Timely initiation of chemotherapy: a systematic literature review of six priority cancers - results and recommendations for clinical practice.

This review evaluated the association between time-to-chemotherapy (TTC) and survival in six priority cancers. A systematic review of the literature was undertaken for papers indexed in the MEDLINE and Cochrane Library databases from the earliest index until April 2014. The methodology used has been published in a separate paper (Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services). The optimal timing of chemotherapy in breast cancer is unclear as available studies are of low quality, report inconsistent results and are limited to the adjuvant setting. However, increased TTC may have a negative prognostic impact, and delays beyond 4 weeks should be avoided. Studies suggest that the optimal timing for initiation of adjuvant chemotherapy for surgically resected colorectal cancer is 4-8 weeks post-surgery. Timing of chemotherapy for metastatic colorectal cancer does not influence survival. There is a paucity of studies to guide the timing of chemotherapy for the treatment of lymphoma and myeloma; no definitive conclusions can be drawn, and clinician discretion should be applied. The optimal timing of chemotherapy in lung cancer is unclear; however, rapid tumour growth and poor disease prognosis suggest that delays should be avoided wherever possible. The optimal timing of chemotherapy in ovarian cancer is unclear as available studies are of low level, report inconsistent results and are limited to the post-surgery setting; however, increased TTC may have a negative prognostic impact; therefore, delays beyond 4 weeks should be avoided.

Safe administration of etoposide phosphate after hypersensitivity reaction to intravenous etoposide.

Etoposide is commonly used in a variety of malignancies. A well known but rare toxicity are hypersensitivity reactions, usually manifested by chest discomfort, dyspnoea, bronchospasm and hypotension. We report the details of a patient who developed hypersensitivity reactions to intravenous etoposide, but subsequently tolerated the administration of intravenous etoposide phosphate with no sequelae.

Differences in the nearpoint of convergence with target type.

PURPOSE: The purpose of this study was to determine the effect on measurements of the nearpoint of convergence (NPC) of different target types. In order to assess the influence of accommodation, the NPC was also measured under conditions of varying accommodative demand. METHODS: The NPC was measured to the nearest 0.5 cm using three targets: the RAF rule, the sharpened tip of a pencil and the tip of the examiner's index finger. All measurements were performed under the same conditions on two groups of asymptomatic subjects, a group of 14 presbyopic subjects and a group of 14, younger, non-presbyopic subjects. The influence of accommodative demand was assessed in the non-presbyopic group by measuring the NPC while subjects viewed the RAF rule target through +2.00 and -2.00 lenses held in front of their eyes. RESULTS: For the presbyopic group, the NPC (break) and NPC (recovery) were independent of target type. However, the NPC (break) was significantly less remote than the NPC (recovery). Comparative data for the non-presbyopic group showed that NPC (break) for the RAF target was less remote than for either the pencil tip or finger tip targets. In agreement with the results from the presbyopic group, the NPC (recovery) was independent of target type. CONCLUSION: For subjects with little or no accommodation, the NPC does not depend on the target used and is the same measured with the RAF rule, a pencil tip or finger tip. In non-presbyopic subjects there appears to be a small accommodative influence on the NPC, which is target dependent. However, the difference is probably not clinically important.

Stereopsis, cyclovergence and the backwards tilt of the vertical horopter.

It is generally recognized that the vertical horopter has a backwards tilt such that it passes through the fixation point and a point near the feet of the observer. The basis of the tilt has been attributed to either a shear in binocular retinal correspondence along the vertical meridian or the presence of cyclovergence eye movements. In an attempt to determine empirically the mechanisms underlying the tilt of the vertical horopter, retinal correspondence along the vertical meridian was investigated as a function of viewing distance. In addition, binocular measurements of torsional eye position were made in the same observers under similar viewing conditions. The vertical horopter was determined using two criteria. In the first instance, increment depth discrimination thresholds for both crossed and uncrossed disparities were measured as a function of retinal eccentricity along the vertical meridian, up to 5 degrees superiorly and inferiorly, and the horopter was defined by the region in space which had the lowest stereo-threshold. Secondly, subjective alignment of dichoptically presented nonius lines defined the horopter by identical visual directions. Both criteria were used to determine the horopter at 2 m while only the criterion of identical visual direction was used at the nearer distance of 50 cm. The vertical horopter showed a backwards tilt that decreased from an average of about 12 degrees at 2 m to 3 degrees at 50 cm, with some variability between observers. Torsional eye position did not change significantly between fixation distances. These results confirmed the geometric relation between the backwards tilt in the vertical horopter and fixation distance and support Helmholtz's original contention that the tilt is a consequence of a shear in retinal correspondence in the vertical meridian.

