Abstract
Purpose: To investigate whether one can replace the Sigma-60 with the Sigma-Eye applicator (or vice versa) during a deep hyperthermia treatment series without a loss in quality of the treatment.
Patients and methods: Hyperthermia data of all 48 patients with locally advanced cervical cancer who were treated with both applicators were analysed. In this study no use was made of the longitudinal SAR steering option of the Sigma-Eye. Hence, the Sigma-Eye was used as a Sigma-60 with a modified shape and water bolus. Power and intraluminal temperature were analysed. Sub-group analyses were performed for six groups, categorised according to the reasons for switching between the applicators.
Results: The ‘all patient’ analysis showed a significant difference for radio frequency (RF) power indices as applied to the two applicators, but for temperatures no difference between applicators was found. Sub-group analyses showed a consistent difference for RF power indices, i.e. the RF power for the Sigma-Eye was 8–29% higher than that for Sigma-60. In contrast, in about 90% of patients the number of switch-offs was 8–62% lower when the Sigma-Eye was applied. Similarly, in 73% of patients total switch-off time was 18–150% lower for the Sigma-Eye than for the Sigma-60. For the largest sub-group (n = 23), patients treated with the Sigma-Eye all had temperature indices slightly lower (ΔT = 0.2–0.5°C) than those for the Sigma-60 (p < 0.028). For the other five sub-groups no relevant difference was found between temperatures obtained by the two applicators.
Conclusion: In the case of severe patient discomfort with the Sigma-60 or Sigma-Eye applicator, or if achieved temperatures are not satisfactory, one can freely switch between both applicators without loss of hyperthermia treatment quality.
Introduction
In Rotterdam, locoregional deep hyperthermia (DHT) using radio frequency (RF) power is routinely applied with annular phased array applicators, i.e. Sigma-60 and Sigma-Eye, as delivered with the BSD2000-3D system.
The Sigma-Eye design differs from the Sigma-60 in that it has 24 radiating dipole antennas divided over three rings of eight dipoles instead of eight dipoles over a single ring. In both applicators, adjacent pairs of dipoles are connected, resulting in 12 or 4 RF channels per applicator, respectively. An important advantage of the Sigma-Eye applicator with its three rings of dipoles antennas is that it can provide full three dimensional control of the energy pattern. In addition to the energy steering in the X and Y directions as provided by the Sigma-60 applicator it has also energy steering in the longitudinal (Z) direction. Furthermore, the Sigma-Eye applicator provides an improved water bolus design, i.e. the length of the water bolus has been increased to provide contact with nearly the entire surface of the patient's body within the array. The advantage of this is that it reduces the concentration of energy, which occurs at the contacting edge of the inwardly tapered water bolus of the Sigma-60. In addition, the Sigma-Eye water bolus thickness above the anterior patient's surface is half to one third of that of the Sigma-60 bolus, which is expected to significantly improve patient comfort. Overall, the elliptical shape of the Sigma-Eye applicator is promoted to be more comfortable for the patient Citation[1]. Measurements of the Sigma-Eye demonstrated that there was no degradation of heating pattern and no increased superficial heating due to the closer proximity of the anterior and posterior dipoles to the phantom's surface. The closer proximity of the dipoles to the surface increases the ability to steer the pattern longitudinally because of the greater difference in the proportional path length from the central and perimeter dipoles to the centre of the array Citation[2]. In a phase I/II study performed by the Berlin hyperthermia (HT) group, Cho et al. have demonstrated that the Sigma-Eye applicator heats the upper abdomen better than the Sigma-60. Furthermore, they showed that the Sigma-Eye applicator theoretically resulted in 1°C temperature increase above the Sigma-60 Citation[3].
Recently, Franckena et al. reported the existence of a thermal dose effect relationship for patients with locally advanced cervical carcinoma (LACC) Citation[4]. It is therefore of great interest to investigate whether for patients with LACC switching between the Sigma-60 applicator and the Sigma-Eye applicator operated as a modified Sigma-60 applicator will result in similar temperatures, i.e. an equal quality of the HT treatment. To answer this question we performed a retrospective study among all our patients with LACC who have been treated with both applicators, to assess whether a difference exists in the applied RF powers and the intraluminal temperatures obtained.
