Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical activity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2-20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 x 10(3)/microliters (range 1.6-9.3) and the median absolute neutrophil (ANC) nadir was 2.0 x 10(3)/microliters (range 0.4-7.2). Thrombocytopenia - 100.0 x 10(3)/microliters was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0-245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemicitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.

PurposeBoth bevacizumab and sunitinib target the vascular endothelial growth factor pathway and demonstrate activity against advanced renal cell carcinoma (RCC). In this phase I study, the maximum-tolerated dose (MTD) and safety of sunitinib in combination with bevacizumab were examined in patients with advanced RCC.Patients and MethodsThree cohorts of three to six patients were treated with escalated doses of daily oral sunitinib (ie, 25 mg, 37.5 mg, 50 mg) for 4 weeks followed by a 2-week break and with fixed doses of bevacizumab (10 mg/kg) intravenously once every 2 weeks. Dose-limiting toxicities (DLTs) were assessed during the first cycle to determine the MTD, and an expanded cohort was treated to obtain additional safety information.ResultsOf 26 study participants, 25 received treatment at one of three dose levels. Grade 4 hemorrhage, identified as a DLT, occurred in one patient in each of cohorts 2 and 3. The MTD was determined to be sunitinib 50 mg/bevacizumab 10 mg/kg, but chronic therapy at this dose level frequently resulted in grades 3 to 4 hypertension and hematologic and vascular toxicities. Overall, 48% of patients discontinued treatment because of adverse events. One complete and 12 partial responses were observed, which provided an objective response rate of 52%.ConclusionIn this phase I trial of patients with metastatic RCC, the combination of sunitinib and bevacizumab caused a high degree of hypertension and vascular and hematologic toxicities at the highest dose level. We do not plan to pursue additional study of this regimen at these doses in patients with RCC.

Background and objectives Nephrotoxicity remains the dose-limiting side effect of cisplatin, an effective chemotherapeutic agent with applications across diverse tumor types. This study presents data on renal outcomes across multiple tumor types in 821 adults. We report on incidence of AKI, initial and long-term changes in eGFR after cisplatin, and relationships between cumulative dose, initial eGFR, age, sex, and long-term renal function.Design, setting, participants, & measurements This was a retrospective study of adult patients treated with cisplatin from January 1, 2000 to September 21, 2011 who had survived $5 years after initial dose. The Modification of Diet in Renal Disease equation was used to calculate eGFR. AKI was defined as an increase from the baseline creatinine of .25% within 30 days after the first cycle of cisplatin. Chi-squared tests were done to evaluate the relationships between categorical or ordinal variables; ANOVAs or t tests were used to evaluate continuous or categorical variables. Changes in eGFR over time were evaluated in a growth curve model.Results Mean follow-up was 6 years (25th and 75th percentiles, 4 and 9 years). AKI occurred in 31.5% of patients, with a median initial decline in eGFR of 10 ml/min per 1.73 m 2 (25th and 75th percentiles, 241.5 and 223.3 ml/min per 1.73 m 2 ). At any time point after the first cycle of cisplatin, ,3% of patients progressed to eGFR,29 ml/min per 1.73 m 2 , and none were known to be on dialysis. Age was associated with a higher risk for AKI after cisplatin. Compared with age ,25 years old, the odds ratios for AKI versus no AKI are 1.22 for .26-44 years old (95% confidence interval [95% CI], 0.60 to 2.4), 1.54 for .45-65 years old (95% CI, 0.78 to 3), and 2.96 for .66 years old (95% CI, 1.4 to 6.1). The lowest dose categories of cisplatin (#100 and 101-250 mg/m 2 ) are associated with increases in eGFR (P=0.06 and P=0.02, respectively) compared with the highest dose category (.701 mg/m 2 ).Conclusions This is the largest study of adult patients with cancer who received cisplatin for treatment across multiple tumor types. Most patients experience small but permanent declines in eGFR, but none progressed to ESRD requiring hemodialysis.

We report that patients treated with cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), occasionally develop a magnesium wasting syndrome with inappropriate urinary excretion. We first observed this phenomenon in a 34-year-old male patient with metastatic colorectal cancer who developed profound fatigue and symptomatic hypocalcemia and hypomagnesemia while on cetuximab plus irinotecan therapy. Other medications with the potential to cause magnesium wasting had not been administered. Intravenous magnesium supplementation was required for the duration of cetuximab therapy, but electrolyte abnormalities resolved after discontinuation of treatment. This case prompted review of serum chemistry reports for a consecutive case series of 154 colorectal cancer patients treated with cetuximab. Thirty-four patients (22%) had at least one serum magnesium measurement during cetuximab treatment, and six had grade 3 (< 0.9 mg/dL) and two had grade 4 (< 0.7 mg/dL) hypomagnesemia. Because EGFR is strongly expressed in the kidney, particularly in the ascending limb of the loop of Henle where 70% of filtered magnesium is reabsorbed, EGFR blockade may interfere with magnesium transport. Because symptoms may be rapidly ameliorated with supplementation, we suggest that, when fatigue or hypocalcemia is encountered during cetuximab therapy, serum magnesium level be measured and repleted as necessary.