0.09). In a multivariate regression analysis of the intensity of fatigue and other clinical variables, three variables remained significant in the reverse elimination analysis: depression (p = 0.0067), albumin level (p = 0.0079), and sensation of well-being (p = 0.0569). The overall explained variance for this model was 0.22. CONCLUSION: Our findings suggest that anemia is not one of the major contributors to fatigue in patients with cancer receiving palliative care.

Interval between palliative care referral and death among patients treated at a comprehensive cancer center.

In recent years, patients with advanced cancer are referred more frequently to palliative care programs. However, the referrals usually occur relatively late for the management of severe physical and psychological distress. The purpose of this retrospective study was to investigate the interval between palliative care referral and death in patients with advanced cancer. We reviewed charts of 240 consecutive patients with advanced cancer referred to the palliative care program at M.D. Anderson Cancer Center between September and December 2003. Demographics, as well as dates of cancer diagnosis, advanced disease diagnosis, palliative care referral, and death were determined. The median age was 61 years old, 173 were male, 304 patients had solid tumors, and 26 had hematologic malignancies. The median time intervals between the diagnosis of the primary cancer and death, diagnosis of advanced disease and death, advanced disease and palliative care referral, and palliative care referral and death were 33.0 months (95% confidence interval [CI]: 25.8-41.9), 9.4 months (95% CI: 7.9-11.1), 5.6 months (95% CI: 4.3-7.7), and 1.9 months (95% CI: 1.6-2.2), respectively. The patients' median time interval from advanced cancer diagnosis to death and from palliative care referral to death was shorter in patients with hematologic malignancies than in those with sold tumors (p = 0.018 and p < 0.001, respectively). Median time interval between palliative care referral and death was longer for patients less than 65 year old than those 65 years old or more (p = 0.03). Our results should help palliative care and oncology programs at comprehensive cancer centers plan how to develop joint programs for patient care.

Bowel and bladder continence, wound healing, and functional outcomes in patients who underwent sacrectomy.

OBJECT: Total or partial sacrectomy is a rare procedure in patients with locally invasive tumors involving the sacrum; it may be associated with functional loss, such as bowel and bladder dysfunction and gait abnormality. In this study the authors examined functional outcome following sacrectomy. METHODS: The authors reviewed the charts of 50 consecutive patients who had undergone sacrectomy between July 1993 and August 2002. There were 23 male and 27 female patients whose mean age was 46 years (range 13-86 years). Twelve patients with rectal cancer underwent a separate analysis. The patients without rectal cancer were divided into two groups: those who had undergone colostomy for bowel diversion (Group 1, six cases), and those who had not (Group 2, 32 cases). In Group 1 patients the median hospital length of stay (LOS) was 48.5 days (the 25th% and 75th percentiles are 26 and 58, respectively), and in Group 2 patients the median LOS was 18.5 days (the 25th and 75th percentiles are 8 and 41, respectively; p = 0.14). In Group 2 (non-rectal cancer without colostomy), LOS was greater in patients in whom a myocutaneous flap was used compared with those in whom no flap was used (36 days compared with 8.5 days, respectively; p = 0.0012); in patients with bowel incontinence the median LOS was significantly longer than that in patients with bowel continence (39 days compared with 8 days, respectively; p = 0.0026). The incidence of bowel incontinence in Group 2 was closely related to the integrity of the S-3 nerve root (p = 0.05). CONCLUSIONS: Awareness of the association between S-3 nerve root resection and bowel and bladder incontinence may help surgeons' decision-making process.

Clinical characteristics and outcome of bone-only metastasis in inflammatory and noninflammatory breast cancers.

BACKGROUND: Inflammatory breast cancer is a rare and aggressive presentation of breast cancer. Bone is a common metastatic site in breast cancer, and bone-only metastatic disease is clinically considered to have a better prognosis than visceral metastasis. However, bone-only metastasis in IBC (bone-only IBC) has not been compared with bone-only metastasis in non-IBC (bone-only non-IBC) in terms of clinical features and outcome. Because of the intrinsically aggressive nature of IBC, we hypothesized that bone-only IBC has a poorer prognosis than does bone-only non-IBC. PATIENTS AND METHODS: We retrospectively identified patients with stage III primary diagnosed breast cancer who, between January 1997 and December 2012, had a first recurrence located only in the bone. Among the 197 patients that we defined as a study cohort, 50 patients had IBC and 147 patients had non-IBC. Progression-free survival (PFS) and overall survival (OS) from the date of recurrence were estimated using the Kaplan-Meier method, and patient characteristic groups were compared using the log-rank test. RESULTS: OS did not differ significantly between the 2 groups (P = .2467), but a shorter PFS was seen in patients with bone-only IBC than in patients with bone-only non-IBC (P = .0357). Among patients with estrogen receptor (ER)-positive disease, a much shorter PFS was seen in bone-only IBC than in bone-only non-IBC (P = .0159). CONCLUSION: Bone-only IBC has a poorer prognosis than does bone-only non-IBC, particularly in those with ER-positive tumors. We might need to consider more aggressive intervention (e.g., chemotherapy) for IBC patients with ER-positive bone-only metastatic disease.