Patients and methods
Patients
In the Netherlands, radiotherapy (RT) plus HT is applied as a standard treatment for patients with LACC. Of all patients with LACC who have been treated with HT in addition to RT in the period June 1999 to December 2005, 51 were treated within both the Sigma-Eye and the Sigma-60 applicator. The switch from one applicator to the other was in the patient's best interest, for the reasons listed below. The Erasmus MC IRB guidelines allow retrospective analysis of anonymised treatment data.
Hyperthermia treatment data of 48 patients with 208 treatments were accessible for analyses. Of the 208 treatments, we choose those treatments in which the highest overall vagina T50 and overall all lumina T50 were provided by each applicator. In this way we used DHT data of 96 treatments, two treatments per patient. One of the treatments was performed with the Sigma-60 and the other with the Sigma-Eye. The selected treatments could be immediate, sequential or not. The reason that we switched from the Sigma-60 to the Sigma-Eye or vice versa, was because of one of the following reasons:
Patient discomfort during the previous treatment (n = 23; 15 Sigma-60 to Sigma-Eye and eight Sigma-Eye to Sigma-60).
The applicator was out of order due to a technical malfunction (n = 12; four Sigma-60 to Sigma Eye and eight Sigma-Eye to Sigma-60).
At the time of the first treatment it was unclear whether the patient would fit in the Sigma-Eye applicator (n = 7; all Sigma-60 to Sigma Eye).
The measured temperatures were not satisfactory (n = 3; all Sigma-Eye to Sigma-60).
Logistical issues (n = 2).
Unknown problems (n = 1).
Radiotherapy
RT was performed at different institutes in the Netherlands. The patients received RT to the whole pelvis, conformal to the standard in the Netherlands, mostly 23–28 daily fractions of 1.8–2 Gy in 5 weeks in combination with a brachytherapy boost. For more details of the RT treatment see Van der Zee et al. Citation[5].
Hyperthermia
DHT was performed using the BSD-2000 annular phased array system with the Sigma-60 and the Sigma-Eye applicators (BSD Medical Corporation, Salt Lake City, Utah, USA) Citation[6]. Selection of the Sigma-60 or the Sigma-Eye applicator was purely a matter of size of the patient, i.e. whether the patient would fit in the Sigma-Eye under the condition that there was a distance of at least 2.5 cm between the dipole antennae and the body surface. Neither International Federation of Gynacoelogy and Obstetric (FIGO) stage nor tumour size affected the choice of the applicator.
In this study the Sigma-Eye was used as a modified Sigma-60 applicator. This means that there was no 3D specific absorption rate (SAR) steering during the treatment; i.e. there was no phase or amplitude difference among the three rings of the Sigma-Eye applicator. The SAR steering was performed in lateral–lateral and posterior–anterior direction with the Sigma-Eye in a similar manner as with the Sigma-60. This means that the Sigma-Eye, operated in the Sigma-60 mode, was considered as a valid replacement for the Sigma-60 applicator anticipating an equivalent quality of the HT treatment.
One to five (mean 4.3) DHT treatments were delivered to the whole pelvis volume once weekly during the period of RT. HT was carried out by the institutional protocol of the department as follows. The frequency used for the Sigma-60 was in the range of 70–90 MHz and for the Sigma-Eye 100 ± 2 MHz. The initial RF power was 400 W (for the four antennae). Every 5 min the RF power output to the applicator was increased (up to a maximum of 1600 W), in steps of 100 W, until the patient's tolerance threshold was reached. Hereafter, we applied SAR steering by changing phase and amplitude settings with the aim to reduce power-limiting hotspots (i.e. normal tissue temperature > 43°C or pain complaints from the patient) and to achieve intraluminal temperatures of 40–43°C as homogeneously as possible.
Patients were carefully instructed to mention any unpleasant sensation that might be the result of a hot-spot, such as a burning sensation, a feeling of pressure, any pain, and bowel or bladder spasm. If the patient reported pain which disappeared within 1 min following power decrease it was considered to indicate too high a temperature, and the treatment settings were adjusted to decrease power input at the specific location. Adjustments of treatment settings could be as follows: adaptation of phase settings, amplitude and frequency, or by placing additional water boluses. For deep pain complaints phase steering was preferred, while for superficial pains amplitude steering was applied.