Variability of measurements of visual acuity in a large eye clinic.

PURPOSE: The aim of this study was to determine the variability of visual acuity in a large eye clinic. METHODS: A cross-sectional study using 50, consecutively presenting adult patients with visual acuity of at least 6/60 and aged between 18 and 75 years was performed. Measurements of visual acuity obtained under normal clinical conditions were compared to measurements obtained using standard clinical research protocols. The variability of visual acuity was assessed by determining the 95% limits of agreement between test and retest measures. RESULTS: There were no significant differences between test-retest measurements of visual acuity, either aided or unaided. Pearson r correlation coefficients between test and retest measurements were high for both aided and unaided visual acuity. The 95% limits of agreement revealed repeatability of about +/-1.5 logMAR or 1.5 lines on a standard logMAR chart. CONCLUSION: In large eye clinics, in order to be confident that a real change in visual acuity has occurred between measurements, a difference of at least 0.15 logMAR (8 letters on a standard logMAR visual acuity chart) is required.

Repeatability of measurements of interpupillary distance.

The purpose of this study was to determine inter- and intra-examiner repeatability of measurements of interpupillary distance (IPD). Three methods were used: Viktorin's, corneal reflection, and pupillometer. In Experiment 1, an experienced optometrist measured IPD on forty-nine subjects, on two occasions, using each method. In Experiment 2, thirty-five optometrists measured the IPD of one subject, on one occasion only, using the same three methods. The results of Experiment 1 showed that measurements of IPD differed depending on the method used, although the differences were small. The 95% limits of agreement were largest with Viktorin's method and least with the pupillometer. The results of Experiment 2 also revealed a small difference in IPD between the three methods of measurement. As in Experiment 1, the 95% limits of agreement were greatest with Viktorin's method and least with the pupillometer. Small differences in IPD were found between Viktorin's, corneal reflection and pupillometer methods of measurement. Not surprisingly, inter-examiner repeatability was slightly poorer than intra-examiner repeatability. However, the differences were small enough not to be clinically significant for the majority of patients.

Assessment of vergence facility in a sample of older adults with presbyopia.

PURPOSE: The aim of this study was to establish whether assessment of vergence facility is clinically useful in older adults with presbyopia and to determine pilot normative data for this age range. METHODS: Vergence facility was measured in a sample of 50 asymptomatic subjects with a mean age of 58.7 years using 8delta base-in (BI) and 12delta base-out (BO) prisms mounted in clinical flipper frames. Testing was performed for 1 min on four separate occasions over the course of a few weeks. RESULTS: Of the 42 subjects that completed the study, vergence facility could be satisfactorily measured on only 21 subjects. The mean vergence facility for this group was approximately 7 cycles per minute (cpm), commensurate with previous results in younger subjects using a similar paradigm. There were no differences in vergence facility between the first and second 30-s periods of testing, nor were there any differences in average vergence facility over the 4 test occasions. Test-retest repeatability, however, was poor. The BI prism phase took longer, on average, to fuse than the BO prism phase (BI 5.2 s and BO 3.7 s). CONCLUSIONS: Our results show a high degree of variability in vergence facility in older subjects with presbyopia. More research is required before deciding whether measurements of vergence facility are of use in investigating binocular vision of older patients with presbyopia.

Non-stereoscopic cues in the Random-Dot E stereotest: results for adult observers.

