Reliability and validity of PRO-CTCAE® daily reporting with a 24-hour recall period.

PURPOSE: The standard recall period for the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE®) is the past 7 days, but there are contexts where a 24-hour recall may be desirable. The purpose of this analysis was to investigate the reliability and validity of a subset of PRO-CTCAE items captured using a 24-hour recall. METHODS: 27 PRO-CTCAE items representing 14 symptomatic adverse events (AEs) were collected using both a 24-hour recall (24 h) and the standard 7 day recall (7d) in a sample of patients receiving active cancer treatment (n = 113). Using data captured with a PRO-CTCAE-24h on days 6 and 7, and 20 and 21, we computed intra-class correlation coefficients (ICC); an ICC ≥ 0.70 was interpreted as demonstrating high test-retest reliability. Correlations between PRO-CTCAE-24h items on day 7 and conceptually relevant EORTC QLQ-C30 domains were examined. In responsiveness analysis, patients were deemed changed if they had a one-point or greater change in the corresponding PRO-CTCAE-7d item (from week 0 to week 1). RESULTS: PRO-CTCAE-24h captured on two consecutive days demonstrated that 21 of 27 items (78%) had ICCs ≥ 0.70 (day 6/7 median ICC 0.76), (day 20/21 median ICC 0.84). Median correlation between attributes within a common AE was 0.75, and the median correlation between conceptually relevant EORTC QLQ-C30 domains and PRO-CTCAE-24 h items captured on day 7 was 0.44. In the analysis of responsiveness to change, the median standardized response mean (SRM) for patients with improvement was - 0.52 and that for patients with worsening was 0.71. CONCLUSION: A 24-hour recall period for PRO-CTCAE items has acceptable measurement properties and can inform day-to-day variations in symptomatic AEs when daily PRO-CTCAE administration is implemented in a clinical trial.

Optimizing dosing of oncology drugs.

The purpose of this article is to acknowledge the challenges in optimizing the dosing of oncology drugs and to propose potential approaches to address these challenges in order to optimize effectiveness, minimize toxicity, and promote adherence in patients. These approaches could provide better opportunities to understand the sources of variability in drug exposure and clinical outcomes during the development and premarketing evaluation of investigational new drugs.

Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions.

BACKGROUND: We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs). METHODS: Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered. RESULTS: All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6-65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR. CONCLUSION: Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.

BACKGROUND: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing. METHODS: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed. RESULTS: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation > or =4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months. CONCLUSION: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

Sentinel node biopsy for the detection of head and neck melanoma: a review.

Worldwide incidence of malignant melanoma is on the rise. Early detection of this malignancy is key to survival, and in the case of more advanced malignancy, early and effective detection of micrometastatic disease is crucial for staging and therapy. Because melanoma spreads primarily via lymphatic drainage patterns, effective methods for tracing these pathways are of paramount importance. The authors summarize the efficacy of blue dye, gamma probe, and lymphoscintigraphy detection methods, both individually and combined; the "missed disease" (or false-negative) rate; and the clinical discordance between expected and actual location of metastatic disease in head and neck melanoma. A clinical meta-analysis of current studies in head and neck melanoma was used to evaluate clinical data. A success rate of 95% to 100% for detection of sentinel lymph nodes can be achieved when blue dye, gamma probe, and lymphoscintigraphy techniques are combined. This is associated with a false-negative rate of 7.7% to 10.4%. With respect to intermediate-depth melanomas of the head and neck, a significant discordance exists between expected and actual lymphatic drainage patterns. This problem is best addressed using a combination of lymphoscintigraphy, blue dye, and gamma probe localization, which yields a success rate of 95% to 100% for detection of sentinel lymph nodes and a low false-negative rate of 7.7% to 10.4%. In the instance of a failed study, one in which sentinel nodes are not detected by the aforementioned methods, elective node dissection is the treatment modality of choice.

A phase I trial of carboxyamido-triazole and paclitaxel for relapsed solid tumors: potential efficacy of the combination and demonstration of pharmacokinetic interaction.