DHT treatment consisted of a heating phase of 30 min followed by 60 min therapeutic time. The temperature of the applicator's water bolus was maintained at 20°C. Increase in systemic temperature was limited by cooling measures: undressing, air-conditioning, wet towels, ice packs, and cooling bolus placed on the neck. The bladder was kept empty with a Foley catheter. For more details of DHT treatment procedure see Van der Wal et al. Citation[7].
Thermometry
For thermometry, closed-tip catheters (William Cook Europe, P5.0-CE-50-SFT-NS-0, Denmark) were inserted intraluminally in the urinary bladder, rectum and vagina lumen at the beginning of each treatment session. Thermistors with high impedance leads, i.e. Bowman probes Citation[8], as standard delivered by the BSD-2000 system were used to assess real-time temperature reading.
After catheter placement, the intraluminal depths were documented. Using a standard caliper, the HT technician measured the insertion length of the thermometry catheters. Temperature mapping was performed along the length of the thermometry catheter in 1-cm increments to a maximum mapping length of 14 cm. Thermal mapping started just before the DHT treatment and was repeated thereafter at 5 min intervals. The accuracy of the temperature measurement was ±0.2°C with a precision of ±0.1°C.
The temperature data were measured intraluminally according to the European Society for Hyperthermic Oncology (ESHO) guidelines for DHT Citation[9]. The overall intraluminal temperature includes all measurements within one catheter.
Data processing and variables
RHyThM software was used to access and analyse the DHT data. An extensive description of this program and the methods of data analysis are included in two previous publications by Fatehi et al. Citation[10], Citation[11]. The following variables were used for the analysis:
mean net power (W), i.e. mean forward power minus mean reflected power,
mean net integrated power or ‘delivered energy’ (kJ), see Equation 2 below,
mean net integrated power per weight (kJ kg−1),
number of times that power was switched off,
total switched-off time (s),
vagina T90, which is T90 of overall intraluminal measurements within vagina lumen. The T90 is representative for minimum temperature. The TX means the temperature that is exceeded by X% of all temperature readings,
vagina T50, which is T50 of overall intraluminal measurements within vagina lumen,
vagina T20, which is T20 of overall intraluminal measurements within vagina lumen,
all lumina T90, which is defined as overall intraluminal bladder, vagina and rectum lumen T90,
all lumina T50, which is defined as overall intraluminal bladder, vagina and rectum lumen T50,
all lumina T20, which is defined as overall intraluminal bladder, vagina and rectum lumen T20,
CEM43°CT90 (cumulative equivalent minutes at 43°C based on T90 temperatures), in which the formulation takes the following form:
Furthermore, net integrated power (NIP) was calculated by:where Pfwd and Prfl are forwarded and reflected power (W), respectively, n is number of measurements and Δt is time interval between two measurements (s).
With our additional quality assurance equipment we have implemented an automatic recording when the RF power is switched off. We hypothesise that the number of power-off switches and the duration of each power-off switch might be related to the relevance and incidence of hot-spots during deep hyperthermia treatment. Clearly the total switch-off time is relevant in calculating the integrated power delivered to the patient.
Statistical analysis
The statistical analysis was based on the temperature evaluation parameters as provided in the American Standard Code for Information Interchange (ASCII) files by RHyThM. Temperature measurements were available per patient, per treatment session, per probe, per mapping position, and per time point. A temperature point below 37°C during the first thermal map was considered indicative for the measuring point to be outside the lumen or to be the effect of local cooling by one of the cold water boluses resulting in non-representative low temperatures. Therefore all these points were excluded from the analyses. The time-points were scaled with respect to the starting time of the treatment. While computing averages, all observations during steady state were weighted equally. The T90, T50, and T20 were calculated per lumen and per treatment. The CEM43°CT90 was calculated per treatment Citation[12]. The averages and standard deviations were computed for the thermal dose parameters of different lumina (bladder, vagina, rectum, and all lumina). For the data analysis we applied two procedures. In the first analysis mode, all the data were pooled in one group and we analysed the data based on the applicator type. In the second analysis mode we split the data into six sub-groups. Then sub-analysis was performed based on the applicator type for each sub-group. The sub-groups were defined based on the reasons why we switched the applicator from the Sigma-60 to the Sigma-Eye or vice versa. T-test was used to compare the average of power and/or temperature indices. The p values are two-sided at a significance level of α = 0.05. SPSS (version 12) was used for the statistical analysis.
