Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy

R. Arriagada1,2,*, M. G. Lê1, M. Spielmann1, L. Mauriac3, J. Bonneterre4, M. Namer5, T. Delozier6, C. Hill1 and T. Tursz1,2

1 Institut Gustave-Roussy, Villejuif; 2 Faculté de Médecine, Université de Paris XI, Paris; 3 Institut Bergonié, Bordeaux; 4 Centre Oscar Lambret, Lille; 5 Centre Antoine Lacassagne, Nice; 6 Centre François Baclesse, Caen, France

* Correspondence to: Dr R. Arriagada, Institut Gustave-Roussy, Bureau 607 A, +1, rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel: +33-1-42-11-61-57; Fax: +33-1-42-11-61-60; Email: arriagada{at}igr.fr


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: The aim of this multicenter trial was to evaluate the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy.

Patients and methods: Nine hundred and twenty-six premenopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm). Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years. The analyses were performed with Cox models stratified by center.

Results: Median follow-up was 9.5 years. Mean age was 43 years. Ninety per cent of patients had histologically proven positive axillary nodes, 63% positive hormonal receptors and 77% had received an anthracycline-based chemotherapy regimen. Ovarian suppression was by radiation-induced ovarian ablation (45% of patients) or with triptorelin (48%). At the time of randomization, all patients had regular menses or their follicle-stimulating hormone and estradiol levels indicated a premenopausal status. The 10-year disease-free survival rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms (P=0.51). The 10-year overall survival rates were 66% (95% CI 61% to 70%) for the ovarian suppression arm and 68% (95% CI 63% to 73%) for the control arm (P=0.19). There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality. However, in patients <40 years of age and with estrogen receptor-positive tumors, ovarian suppression significantly decreased the risk of recurrence (P=0.01).

Conclusions: The results of this trial, after at least 10 years of follow-up, do not favor the use of ovarian suppression after adjuvant chemotherapy. The potential beneficial effect in younger women with hormono-dependent tumors should be further assessed.

Key words: early breast cancer, premenopause, ovarian suppression, randomized trial


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Ovarian suppression is the oldest systemic treatment available to patients with breast cancer [1Go]. It was also the first systemic adjuvant treatment to be tested in a randomized trial in oncology [2Go]. Since then, several trials have evaluated its potential role as an adjuvant therapy in patients with early breast cancer [3Go]. Although there is evidence that ovarian suppression affords an overall survival benefit at least up to 20 years of follow-up in premenopausal patients [3Go], its use is still highly controversial. The first trials on adjuvant ovarian suppression were conducted in patients who did not receive chemotherapy. Five of these randomized trials, which each included more than 100 patients and together totaled 1243 patients, were analyzed in a meta-analysis [3Go]. The results showed a 24% reduction in the risk of death (P=0.0006). However, in the trials evaluating ovarian ablation in the presence of adjuvant chemotherapy, the effect was smaller and non-significant [3Go]. One reason is that as adjuvant chemotherapy per se induces an estrogen blockade in a high proportion of patients, ovarian suppression may not add any benefit [4Go, 5Go]. Since the first Milan trial and others that followed [6Go, 7Go], adjuvant chemotherapy has been widely used in premenopausal patients, and adding ovarian suppression has generally been considered unnecessary. It may be reasonably assumed that the effect of ovarian suppression would be greater in patients with positive hormonal receptors. However, most randomized trials were conducted at a time when the determination of hormonal receptors was not carried out or was unreliable. These are the reasons why we decided, in the late 1980s [8Go], to investigate the role of ovarian suppression in the treatment of premenopausal women with early breast cancer who systematically received adjuvant chemotherapy, taking into account the tumor hormonal receptor status.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
All women presenting with a primary infiltrating ductal or lobular breast carcinoma without distant metastasis and still menstruating for the 3 months preceding the diagnosis [or with plasma estradiol ≥60 pmol/ml or follicle-stimulating hormone (FSH) ≤30 mU/ml] were eligible for inclusion in the study if neo-adjuvant or adjuvant chemotherapy was planned. The two main inclusion criteria were histologically proven positive axillary lymph nodes, or grade II or III tumors according to the modified Scarff, Bloom and Richardson histologic grading system [9Go]. All patients had initial laboratory tests, a chest X-ray and mammograms. Liver ultrasound and bone scan were systematic for patients with positive axillary lymph nodes, and when requested for the other patients. All patients gave their informed consent prior to inclusion in the study, according to French regulations, and the Kremlin-Bicêtre Ethics Committee (France) approved the protocol.

Women with a history of cancer were excluded, except for patients who had had baso-cellular skin or in situ cervix carcinoma. Another exclusion criterion was a histologic type other than primary adenocarcinoma. Patients with intraductal or in situ lobular carcinoma, inflammatory cancer or simultaneous contralateral tumors were also excluded, as well as patients whose medical condition contraindicated the use of adjuvant chemotherapy.