PURPOSE: Preclinical and clinical investigation of the combination of the antiangiogenesis/anti-invasion agent carboxyamido-triazole (CAI) administered with the cytotoxic agent paclitaxel (PAX). EXPERIMENTAL DESIGN: Colony-forming assays were used to test the activity of CAI plus PAX on A2780 human ovarian cancer. The sequence of CAI followed by PAX (CAI>Pax) was modeled in nude mice to test for potential additive toxicity. The Phase I clinical dose escalation schema tested p.o. administered CAI in PEG-400 (50-100 mg/m(2)) or micronized CAI (250 mg/m(2)) for 8 days followed by a 3-h infusion of PAX (110-250 mg/m(2)) every 21 days. Patients were assessed for toxicity, pharmacokinetics of CAI and PAX, and disease outcome. RESULTS: In preclinical studies, CAI>Pax was additive in A2780 human ovarian cancer cell lines when CAI (1 or 5 microM) preceded subtherapeutic doses of PAX. CAI did not reverse PAX resistance and collateral resistance to CAI was documented in PAX-resistant cells. CAI>PAX administration had no overt additive toxicity in nude mice. Thirty-nine patients were treated on a dose-escalation Phase I trial using daily oral CAI for 8 days followed by the PAX infusion. Pharmacokinetic analysis revealed that PAX caused an acute increase in circulating CAI concentrations in a dose-dependent fashion. No additive or cumulative toxicity was observed, and grade 3 nonhematological toxicity was rare. Three partial responses and two minor responses were observed. CONCLUSIONS: The sequential combination of CAI and PAX is well tolerated, and the activity observed suggests that further study of the combination is warranted.

A phase I study of anti-GD3 ganglioside monoclonal antibody R24 and recombinant human macrophage-colony stimulating factor in patients with metastatic melanoma.

BACKGROUND: Macrophages activated by macrophage-colony stimulating factor (M-CSF) are potent immune effector cells and can mediate both in vitro cytotoxicity and antitumor effects in vivo. A Phase I trial combining M-CSF with R24, a mouse monoclonal antibody against GD3 ganglioside that has been shown to localize to melanoma tumors, induce inflammation at tumor sites, and result in major tumor responses in some patients with melanoma was performed. METHODS: Nineteen patients with metastatic melanoma received a 14-day continuous intravenous infusion of 80 micrograms/kg/day of recombinant human M-CSF. R24 was administered daily by intravenous infusion on days 6-10 at doses of 1, 3, 10, 30, and 50 micrograms/m2/day. RESULTS: All patients developed pruritus and urticaria; 13 patients developed transient thrombocytopenia less than 100,000/mm3. The maximum tolerated dose was not reached. All patients developed a monocytosis characterized by increased expression of the antigen HLA-DR and decreased expression of CD14, a phenotype reported to represent a subpopulation of monocytes active in mediating antibody-directed cellular cytotoxicity. Other biologic effects of treatment included marked but transient decreases in total cholesterol, low density lipoprotein, and high density lipoprotein. Three patients experienced tumor regression in breast, liver, and lymph node metastases and received a second course of therapy. Six of the 19 patients, one of whom received no further therapy, survived more than 2 years and 4 of these patients remain alive 24 to 37 months after treatment. Of the six patients with liver metastases, three (50%) survived more than 2.5 years and one remains alive at 37+ months. CONCLUSIONS: Combination therapy with R24 and M-CSF resulted in both clinical and biologic effects that warrant further investigation of this combination.

CD16+ monocytes in patients with cancer: spontaneous elevation and pharmacologic induction by recombinant human macrophage colony-stimulating factor.

The small subset of circulating monocytes that express the maturation-associated CD16 antigen has recently been reported to be elevated in patients with bacterial sepsis. We now show that this novel CD16+ monocyte population is also spontaneously expanded in patients with cancer. We studied 14 patients with metastatic gastrointestinal carcinoma enrolled ina clinical trial of recombinant human macrophage colony-stimulating factor (rhMCSF) plus monoclonal antibody D612. We found that before any cytokine treatment, 12 of 14 patients constitutively displayed significant elevations in both the percentage and the absolute number of CD16+ monocytes, as compared with both normal subjects and ill patients with elevated monocyte counts but without malignancy. CD16+ monocytes accounted for 46% +/- 22% of total monocytes in the patients with cancer versus 5% +/- 3% for controls (P < .01). The increase was not attributable to infection or intercurrent illness and appeared to be associated with the underlying malignancy itself. A similar spontaneous elevation of CD16+ monocytes was observed in 35 of 44 additional patients diagnosed with a variety of other solid tumors. When patients with gastrointestinal carcinoma were treated with rhMCSF, there was a marked further increase in the percentage of CD16+ monocytes (to 83% +/- 11%), as well as in the absolute number of CD16+ cells and the level of CD16 antigen expression. In every case, the patients with cancer showed a greater CD16+ monocyte response than the maximal response obtained in normal volunteer subjects treated witha similar regimen of rhMCSF (n = 5, P < .001), suggesting that the presence of malignancy primed patients for enhanced responsiveness to rhMCSF. We hypothesize that spontaneous expansion of the CD16+ monocyte population may represent a novel biologic marker for a widespread and previously unsuspected host immune response to malignancy.

Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma.

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.

Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up.

PURPOSE: Three trials were conducted to define the efficacy and toxicity of interferon alfa-2a in the treatment of metastatic renal cell cancer. Univariate and multivariate analyses were performed to identify prognostic factors for survival. PATIENTS AND METHODS: Prospectively, 159 patients were treated with interferon alfa-2a. In the first trial, 42 patients received 50 x 10(6) U/m2 intramuscularly three times per week. In the second trial, 64 patients received gradually escalating doses of interferon alfa-2a from 3 to 36 x 10(6) U subcutaneously administered daily. The third trial was randomized; 25 patients received daily interferon alfa-2a alone and 28 were treated with daily interferon alfa-2a and 0.15 mg/kg vinblastine every 3 weeks. RESULTS: The overall response proportion was 10% (two complete and 14 partial responses). The median response duration was 12.2 months. The median survival duration was 11.4 months, with 3% of patients alive at 5 or more years. A univariate statistical analysis showed that a Karnofsky performance status > or = 80, prior nephrectomy, and interval from diagnosis to treatment of longer than 365 days were significant prognostic factors for survival. In a multivariate analysis, only prior nephrectomy and Karnofsky performance status > or = 80 were shown to be independent predictors of survival. CONCLUSION: Interferon alfa-2a had minimal antitumor activity in patients with advanced renal cell carcinoma and long-term survival was achieved in a small proportion of patients. The need for continued investigation and the identification of more effective therapy for advanced renal cell carcinoma is evident from the poor overall survival rate observed in these 159 patients. The investigation of new agents and of interferon alfa-2a in combination with other agents remains a priority.

[Clinical-laboratory parallels in crush syndrome]. / Kliniko-laboratornye paralleli pri sindrome dlitel'nogo sdavleniia.

Biochemical evaluation of 60 patients with crush syndrome developing after the Armenian earthquake demonstrated informative value of some parameters: total blood protein, aspartate and alanine aminotransferase, myoglobin and middle-mass molecules. An aggravation of the disease accompanied acute renal failure and concomitant injuries. The above parameters proved valuable criteria in diagnosis of the clinical alterations.

[Relation between the energetic and contractile functions of the myocardium]. / O vzaimosviazi énergeticheskoi i sokratitel'noi funktsii miokarda.

A comprehensive intraoperative examination of myocardial contractility and energy function in patients with acquired heart disease with predominant stenosis has enabled the significant correlations to be established between the complex of the functional indices of right ventricular myocardial and the levels of energy substrates in the myocardium of the left atrial auricular and coronary arteriovenous ATP difference. The magnitudes of changes were found in the functional parameters, which indicated myocardial energy deficiency.

Effects of 7,12-dimethylbenz(a)anthracene on rat mammary epithelial cell macromolecules: a time study.

The effects of 7,12-dimethylbenz[a]anthracene (DMBA) on levels of four mammary epithelial cell macromolecules were investigated at various times between 1 and 14 days after Sprague-Dawley virgin female rats were fed the carcinogen. Whereas the level of nuclear protein remained relatively constant throughout this period, comparison with normal controls revealed that significant reductions in nuclear RNA and cytosol protein levels occurred in cells from DMBA-treated animals 24 hours after carcinogen treatment; levels were lowest within the first 3 days. Cytosol protein and nuclear RNA values then increased progressively, reaching normal levels between 4 and 6 days; they were elevated 122% (+/-6 SD) and 41% (+/-5), respectively, above controls by the 14th day. DNA levels remained within normal limits up to the 4th day, after which they gradually increased to 36% (+/-5) above normal by the 14th day. All four macromolecules in neoplastic epithelial cells derived from three mammary adenocarcinomas approximately 135 days after DMBA was fed to rats showed increases similar to, though more pronounced than, those seen in mammary epithelial cells 14 days after carcinogen administration, which suggested that early changes in these macromolecules, especially in RNA and cytosol protein, may be related to DMBA mammary carcinogenesis. The data further suggested that malignant transformation of the epithelial cells may occur within the first 4-6 days, after which there appears to be a loss of normal synthetic control of nuclear DNA, RNA, and cytosol protein.