Results
The average values of RF power-related parameters and measured temperature indices for the two applicators are shown in Tables .
Table I. Average values of RF-power and temperature data for the Sigma-60 and the Sigma-Eye applicators.
Table II. Average values of applied RF-power indices to the Sigma-60 and the Sigma-Eye applicators in different sub-groups.
Table III. Average values of measured temperature indices for the Sigma-60 and the Sigma-Eye applicators in different sub-groups.
Table IV. Overview of the results by applicator type at individual patient level analysis.
Discomfort of the patient with the position in the applicator was the most common reason to switch between applicators, i.e. 15 times from Sigma-60 to Sigma Eye and eight times from Sigma-Eye to Sigma-60. Malfunction of the applicator was the second reason to switch between applicators (four times from Sigma-60 to Sigma Eye and eight times from Sigma-Eye to Sigma-60). In seven patients doubt whether the patient would fit in the Sigma-Eye was the reason to start with the Sigma-60 and subsequent switching to the Sigma-Eye in the second treatment. Only in three cases were unsatisfactory temperatures as achieved in the Sigma-Eye the reason to switch to the Sigma-60.
Results of the first analysis mode
Power data analysis
As shows, when we pooled all the data in one category and compared the data for the two applicators, the power-related parameters, i.e. net power, net integrated power, and net integrated power per weight for the Sigma-Eye applicator were 12–17% higher than those for the Sigma-60. These differences are statistically significant (p < 0.002; , row 3).
The number of power switch-offs for the Sigma-Eye applicator was almost equal to that of the Sigma-60 (7% lower). There was, however, a significant different between ‘each switched-off time’ for the two applicators (39.4 ± 25.8 s for the Sigma-Eye versus 51.4 ± 41.3 s for the Sigma-60) (p = 0.04). As a consequence, when DHT was applied by the Sigma-Eye applicator, the total switched-off time was 36% lower than that for the Sigma-60, which difference was significant (p = 0.006).
Temperature data analysis
As shows, all of the representative temperature indices are equal for the Sigma-Eye and the Sigma-60 applicator, the range of ΔT is 0.1–0.2°C. Only the vagina lumen T90, was found to be significantly higher (0.2°C) for the Sigma-60 (p = 0.014). Note that no Bonferroni correction has been applied for multiple testing. Finally, the CEM43°CT90 proved to be lower for the Sigma-Eye (1 ± 0.9 min) than for the Sigma-60 (1.36 ± 1.23 min). This difference was significant at a level of p = 0.04.
Results of the second analysis mode
The data show that the applicator was switched from the Sigma-60 to the Sigma-Eye for 60.4% of the patients (29 of 48) and it was switched from the Sigma-Eye to the Sigma-60 for 39.6% of the patients (19 of 48).
Power data analysis
The results of sub-analysis for the power indices are reported in . It shows for all six sub-groups that when applying DHT with the Sigma-Eye the net power input was 13–28% higher than with the Sigma-60. Only in the first (and the largest) sub-group, ‘patient discomfort’, was this difference in net powers statistically significant (p = 0.037). Similarly, when we compared the net integrated power applied to the two applicators for the six sub-groups, the data of the Sigma-Eye were 9–28% higher than those for the Sigma-60. This difference in net integrated power was significant in the first sub-group (p = 0.027) and the third sub-group, named ‘doubtful if patient fits’, (p = 0.044). A similar result was found for the net integrated power per weight, the values for the Sigma-Eye were 8–29% higher than that for the Sigma-60, and the difference was statistically significant in the first and third sub-group, respectively, p = 0.025 and p = 0.044.
As shown in , when DHT was applied by the Sigma-Eye, in 91.6% of the patients (44 of 48) the number of switch-offs was 8–62% lower than that for the Sigma-60. In the sub-groups analyses this difference is lost. Similarly, when the patients have been treated within the Sigma-Eye applicator, in 73% of the cases (35 of 48) the total switched-off time was 24–150% lower than that for the Sigma-60. In the sub-group analyses the difference in total switched-off time for the two applicators was significant only for the first (p = 0.021) and the third sub-group (p = 0.046).
