Pre-treatment neutrophil/lymphocyte ratio and platelet/lymphocyte ratio are prognostic of progression in early stage classical Hodgkin lymphoma.

To determine whether pre-treatment neutrophil/lymphocyte (NLR) or platelet/lymphocyte ratios (PLR) are predictive for progression in early-stage classical Hodgkin lymphoma (cHL), we derived NLR and PLR values for 338 stage I/II cHL patients and appropriate cut-off point values to define progression. Two-year freedom from progression (FFP) for patients with NLR ≥6·4 was 82·2% vs. 95·7% with NLR <6·4 (P < 0·001). Similarly, 2-year FFP was 84·3% for patients with PLR ≥266·2 vs. 96·1% with PLR <266·2 (P = 0·003). On univariate analysis, both NLR and PLR were significantly associated with worse FFP (P = 0·001). On multivariate analysis, PLR remained a significant, independent prognostic factor (P < 0·001).

Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases.

OBJECTIVES: To identify the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) treated with either pazopanib or sunitinib and assess whether PM is an independent prognostic variable in the current therapeutic environment. PATIENTS AND METHODS: A retrospective review of patients with mRCC in an outpatient clinic was carried out for the period January 2006 to November 2011. Patient characteristics, including demographics, laboratory data and outcomes, were analysed. Baseline characteristics were compared using chi-squared and t-tests and overall survival (OS) and cancer-specific survival (CSS) rates were estimated using Kaplan-Meier methods. Predictors of OS were analysed using Cox regression. RESULTS: A total of 228 patients were reviewed, of whom 44 (19.3%) had PM and 184 (81.7%) had metastases to sites other than the pancreas. The distribution of baseline characteristics was equal in both groups, with the exception of a higher incidence of previous nephrectomy, diabetes and number of metastatic sites in the PM group. Four patients had isolated PM, but the majority of patients (68%) with PM had at least three different organ sites of metastases, as compared with 29% in patients without PM (P < 0.01). The distribution of organ sites of metastases was similar, excluding the pancreas, in those with and those without PM (P > 0.05). The median OS was 39 months (95% confidence interval [CI] 24-57, hazard ratio 0.66, 95% CI 0.42-0.94; P = 0.02) for patients with PM, compared with 26 months (95% CI 21-31) for patients without PM (P < 0.01). CSS was 42 months (95% CI 30-57) in the PM group and 27 months (95% CI 22-33) in the control group (P = 0.05). CONCLUSIONS: Despite a higher number of affected organ sites in the PM cohort, mRCC behaviour in this cohort appears to be more indolent, as demonstrated by a higher median OS. These findings suggest that host or tumour features associated with PM may represent a less aggressive tumour phenotype.

Proteinuria with first-line therapy of metastatic renal cell cancer.

BACKGROUND: Vascular endothelial growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, and tyrosine kinase inhibitors are approved for metastatic renal cell cancer. Proteinuria can occur, but there is limited data regarding the incidence, monitoring, and management in metastatic renal cell cancer patients. OBJECTIVE: Our primary objective was to describe the incidence and severity of proteinuria in metastatic renal cell cancer patients treated in the first-line setting with pazopanib, bevacizumab, or everolimus. METHODS: We conducted a retrospective review of patients with metastatic renal cell cancer enrolled from January 2011-April 2013 in a phase II trial. Baseline and toxicity data were extracted from the electronic medical record. Descriptive statistics were used. RESULTS: In all, 129 patients were eligible for analysis. The overall incidence of proteinuria was 81%, with most events being Grade 1 or 2. The incidence of proteinuria was 80% (n = 35) for pazopanib, 64% (n = 25) for bevacizumab, and 96% (n = 44) for everolimus. At peak proteinuria, 80% (n = 28), 64% (n = 16), and 80% (n = 35) of patients on pazopanib, bevacizumab, and everolimus, respectively, were managed with continued monitoring at the same dose. The overall incidence of Grades 3 and 4 events was 24% (n = 6) and found in the bevacizumab group. CONCLUSION: A high incidence of proteinuria with minor severity within each class was demonstrated. It may be reasonable to continue therapy at the same dose for Grade 1 or 2 proteinuria. Treatment modification or discontinuation of therapy may be warranted with Grade 3 or 4 proteinuria.

Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules.

PURPOSE: We identified sunitinib alternative schedules that maintained dose intensity while decreasing adverse events in patients with metastatic renal cell cancer. We also determined the impact of alternative schedules on clinical outcomes. MATERIALS AND METHODS: We retrospectively reviewed the records of patients 18 years old or older with clear cell metastatic renal cell cancer who received first line sunitinib between January 26, 2006 and March 1, 2011 at our major comprehensive cancer center. A subset of patients was switched at the first intolerable adverse event from the traditional schedule of 28 days on and 14 days off to a schedule of 14 days on and 7 days off or other alternative schedules. A control group underwent standard dose reduction. We estimated progression-free and overall survival by the Kaplan-Meier method. Predictors of progression-free and overall survival were analyzed using Cox regression. RESULTS: A total of 187 patients were included in analysis, of whom 87% were on the traditional schedule at baseline. During treatment 53% of patients continued on the traditional schedule and 47% began or were transitioned to alternative schedules. Baseline characteristics were similar. Adverse events prompting schedule modification included fatigue in 64% of cases, hand-foot syndrome in 38% and diarrhea in 32%. Median time to alternative schedules was 5.6 months. Median overall survival was 17.7 months (95% CI 10.8-22.2) on the traditional schedule compared to 33.0 months (95% CI 29.3-not estimable) on alternative schedules (p <0.0001). On multivariable analysis poor Eastern Cooperative Oncology Group (ECOG) performance status, increased lactate dehydrogenase, decreased albumin, unfavorable Heng criteria and the traditional schedule were associated with decreased overall survival (p <0.05). CONCLUSIONS: Sunitinib administered on alternative schedules may mitigate adverse events while achieving outcomes comparable to those of the traditional schedule in patients with metastatic renal cell cancer. Prospective investigations of alternate dosing schemas are warranted.

Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes.

OBJECTIVE: To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Retrospective review of 310 patients with mRCC who received temsirolimus and/or everolimus between June 2007 and October 2010. Clinical correlations were made with serial radiological imaging. Fisher's exact, Wilcoxon rank-sum, and logistic regression analyses were used to evaluate the association of NIP with demographic or clinical factors. Log-rank and Cox proportional hazards regression analyses were used for the time-to-event analysis. RESULTS: NIP occurred in 6% of temsirolimus-treated and 23% of everolimus-treated patients. Symptoms included cough, dyspnoea, and fever (median of two and three symptoms per patient, respectively). The median National Cancer Institute Common Toxicity Criteria for Adverse Events pneumonitis grade was 2 for both groups. Older age and everolimus treatment were predictive of NIP. Patients who developed NIP had a significantly longer time on treatment (median 4.1 vs 2 months) and overall survival (OS) (median 15.4 vs 7.4 months). NIP was a predictor of improved OS by multivariate analysis. CONCLUSIONS: There was an increased incidence of NIP in everolimus-treated patients. Improved OS in patients who developed NIP is an intriguing finding and should be further investigated. Given the incidence, morbidity, and outcomes seen in patients on everolimus who develop NIP, management should include proactive monitoring and treatment of NIP with the goal of preserving mTOR inhibitor therapy.

Treatment of metastatic renal carcinoma patients with the combination of gemcitabine, capecitabine and bevacizumab at a tertiary cancer centre.