The purpose of this study was to investigate performance on the Random-Dot E (RDE) stereotest under binocular and monocular non-stereoscopic viewing conditions. Sixteen adult observers with normal vision were tested with the RDE stereotest. Four new RDE tests were shown to each observer in varying combinations of monocular viewing, binocular but non-stereoscopic viewing, and normal binocular viewing conditions. The test conditions were masked (where possible) and were presented in pseudo-random order. Control experiments were also conducted using the Frisby stereotest. Fifteen of the sixteen observers could discern some differences between the plates monocularly and therefore satisfied the passing criterion of the RDE test. Under these conditions, no observers could discern the stereoscopic E figure nor did any observer report a sensation of depth. No observer satisfied the passing criterion of the Frisby test monocularly. We conclude that caution should be used when interpreting results from the RDE stereotest, since adult observers could discern some differences between the test plates monocularly.

Effect of proparacaine on tropicamide-induced mydriasis.

PURPOSE: The use of a topical anesthetic before the instillation of a mydriatic is recommended in order to enhance both the rate and magnitude of pupillary dilation. However, there is a paucity of data supporting the prior use of topical anesthetics with tropicamide, the most commonly used mydriatic agent in optometric practice. Therefore, we conducted a study to determine the clinical effect of proparacaine on tropicamide-induced pupillary dilation. METHODS: We investigated the effects of prior instillation of 0.5% proparacaine (Ophthetic) on pupillary dilation with 0.5% tropicamide (Mydriacyl) using a double-blind, placebo-controlled protocol on two groups of young adult subjects. Thirty subjects, aged between 18 and 30 years, were divided into 2 groups of 15, based on whether they had light- or dark-colored irides. The pupils of both eyes of each subject were dilated with tropicamide, but only one eye, chosen at random, received proparacaine (experimental condition), whereas the other was administered a saline placebo (control condition). Pupil diameter was measured using a ruler and magnifying loupe. RESULTS: Subjects with light-colored irides had a greater average pupil dilation than subjects with dark-colored irides. There was a small, statistically significant difference in pupil diameter between the control and experimental conditions, but only for subjects with light-colored irides. The rate of pupillary dilation to peak pupil diameter and the rate of decrease in pupil diameter after peak pupil diameter was reached did not differ between experimental conditions or subject groups. CONCLUSIONS: Although prior instillation of topical proparacaine produced a statistically significant difference in pupil diameter for subjects with light-colored irides, the result was not clinically significant. Therefore, we do not recommend the use of a topical anesthetic before tropicamide-induced mydriasis for young adult patients.

The role of 5-fluorouracil dose in the adjuvant therapy of colorectal cancer.

BACKGROUND: In many centres, the use of 5-fluorouracil (5-FU) combined with levamisole has become standard therapy for the treatment of patients with Dukes' C colon cancer. However, the role of levamisole remains unclear. MATERIALS AND METHODS: All of the published adjuvant studies for colorectal cancer in which 5-FU (either as a single agent or in combination with other cytotoxics or levamisole) was compared to a no-treatment control group were ranked according to the total planned dose of 5-FU (assuming a body weight of 70 kg or a body surface area of 1.7 m2) over a three-month time frame. The effect of planned total dose of adjuvant therapy on the reduction of mortality was analysed using indirect comparisons of dose on the log odds ratio of death in a linear regression analysis. RESULTS: Overall, this analysis demonstrated a significant reduction in the odds of death for those receiving 5-FU regimens compared to untreated controls (estimate 0.82, 95% CI 0.74 to 0.91, p < 0.001). This effect was larger in those receiving a larger planned dose; for a total dose of 5-FU in the first three months of greater than 10 grams, 8 to 10 grams, less than 8 grams or oral 5-FU, estimates were 0.71, 0.79, 0.93 and 1.04, respectively (p = 0.02 for trend). Similar results were observed when the planned total dose of 5-FU received over 12 months was analysed. The analysis was then repeated by separating those studies in which 5-FU and levamisole were compared to a no-treatment control. A larger effect was seen in the 5-FU/levamisole trials (odds ratio, 0.64) compared to the other 5-FU regimens (odds ratio 0.86, p = 0.04). However, when adjusted for dose, the effect of levamisole was no longer significant (p = 0.09). CONCLUSION: These data suggest two separate hypotheses. The first is that the benefit associated with the use of 5-FU and levamisole given as adjuvant therapy in Dukes' C colon cancer is directly related to the planned total dose of 5-FU administered. Alternatively, in view of the fact that levamisole was part of the treatment regimens in two of the three studies in which the total planned dose of 5-FU exceeded 10 grams in three months (or 40 grams in 12 months), levamisole may be critical to outcome and the 5-FU total dose or dose intensity less relevant.

