Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292).

BACKGROUND: Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. PATIENTS AND METHODS: This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy. RESULTS: From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

Optical extinction efficiency measurements on fine and accumulation mode aerosol using single particle cavity ring-down spectroscopy.

A new experiment is presented for the measurement of single aerosol particle extinction efficiencies, Qext, combining cavity ring-down spectroscopy (CRDS, λ = 405 nm) with a Bessel beam trap (λ = 532 nm) in tandem with phase function (PF) measurements. This approach allows direct measurements of the changing optical cross sections of individual aerosol particles over indefinite time-frames facilitating some of the most comprehensive measurements of the optical properties of aerosol particles so far made. Using volatile 1,2,6-hexanetriol droplets, Qext is measured over a continuous radius range with the measured Qext envelope well described by fitted cavity standing wave (CSW) Mie simulations. These fits allow the refractive index at 405 nm to be determined. Measurements are also presented of Qext variation with RH for two hygroscopic aqueous inorganic systems ((NH4)2SO4 and NaNO3). For the PF and the CSW Mie simulations, the refractive index, nλ, is parameterised in terms of the particle radius. The radius and refractive index at 532 nm are determined from PFs, while the refractive index at 405 nm is determined by comparison of the measured Qext to CSW Mie simulations. The refractive indices determined at the shorter wavelength are larger than at the longer wavelength consistent with the expected dispersion behaviour. The measured values at 405 nm are compared to estimates from volume mixing and molar refraction mixing rules, with the latter giving superior agreement. In addition, the first single-particle Qext measurements for accumulation mode aerosol are presented for droplets with radii as small as ∼300 nm.

Deviations from plane-wave Mie scattering and precise retrieval of refractive index for a single spherical particle in an optical cavity.

The extinction cross-sections of individual, optically confined aerosol particles with radii of a micrometer or less can, in principle, be measured using cavity ring-down spectroscopy (CRDS). However, when the particle radius is comparable in magnitude to the wavelength of light stored in a high-finesse cavity, the phenomenological cross-section retrieved from a CRDS experiment depends on the location of the particle in the intracavity standing wave and differs from the Mie scattering cross-section for plane-wave irradiation. Using an evaporating 1,2,6-hexanetriol particle of initial radius ∼1.75 µm confined within the 4.5 µm diameter core of a Bessel beam, we demonstrate that the scatter in the retrieved extinction efficiency of a single particle is determined by its lateral motion, which spans a few wavelengths of the intracavity standing wave used for CRDS measurements. Fits of experimental measurements to Mie calculations, modified to account for the intracavity standing wave, allow precise retrieval of the refractive index of 1,2,6-hexanetriol particles (with relative humidity, RH < 10%) of 1.47824 ± 0.00072.

Measurements of the evaporation and hygroscopic response of single fine-mode aerosol particles using a Bessel beam optical trap.

A single horizontally-propagating zeroth order Bessel laser beam with a counter-propagating gas flow was used to confine single fine-mode aerosol particles over extended periods of time, during which process measurements were performed. Particle sizes were measured by the analysis of the angular variation of light scattered at 532 nm by a particle in the Bessel beam, using either a probe beam at 405 nm or 633 nm. The vapour pressures of glycerol and 1,2,6-hexanetriol particles were determined to be 7.5 ± 2.6 mPa and 0.20 ± 0.02 mPa respectively. The lower volatility of hexanetriol allowed better definition of the trapping environment relative humidity profile over the measurement time period, thus higher precision measurements were obtained compared to those for glycerol. The size evolution of a hexanetriol particle, as well as its refractive index at wavelengths 532 nm and 405 nm, were determined by modelling its position along the Bessel beam propagation length while collecting phase functions with the 405 nm probe beam. Measurements of the hygroscopic growth of sodium chloride and ammonium sulfate have been performed on particles as small as 350 nm in radius, with growth curves well described by widely used equilibrium state models. These are the smallest particles for which single-particle hygroscopicity has been measured and represent the first measurements of hygroscopicity on fine mode and near-accumulation mode aerosols, the size regimes bearing the most atmospheric relevance in terms of loading, light extinction and scattering. Finally, the technique is contrasted with other single particle and ensemble methods, and limitations are assessed.