OBJECTIVE: • To investigate the effect of combining gemcitabine plus capecitabine (GX) with bevacizumab (A) in patients with metastatic RCC previously treated with cytokines and targeted agents. METHODS: • The combination of GX + A was evaluated in patients with metastatic RCC using institutional databases. • Data included demographics, previous therapies, number of metastatic sites, Memorial Sloan-Kettering Cancer Center risk stratification variables, and previous nephrectomy status. • Descriptive statistics and survival analysis were employed for data analysis. RESULTS: • Between January 2005 and October 2008, 28 patients were identified. Mean age was 55.7 years. Fifteen (53.57%) patients had been given tyrosine kinase inhibitor (TKI) previously. Nine (32.14%) patients had clear cell histology, 10 (35.71%) patients had sarcomatoid features on histopathology, and 19 patients (67.86%) had a prior nephrectomy. • Initial treatment consisted of G (mean dose 786.07 mg/m²) every 2 weeks, X (mean dose 2.73 g/day), and A (mean dose 10 mg/kg) every 2 weeks. Median progression-free survival (PFS) was 5.9 months and the median overall survival (OS) was 10.4 months. • In patients with previous TKI therapy, median PFS was 6.2 months and median OS was 11.7 months. • In patients with sarcomatoid features, median PFS was 3.9 months and OS was 9.0 months. • Three patients discontinued one or more of the drugs because of adverse reactions. CONCLUSIONS: • The combination of GX + A shows potential efficacy and acceptable tolerability in patients with intermediate and poor prognosis metastatic RCC. • Based on these observations, a phase II trial is now underway assessing this combination in patients with sarcomatoid RCC.

Rhabdomyolysis in a Prostate Cancer Patient Taking Ketoconazole and Simvastatin: Case Report and Review of the Literature.

OBJECTIVE: To report a case of severe rhabdomyolysis resulting in acute renal failure caused by an interaction between ketoconazole and simvastatin in a patient with prostate cancer. CASE SUMMARY: A 64-year-old man who received ketoconazole for prostate cancer, along with simvastatin and fenofibrate for dyslipidemia, presented to our ambulatory clinic with complaints of blood in his urine and weakness following an increase in his ketoconazole dose. Two days after presentation, the patient was admitted with rhabdomyolysis and acute renal failure, as evidenced by elevated serum creatine kinase (>32,000 IU/L), serum myoglobin (20.6 ng/mL), and serum creatinine (4.2 mg/dL) as well as abnormal bone scintigraphy findings. Ketoconazole, fenofibrate, and simvastatin were discontinued. Renal function did not normalize with hydration, and intermittent hemodialysis was initiated; 10 days of hemodialysis resulted in normalization of electrolytes and creatine kinase. Symptom improvement and normalization of laboratory parameters were observed after prolonged hospitalization (24 days). DISCUSSION: Prostate cancer is the most common malignancy among men in the US. Androgen deprivation therapy is the standard initial treatment for biochemical recurrence or metastatic disease. Most patients experience progression to a castrate-resistant disease state, requiring the use of additional therapies. Ketoconazole is considered a secondary hormonal treatment option. We describe an interaction in a patient with prostate cancer between a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and ketoconazole resulting in rhabdomyolysis, requiring hemodialysis. An objective causality assessment using the Horn Drug Interaction Probability Scale revealed that the adverse drug reaction was a possible result of the interaction. CONCLUSIONS: The temporal fashion in which the episode occurred suggests that a possible simvastatin-ketoconazole interaction precipitated rhabdomyolysis in this patient. The use of ketoconazole for castrate-resistant prostate cancer can lead to drug-drug interactions in patients taking simvastatin or other HMG-CoA reductase inhibitors. Clinicians should be aware of this severe adverse event and take steps to minimize its occurrence.

Safety of Same-day Pegfilgrastim Administration in Metastatic Castration-resistant Prostate Cancer Treated With Cabazitaxel With or Without Carboplatin.

INTRODUCTION: Although myeloid growth factors are commonly used to treat metastatic castration-resistant prostate cancer (mCRPC), the optimal timing of administration has not been well studied. We assessed the effects of same-day pegfilgrastim, a neutrophil stimulator, after cabazitaxel treatment with or without carboplatin in patients with mCRPC. We also evaluated the frequency of urinary tract inflammation during treatment. PATIENTS AND METHODS: Between September 2010 and September 2014, 151 consecutive patients with mCRPC underwent cabazitaxel treatment with or without the addition of carboplatin at a single institution. We assessed absolute neutrophil count recovery, incidence of neutropenia, neutropenic fever, antibiotic usage, treatment delays or discontinuation, dose reduction, and hospitalization with pegfilgrastim administration. Radiologists blinded to therapy reviewed computed tomography scans to detect urinary tract inflammation. RESULTS: The median patient age was 69 years (range, 41-88 years); 78% of patients were white, and 54% had a Gleason score ≥ 9. Median overall survival was 9 months (95% confidence interval, 8-11 months). One patient (< 1%) had neutropenia; 38 patients (25%) had infection. During cycle 1, a significantly higher proportion of patients receiving pegfilgrastim after 24 hours developed infection than did those receiving pegfilgrastim the same day (26% vs. 6%; P = .01). CONCLUSION: Same-day pegfilgrastim administration after cabazitaxel treatment with or without carboplatin in patients with mCRPC is feasible. The urinary tract inflammation rate (21%) was higher than that reported anecdotally. Results need to be prospectively validated.