Temperature data analysis
The results of sub-group analysis for the temperature indices are given in . As shown, in the first (and largest) sub-group, ‘patient discomfort’, all reported temperature indices were slightly lower for the treatments delivered with the Sigma-Eye in comparison to those delivered with the Sigma-60, with the temperature difference ranging between 0.2 and 0.5°C. This difference was statistically significant for five of the six temperature indices (p values from 0.001 to 0.028; , row 1).
In the analyses for the other five sub-groups, temperature differences were small and were not statistically significant. An exception was found in the fourth sub-group, ‘temperature not satisfactory’. In this sub-group all lumina T50 and all lumina T20, for treatments applied by the Sigma-Eye, were significantly different from those of the Sigma-60. However, the all lumina T50 for the Sigma-Eye was 0.3°C lower than that for the Sigma-60 (p = 0.02), whereas the all lumina T20 for the Sigma-Eye was 0.8°C higher than that for the Sigma-60 (p = 0.029).
In the analysis investigating the alternative order of applicator change, i.e. where the primary treatment was performed by the Sigma-60 and the alternative treatment by the Sigma-Eye, we found an average vagina lumen T50 of 40.5°C for the Sigma-60 versus 40.4°C for the Sigma-Eye (p = 0.43). For the same group but on the level of the individual patient we noticed that the vagina lumen T50 for treatments applied by the Sigma-60 were higher for 15 patients and equal or lower for 14 patients () in comparison to the vagina lumen T50 as obtained by the Sigma-Eye. In addition, when the primary treatment was performed by the Sigma-Eye and the alternative treatment by the Sigma-60, the average vagina lumen T50 was 40.5°C for both applicators (p = 0.47), with the vagina lumen T50 being higher for 11 patients and equal or less for eight patients () when comparing Sigma-60 to Sigma-Eye.
Discussion
Nowadays, multimodality treatment approaches for malignancies have become increasingly sophisticated Citation[13], Citation[14]. HT is one of the potentially effective cancer treatment procedures that is applied in conjunction with conventional treatments such as RT, and/or chemotherapy to improve treatment outcome Citation[15–18]. In some of the HT departments around the world, DHT is performed using the BSD-2000 HT system with the Sigma-60 or the Sigma-Eye annular phased array applicators. From a quality assurance point of view, evaluation of the performance of devices and equipment providing HT is essential to apply good quality treatments.
In this study we evaluated the performance of the Sigma-60 and the Sigma-Eye applicators in respect to the applied power and the achieved intraluminal temperatures when treating patients with LACC. The purpose of the study was to investigate whether the use of the Sigma-Eye applicator (as a modified Sigma-60 applicator) would result in an equal or higher quality of the hyperthermia treatment in comparison to the treatments applied by the Sigma-60 applicator. Although the Sigma-Eye applicator has technical advantages with regard to the 3-dimensional power steering, it must be noted that the option to perform longitudinal SAR steering was not used in this study. In practice this means that the Sigma-Eye SAR steering features are identical to those of the Sigma-60 and only the advantage of a lower water bolus pressure remains. The idea is that the lower water bolus pressure results in more comfort for the patient while still offering the same quality of HT treatment.
The whole group comparison as performed in this study showed no relevant difference between intraluminally measured temperatures for patients with LACC treated with either of the two applicators. In our opinion a difference in temperature should be a minimum of 0.3°C in order to be relevant (in practice this correlates with a 10% increase in the median temperature, T50, considering a normal body temperature of 37°C and an average intraluminal temperature of 40.4°C for deep hyperthermia in patients with LACC). A difference of less than 0.3°C is too small to discriminate from the temperature variation between subsequent treatments. The difference in CEM43T90 between the Sigma-60 and Sigma-Eye is a direct consequence of the 0.2°C difference between the average T90 index temperatures as measured for each applicator type. On the other hand, the analyses of the RF power for the two applicators showed that in all of the 48 patients when we applied the Sigma-60 applicator, the power indices; i.e. net power, net integrated power, and net integrated power per weight, were 8–29% lower than those for the Sigma-Eye. Based on our knowledge of the characteristics of the Sigma-Eye applicator, these results are to be expected from the difference in RF output efficiency between the Sigma-Eye and Sigma-60 applicator. From laboratory experience we know that the efficiency of the Sigma-Eye is about 30% lower than that of the Sigma-60. In clinical treatment the difference in efficiency is also dependent on the phase settings for the various antennas. Hence, in this study the RF power input indices for the Sigma-Eye applicator are 8–29% higher than for the Sigma-60 applicator, in good agreement with the differences in efficiency of the applicators. In addition, sub-analyses performed for the whole patient group demonstrated in 92% of the patients (44 of 48) a lower, 8–62%, incidence of the RF power ‘switched-off’, for the Sigma-Eye in comparison to the Sigma-60. Likewise, the total switched-off time applied to the Sigma-Eye applicator was 24–150% lower than that for the Sigma-60. These results are also to be expected based on the anticipated better tolerance of the Sigma-Eye due to its improved design. The Sigma-Eye has less restriction on patient breathing, smaller water bolus thickness above the anterior surface of the patient, and the elliptical shape, all of which significantly improve patient comfort Citation[1], Citation[19].