Trial design
Eligible patients who agreed to participate in the study had their treatment randomized during or at completion of adjuvant chemotherapy to either of the following arms: ovarian suppression after adjuvant chemotherapy (ovarian suppression arm) or no further treatment (control arm). When postoperative radiotherapy was indicated, it was given after the completion of adjuvant chemotherapy. Ovarian suppression was generally performed or started during locoregional radiotherapy.

Treatment and follow-up
The general policy for surgical treatment was a lumpectomy for patients with tumors whose macroscopic diameter was ≤3 cm and a mastectomy for patients with larger tumors. Most patients underwent axillary clearance.

If adjuvant chemotherapy was not administered preoperatively, it generally began 2–4 weeks after surgery. The chemotherapy regimens were those usually prescribed in each center. The schedules most commonly used at the time were six cycles of FAC or FEC (5-fluorouracil 500 mg/m2, doxorubicin or epidoxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) delivered intravenously on day 1, or CMF-like regimens (combining cyclophosphamide, methotrexate and 5-fluorouracil) with different dose schedules. The interval between two cycles varied from 21 to 28 days according to tolerance and the chemotherapy regimen. Doses were reduced and/or intervals between cycles were prolonged when blood counts showed <2000/µl neutrophils or when platelets were <100 000/µl.

Ovarian suppression was obtained by injecting 3.75 mg of triptorelin (DecapeptylTM) intramuscularly every month over 3 years, by radiation-induced ovarian ablation or by surgical oophorectomy when a concurrent gynecological disease necessitated a hysterectomy. The recommended radiation dose delivered to the mid-plane of the pelvis was 12 Gy in four fractions, on four consecutive days, with a field of 14 x 10 cm. Ultrasound localization of the ovaries was not mandatory. Triptorelin was systematically used in all centers except at the Institut Gustave-Roussy, in Caen and in Chile. In the first two centers, the ovarian suppression modality was at the patient's discretion and that of her doctor. In general, radiation-induced ovarian ablation was preferred for the older patients and triptorelin for the younger patients who hoped to recover menses after 3 years of treatment. In Chile, ovarian suppression was achieved by radiotherapy.

Postoperative radiotherapy was delivered according to the protocol used in each center. However, general principles were common: adjuvant radiotherapy was always given to the breast after a lumpectomy at a total dose of 45–50 Gy using conventional fractionation, followed by a boost dose of ~15 Gy to the tumor bed. Supraclavicular and internal mammary chain nodes were irradiated only in patients with positive axillary nodes. Patients submitted to a total mastectomy received postoperative radiotherapy (chest wall, supraclavicular and internal mammary chain) only if the axillary nodes were positive. Axillary irradiation was exceptionally done, and only indicated if the axilla clearance was considered incomplete for lymph node-positive patients.

After completion of treatment, patients were seen every 6 months for the first 2.5 years, and yearly thereafter, with a yearly mammogram and a clinical examination at each visit. Complementary examinations were conducted according to the policy prevalent in each center.

Statistical methods
Randomization was centralized at the Institut Gustave-Roussy by telephone or fax and stratified on center and on four hormone receptor categories: both estrogen and progesterone positive, either estrogen or progesterone positive (the others were negative or were not measured), both negative, and both unknown.

Initially, a sample size of 800 patients was expected to yield 80% power to detect a difference of 8% in 5-year overall survival rates (from 70% to 78%), with a type 1 error of 5% (two-sided test). In 1994, the trial had accrued 750 patients and the group decided to continue accrual to attain a sample size of 1000 patients, guaranteeing 90% power to detect the same 8% difference in 5-year overall survival.

All eligible patients were to be included in the final analysis, according to the arm allocated (intention-to-treat analysis).

Overall survival and disease-free survival (DFS) were the main end points. They were analyzed by Cox models stratified on participating centers (centers that included <30 patients were pooled in a unique category). Overall survival was defined as the time between the date of randomization and the date of the last follow-up or death. DFS was defined as the time between the date of randomization and the date of the last follow-up or the date of the best available evidence concerning the first unfavorable event: locoregional recurrence, distant metastasis, contralateral breast cancer or death. Each event was analyzed separately (as were new primary malignancies), ignoring the occurrence of all other events, except death [10Go].