Outcomes of Patients With Metastatic Renal Cell Carcinoma and Bone Metastases in the Targeted Therapy Era.

BACKGROUND: Bone metastases (BMs) occur commonly in patients with metastatic renal cell carcinoma (mRCC). Tyrosine kinase inhibitors (TKIs) have improved the outcomes for patients with mRCC. However, data on the outcomes of mRCC patients with BMs treated with TKIs are limited. We describe the outcomes of patients with BMs treated with TKI therapy and compare them with the outcomes from a pre-TKI group. PATIENTS AND METHODS: Using an institutional tumor registry, a retrospective review of patients with mRCC from 2002 to 2003 and 2006 to 2007 was performed. The baseline characteristics were analyzed, and overall survival (OS) was estimated using the Kaplan-Meier method. The predictors of OS were analyzed using Cox regression analysis. RESULTS: The data from 375 patients were reviewed. Of these patients, 188 (50%) started treatment with TKIs and 187 (50%) had started treatment in the pre-TKI era. The distribution of patient characteristics was similar. The sites of organ metastases were equally distributed, including BMs in 48% of the patients in each cohort. The median OS for the patients treated in the TKI era was 22 months (95% confidence interval [CI], 17-25 months) compared with 14 months (95% CI, 10-19 months; P < .01) for the historical controls. A subset analysis of patients with BM in the TKI era demonstrated a median OS of 24 months (95% CI, 17-28 months) compared with 18 months (95% CI, 10-21 months; P < .01) in pre-TKI era. The predictors of shorter OS were a higher Memorial Sloan Kettering Cancer Center score; liver, lung, and brain metastases; and multiple sites of BMs (hazard ratio, 1.38; 95% CI, 1.02-1.91; P = .04). The rate of new BM development was the same in the pre- and post-TKI era. CONCLUSION: The rate of BM development was the same in the pre- and post-TKI era. The management of BMs in patients with mRCC remains challenging.

High-density and very-low-density lipoprotein have opposing roles in regulating tumor-initiating cells and sensitivity to radiation in inflammatory breast cancer.

PURPOSE: We previously demonstrated that cholesterol-lowering agents regulate radiation sensitivity of inflammatory breast cancer (IBC) cell lines in vitro and are associated with less radiation resistance among IBC patients who undergo postmastectomy radiation. We hypothesized that decreasing IBC cellular cholesterol induced by treatment with lipoproteins would increase radiation sensitivity. Here, we examined the impact of specific transporters of cholesterol (ie lipoproteins) on the responses of IBC cells to self-renewal and to radiation in vitro and on clinical outcomes in IBC patients. METHODS AND MATERIALS: Two patient-derived IBC cell lines, SUM 149 and KPL4, were incubated with low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), or high-density lipoproteins (HDL) for 24 hours prior to irradiation (0-6 Gy) and mammosphere formation assay. Cholesterol panels were examined in a cohort of patients with primary IBC diagnosed between 1995 and 2011 at MD Anderson Cancer Center. Lipoprotein levels were then correlated to patient outcome, using the log rank statistical model, and examined in multivariate analysis using Cox regression. RESULTS: VLDL increased and HDL decreased mammosphere formation compared to untreated SUM 149 and KPL4 cells. Survival curves showed enhancement of survival in both of the IBC cell lines when pretreated with VLDL and, conversely, radiation sensitization in all cell lines when pretreated with HDL. In IBC patients, higher VLDL values (>30 mg/dL) predicted a lower 5-year overall survival rate than normal values (hazard ratio [HR] = 1.9 [95% confidence interval [CI]: 1.05-3.45], P=.035). Lower-than-normal patient HDL values (<60 mg/dL) predicted a lower 5-year overall survival rate than values higher than 60 mg/dL (HR = 3.21 [95% CI: 1.25-8.27], P=.015). CONCLUSIONS: This study discovered a relationship among the plasma levels of lipoproteins, overall patient response, and radiation resistance in IBC patients and IBC patient-derived cell lines. A more expansive study is needed to verify these observations.