Quality of pharmacokinetic research in oncology.

The usefulness of pharmacokinetically guided individualisation of drug therapy will depend, among other things, on the quality of the analytical and pharmacokinetic methods used. We surveyed the quality of analytical and pharmacokinetics methodology and reporting in a literature search of the oncology literature from 1987 to 1992, using the Medline database. Thirty articles that examined relationships between normal tissue toxicity and area under the plasma concentration-time curve (AUC) formed the study sample. Analytical procedures were adequately described in 77% of the articles, but details of validation of the assay were seriously deficient in the great majority of articles. Methods for calculation of AUC were also deficient in over half of the articles. The findings suggest that greater attention needs to be paid to the quality of pharmacokinetic investigation in oncology, otherwise progress in the use of pharmacokinetically guided individualisation of dosage may be hindered.

Stereopsis, spatial frequency and retinal eccentricity.

Stereoscopic depth discrimination thresholds increase with retinal eccentricity and distance from the horopter. However, in contrast to spatial resolution, the effects of spatial frequency on stereo-thresholds in the periphery are unknown. For spatial vision, it is generally assumed that the retina is comprised of a series of overlapping spatial filter mechanisms and that there is a commensurate increase in spatial scale as a function of retinal eccentricity. If the same holds true for mechanisms sensitive to stereoscopic depth, then stereo-thresholds for low spatial frequency stereoscopic stimuli may remain relatively invariant across the visual field, while thresholds for relatively high spatial frequency stimuli would increase. To further understand the role of the disparity sensitive mechanisms involved in depth discrimination, increment depth discrimination thresholds for both crossed and uncrossed disparities were measured as a function of eccentricity for retinal locations up to 10.0 deg along the horizontal meridian. We found that stereoscopic depth discrimination thresholds, as a function of distance from the horopter, increased in an exponential manner irrespective of spatial frequency. Stereo-thresholds also increased as a function of retinal eccentricity, however, the rate of increase depended on the spatial frequency composition of the stimuli. Best stereo-thresholds for stimuli composed of low spatial frequencies remained relatively invariant for retinal eccentricities up to 10.0 deg, while thresholds for the high spatial frequency stimuli increased with eccentricity.

Behavioral studies of local stereopsis and disparity vergence in monkeys.

Investigations on macaque monkeys have provided much of our knowledge of the neural mechanisms of binocular vision, but there is little psychophysical data on the accuracy of vergence responses or the precision of stereoscopic depth perception in these primates. We have conducted comparative behavioral studies of binocular disparity processing in rhesus monkeys and humans via measurements of prism-induced fixation disparities (disparity vergence) and relative depth discrimination for spatially localized stimuli (local stereopsis). The results of these studies demonstrated a remarkable similarity in both the oculomotor and the sensory aspects of binocular vision in the two species when the stimulus dimensions were specified in visual angles, which were independent of interocular separation. The disparity vergence functions for the two species revealed fusion responses over the same range of prism-induced vergence and comparable vergence errors for stimuli near their fusional limits. Disparity vergence responses were independent of the spatial frequency of the binocular fusion stimulus. Stereothresholds as a function of the spatial frequency of the difference-of-Gaussian stimuli were of the same form, with equivalent stereoacuities, in monkey and human observers. The presence of substantial vergence errors had only a small effect on the precision of stereoscopic depth perception. We conclude that, after compensation for the differences in the lateral separation of their eyes, the operating characteristics of disparity vergence and stereoscopic vision are virtually identical in rhesus monkeys and humans and, consequently, the performance limits for these visual functions must be determined by anatomical and/or neural constraints that are similar in both species.