As in the present study the main reason to switch from the Sigma-60 to the Sigma-Eye applicator was the reported discomfort of patients during the previous treatment session, it justifies sub-group analyses with regard to the reason for applicator exchange. Exchange due to complaints of discomfort occurred in 48% of the patients (23 of 48). Although not registered, we suppose that the higher water bolus pressure of the Sigma-60 applicator might be the most important reason for the discomfort.
Overall, the sub-group analysis for the two applicators demonstrates only relatively small differences in the measured temperatures. Only for the 23 patients of the first sub-group ‘patient discomfort’ were the temperature indices as measured for the Sigma-Eye applicator lower in general (0.2–0.5°C; p < 0.03) than the temperatures measured for the Sigma-60. Earlier we have already reported that the average variation between treatments during a whole series of five DHT treatments is 0.8°C.11 Hence under the current study conditions we consider the observed difference in the HT quality between the treatments of both applicators for the sub-group ‘patient discomfort’ as a predictable difference that falls well in the range of average temperature differences between two subsequent treatments. In our opinion this position finds additional support by the fact that the analyses for the other four sub-groups indicates a rather equal level of the HT quality as obtained with the Sigma-Eye or the Sigma-60 applicator. For the remaining four sub-groups the temperature differences are marginal or slightly better for the treatments applied with the Sigma-Eye applicator (see ). In addition, the intra-patient analyses are showing identical results. When the primary treatment was performed by the Sigma-60 an average vagina lumen T50 of 40.5°C is achieved versus 40.4°C for the Sigma-Eye. When the applicator change was from Sigma-Eye to Sigma 60 the average vaginal lumen T50 was 40.5°C for both applicators. On basis of the individual patient T50s it follows that in 26 out of the 48 patients the vagina lumen T50 was higher with the Sigma-60 than those provided by the Sigma-Eye. In 19 patients the T50 was higher for the Sigma-Eye and in three patients they were equal (see ). Overall, the indicators point towards an equal quality in the hyperthermia treatments independent of the applicator type, following the 2D SAR steering procedure.
Conclusion
In this study of 48 patients with locally advanced cervical cancer and treated by radiotherapy and hyperthermia, we investigated the quality of the hyperthermia treatment as a function of the type of annular phased array applicator, i.e. the Sigma-60 and the Sigma-Eye, as provided by the BSD-2000 hyperthermia system. Extensive analyses of all intra-luminal temperatures as obtained for the best treatment for each applicator type showed that the differences in the quality of the hyperthermia treatment are of the same order as those found between the subsequent treatments with the Sigma-60 applicator only. We emphasise that this finding is valid only under the condition that the Sigma-Eye is used as a modified Sigma-60 applicator, i.e. without longitudinal SAR steering. From this study we conclude that switching between the Sigma-60 and Sigma-Eye applicator is a valid option to continue the hyperthermia treatment when the patient has serious complaints of discomfort from one applicator type, technical or logistical unavailability of one applicator, provided the Sigma-Eye is used as a modified Sigma-60 applicator.
Acknowledgements
The authors would like to thank Greta M. Wende van der Bijdevaate and all other hyperthermia staff members of the Daniel den Hoed Cancer Centre in Rotterdam for their technical assistance. We also thank Fatemeh Drees for her valuable statistical consults.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Related Research Data
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