Outcomes of patients with metastatic renal cell carcinoma and end-stage renal disease receiving dialysis and targeted therapies: a single institution experience.

INTRODUCTION: Limited data are available regarding patients with renal cell carcinoma and ESRD treated with TTs. The objective of this study was to explore the tolerability and safety of TT in patients with mRCC and ESRD. PATIENTS AND METHODS: We retrospectively identified patients with mRCC and ESRD treated at the University of Texas M.D. Anderson Cancer Center from 2002 to 2012. Patient characteristics including demographic, histology, treatment, and adverse events are reported. Duration of treatment (TOT) was determined from date of drug initiation to discontinuation. Overall survival (OS) was determined from initiation of TT to death. Statistics are descriptive. RESULTS: Fourteen patients were identified. Ten patients had clear-cell histology and 4 had papillary histology. The median number of TTs per patient was 3 (range, 1-4) with median TOT of 28 months for all TTs. Eighty-eight percent of all toxicities were Grade 1 to 2; no Grade 4 toxicities were noted. Treatment discontinuations included 3 patients treated with sorafenib due to hand-foot syndrome, intolerable fatigue, and squamous cell skin cancer development; 2 patients treated with pazopanib due to intolerable fatigue and increased transaminase levels; and 1 patient treated with everolimus due to pneumonitis. Eight patients died from progressive disease. Median OS from initiation of TT was 28.5 months and 35 months from time of diagnosis. CONCLUSION: Toxicities were mild to moderate and consistent with those reported in previous studies. TTs appear to be safe, well tolerated and produce antitumor response in patients with mRCC and ESRD receiving dialysis.

Cancer immunotherapy: sipuleucel-T and beyond.

In April 2010, sipuleucel-T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4(+) and CD8(+) T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T-cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor-associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel-T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte-macrophage colony-stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen-presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double-blind, placebo-controlled, phase III clinical trial, sipuleucel-T significantly improved median overall survival by 4.1 months in men with metastatic castration-resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel-T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer vaccines and immunotherapies for other tumor types are currently under investigation and in clinical trials. These immunotherapies were formulated to incorporate tumor-associated antigens aimed at stimulating effector T-cell responses or to block regulatory mechanisms that suppress the function of effector T cells. Additional studies will determine how these therapies can best improve clinical outcomes in patients with cancer.

Candida lusitaniae fungemia in cancer patients: risk factors for amphotericin B failure and outcome.

Candida lusitaniae, a Candida species frequently resistant to amphotericin B (AMB), is a rare cause of candidemia. The clinical significance of this in vitro resistant phenotype, the risk factors for, and the clinical presentation of C. lusitaniae fungemia in comparison with those of Candida albicans have not been completely characterized. We reviewed 13 consecutive cases of C. lusitaniae fungemia in cancer patients and compared them with 41 consecutive cases of C. albicans fungemia (1990-2004). The AMB mutational frequency and rate of fungicidal activity was compared between a bloodstream, AMB-susceptible C. lusitaniae isolate associated with clinical failure and reference C. albicans and Candida glabrata strains. In multivariate analysis, patients having C. lusitaniae fungemia were more likely to have neutropenia (p=0.001), stem cell transplantation (p=0.014) and to have received prior antifungals (p=0.04). Mutational frequencies at clinically-achievable AMB exposures were 8 x 10(5) for C. lusitaniae and <1 x 10(9) for C. albicans and C. glabrata reference strains. Compared to C. albicans and C. glabrata, AMB had much less fungicidal activity against C. lusitaniae in time-kill curve analysis. Clinically, C. lusitaniae fungemia was more frequently associated with stem cell transplant and neutropenia. C. lusitaniae, even originally susceptible to AMB, might be less amenable to AMB therapy.