Comparison of the accuracy of aerosol refractive index measurements from single particle and ensemble techniques.

The ability of two techniques, aerosol cavity ring down spectroscopy (A-CRDS) and optical tweezers, to retrieve the refractive index of atmospherically relevant aerosol was compared through analysis of supersaturated sodium nitrate at a range of relative humidities. Accumulation mode particles in the diameter range 300-600 nm were probed using A-CRDS, with optical tweezer measurements performed on coarse mode particles several micrometers in diameter. A correction for doubly charged particles was applied in the A-CRDS measurements. Both techniques were found to retrieve refractive indices in good agreement with previously published results from Tang and Munkelwitz, with a precision of ±0.0012 for the optical tweezers and ±0.02 for the A-CRDS technique. The coarse mode optical tweezer measurements agreed most closely with refractive index predictions made using a mass-weighted linear mixing rule. The uncertainty in the refractive index retrieved by the A-CRDS technique prevented discrimination between predictions using both mass-weighted and volume-weighted linear mixing rules. No efflorescence or kinetic limitations on water transport between the particle and the gas phase were observed at relative humidities down to 14%. The magnitude of the uncertainty in refractive index retrieved using the A-CRDS technique reflects the challenges in determining particle optical properties in the accumulation mode, where the extinction efficiency varies steeply with particle size.

Phase II Trial of Docetaxel and Carboplatin in Patients With Advanced Squamous Carcinoma of the Esophagus (E2298): A Trial of the Eastern Cooperative Oncology Group.

BACKGROUND: Occasional complete responses have been reported in patients with squamous-cell carcinoma of the esophagus treated with carboplatin, and the inferior outcomes seen in early studies might have been the result of underdosing using BSA calculations. Docetaxel was reported to have single-agent activity in squamous-cell carcinoma of the esophagus, with a 50% response rate in a pilot study performed in South Africa. Thus, ECOG investigated the potential role of combination carboplatin using AUC-based dosing and docetaxel in patients with squamous-cell carcinoma of the esophagus. PATIENTS AND METHODS: ECOG 2298 was a multicenter, international, phase II clinical study of docetaxel and carboplatin in patients with histologically confirmed, measurable squamous-cell carcinoma of the esophagus. Docetaxel 75 mg/m(2) was infused over 1 hour on day 1 of each cycle. The carboplatin dose was calculated to an AUC of 6 and infused over 15-30 minutes immediately after the docetaxel. The regimen was repeated every 3 weeks for a total of 6 cycles or until disease progression occurred or unacceptable toxicity developed. RESULTS: A total of 32 patients were accrued, mostly men (78%) with a median age of 64 (range, 41-86). Half the patients were black and half were white. Five patients were not evaluable due to protocol violations. Of the remaining 27 patients, one (3%) achieved a complete clinical response. Four others (13%) achieved partial responses. Thirteen (41%) had stable disease and 9 (28%) had progression of disease. Overall objective response rate was 15.6% (95% CI 5.9% to 36%). The most common grade 3 and 4 toxicities were leukopenia (25/32=78%) and neutropenia (27/32=84%). Most nonhematologic toxicities were infrequent and ≤ grade 3; however, two patients experienced grade 5 toxicities; one died of bowel obstruction and another died of infection with grade 4 neutropenia. CONCLUSIONS: The high toxicity and poor efficacy shown in this study suggest that the combination of carboplatin and docetaxel in squamous-cell carcinoma of the esophagus should not be investigated further. Newer agents need to be investigated in this malignancy.

A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3-times-daily regimen to treat patients with recurrent metastatic breast cancer.

BACKGROUND: A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. METHODS: Ninety-one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m(2), administered in 3 doses of 100 mg/m(2) each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival. RESULTS: Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug-related > or = grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea. CONCLUSIONS: The combination of UFT and leucovorin administered orally in a 3-times-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.

The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families.

The demand for BRCA1 and BRCA2 mutation screening is increasing as their identification will affect medical management. However, both the contribution of different mutation types in BRCA1 and BRCA2 and whom should be offered testing for large genomic rearrangements have not been well established in the U.S. high-risk population. We define the prevalence and spectrum of point mutations and genomic rearrangements in BRCA genes in a large U.S. high-risk clinic population of both non-Ashkenazi and Ashkenazi Jewish descent, using a sample set representative of the U.S. genetic testing population. Two hundred fifty-one probands ascertained through the University of Pennsylvania high-risk clinic, all with commercial testing for BRCA1 and BRCA2, with an estimated prevalence of BRCA mutation >or=10% using the Myriad II model and a DNA sample available, were studied. Individuals without deleterious point mutations were screened for genomic rearrangements in BRCA1 and BRCA2. In the 136 non-Ashkenazi Jewish probands, 36 (26%) BRCA point mutations and 8 (6%) genomic rearrangements (7 in BRCA1 and 1 in BRCA2) were identified. Forty-seven of the 115 (40%) Ashkenazi Jewish probands had point mutations; no genomic rearrangements were identified in the group without mutations. In the non-Ashkenazi Jewish probands, genomic rearrangements constituted 18% of all identified BRCA mutations; estimated mutation prevalence (Myriad II model) was not predictive of their presence. Whereas these findings should be confirmed in larger sample sets, our data suggest that genomic rearrangement testing be considered in all non-Ashkenazi Jewish women with an estimated mutation prevalence >or=10%.

Multicentric glioblastoma multiforme in a patient with BRCA-1 invasive breast cancer.

Breast cancer is the most common cancer in women. Germline mutations in BRCA-1 and BRCA-2 significantly increase the risk of developing breast and ovarian cancers, and are also associated with an increased incidence of primary cancers at other sites. We report the case of a 46-year-old woman previously treated for ductal adenocarcinoma of the breast with BRCA-1 who subsequently was diagnosed with multicentric glioblastoma multiforme (GBM) in the right temporal and right occipital lobes. We briefly discuss the incidence of BRCA-1 mutations in breast cancer as well as other primary neoplasms and consider potential mechanisms shared in the pathogenesis of breast and glial tumors.

On the need for biopsy confirmation at suspected first recurrence of cancer.

At the time of suspected first recurrence of cancer, it is unclear whether biopsy confirmation is routinely performed, although this is a very common clinical situation. First, 20 oncologists were surveyed to ascertain the pattern of practice in our community. A questionnaire with hypothetical typical cases suspected of having recurrent cancer was distributed. Second, eligibility criteria were reviewed from investigational protocols from the National Cancer Institute (NCI) and the Eastern Cooperative Oncology Group to see whether confirmation of recurrence was specifically required in these research studies. Third, 64 cases from our own practice were reviewed retrospectively to determine our patterns and results in performing biopsies to document suspected recurrence. Finally, criteria were developed that might suggest the need for biopsy confirmation of recurrence and then retrospectively tested against our cases. There was no clear consensus among oncologists regarding the need for tissue confirmation in patients with solid tumor with suspected recurrences, although rebiopsy was routinely requested for recurrent lymphoma. Published Eastern Cooperative Oncology Group and NCI protocols reviewed did not require biopsy proof specifically of recurrence. Retrospective review of our own cases suggested that, in the absence of one of the proposed indicators, the risk of making an erroneous diagnosis without biopsy confirmation is low. It is suggested that biopsy is not routinely necessary for confirmation of recurrence in all cases of suspected recurrent solid tumors, but criteria are proposed that would help to reduce the possibility of misdiagnosis when biopsy of suspected recurrence is not performed.

Breast cancer in the very young patient: a multidisciplinary case presentation.

A case is presented that exemplifies many issues and controversies in the diagnosis and treatment of breast cancer in the very young. This woman was 22 years of age at diagnosis; she initially underwent breast-conservation therapy and adjuvant chemotherapy, retained fertility, had a subsequent uncomplicated pregnancy and delivery, and 7 years later developed a local recurrence in the breast. The discussion addresses risk factors, diagnosis, and treatment of breast cancer in the young; the impact of treatment on fertility; implications regarding pregnancy, and the management of local recurrence after breast conservation.