Variations in treatment effects were tested according to hormone receptors, age and the ovarian suppression modality using DFS as the end point. To compare the effect of ovarian suppression achieved by radiotherapy with that obtained by triptorelin, we proceeded in the following manner: (i) in the two centers where the treatment modality was a personal choice, patients in each ovarian suppression modality were matched with controls according to their date of birth; and (ii) in the other centers, where a single modality was used, the controls were identified directly. All comparisons were done with stratification by center. All tests of statistical significance were two-sided with a P value of 0.05.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Accrual
Accrual started in January 1989. During 1997, accrual had slowed down markedly and the group decided to close the trial having accrued 926 patients by February 1998. One ineligible patient, randomized during the treatment of a second breast cancer that had developed 4 years after the first cancer, was included in the analysis. Of the 926 women included in the trial, 465 were assigned to the control arm and 461 to the ovarian suppression arm. The median follow-up was 9.8 years in the control arm, and 9.7 years in the ovarian suppression arm, estimated by the inverted Kaplan–Meier method [11Go].

Patient characteristics
The distribution of baseline characteristics according to treatment arm is shown in Table 1. Most patients presented with positive axillary lymph nodes, as at the time of the trial it was not usual to indicate chemotherapy or ovarian suppression for lymph node-negative patients. In total, at the time of randomization, during or at completion of adjuvant chemotherapy, 90% of the patients had regular menses, and 10% were amenorrhoeic but their FSH and estradiol levels indicated a premenopausal status. In the control arm, excluding patients who had ovarian suppression because of protocol violation, the actuarial menopausal rates at 1, 2, 3 and 5 years after randomization were 52%, 64%, 73% and 83%, respectively. In this group, menopausal rates varied significantly with the initial age of patients (P=10–6): the 3- and 5-year rates were 41% and 60% for patients aged <40 years, and 81% and 89%, respectively, for those aged ≥40 years.


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Table 1. Patient characteristics according to treatment arm

 
Surgery, radiotherapy and chemotherapy
The description of treatment according to treatment arm is summarized in Table 2. A lumpectomy was performed in more than half of the patients; nearly all patients had axillary surgery and ~90% had axillary clearance. The average number of lymph nodes examined was ~15 (standard deviation 5.5). Radiotherapy was delivered to the breast or chest wall in 90% of the patients, and ~80% had lymph node irradiation.


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Table 2. Treatment description according to treatment arm

 
Adjuvant chemotherapy was given postoperatively in >80% of patients. FAC or FEC were the most commonly used regimens (69% of patients).

Treatment compliance
Compliance with the allocated treatment is shown in Table 2. In the control arm, 4% of patients had ovarian suppression. This treatment was prescribed by mistake, or was requested by the patients after randomization. In the ovarian suppression arm, 27 patients (6%) did not receive the allocated treatment: four were found to be menopausal after randomization, four developed distant metastases and a second line of chemotherapy was prescribed rather than ovarian suppression, 11 refused ovarian suppression after randomization, and eight did not receive the treatment by mistake.

In the ovarian suppression arm, 45% of patients received pelvic irradiation, 1% had a surgical oophorectomy and 48% received triptorelin. Among the 223 patients who received triptorelin, treatment was interrupted because of a tumor recurrence in 46 patients. Among the 177 other patients, 151 (85%) received the treatment for at least 36 months, 10 (6%) for between 24 and 35 months, 10 (6%) for between 12 and 23 months and only six cases (3%) for <12 months. The main reasons for stopping the treatment were as follows: another ovarian suppression modality chosen (three patients), adverse effects such as weight gain and hot flashes (12 patients), and other miscellaneous reasons, such as weariness, patients older than 50 years who did not consider possible a return of menses, a desire to have menses or medical recommendation (11 patients).

Finally, 5% of the patients in the ovarian suppression arm and 6% in the control arm were given adjuvant tamoxifen, in violation of the protocol.

DFS, overall survival and tumor events
A total of 226 patients in the control arm developed a recurrence (locoregional or distant recurrence, contralateral breast cancer) or died of any cause, compared with 229 in the ovarian suppression arm. This difference is not statistically significant (P=0.51), as shown in Table 3. The Kaplan–Meier curves for DFS are shown in Figure 1. Ten-year DFS rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms.


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Table 3. Death and tumor events according to treatment arm

 


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Figure 1. Disease-free survival according to treatment arm.

 
One hundred and forty-five deaths occurred in the control arm versus 160 in the ovarian suppression arm; this difference is not significant (P=0.19). The overall survival curves according to treatment arms are shown in Figure 2. The 10-year survival rate was 68% in the control arm (95% CI 63% to 73%) and 66% in the ovarian suppression arm (95% CI 61% to 70%). Events are detailed by type in Table 3; differences were not significant. There were 11 new primary malignancies in the control arm (sites: one esophagus, two colorectum, one liver, one soft tissue sarcoma, two uterus, one ovary, one bladder, one brain and one thyroid) and 12 in the ovarian suppression arm (sites: one colon, one melanoma, four uterus, two in situ cervix carcinoma, one kidney, one non-Hodgkin's lymphoma, one acute lymphocytic leukemia and one acute myeloid leukemia).



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Figure 2. Overall survival according to treatment arm.

 
Variations in treatment effect according to patient, tumor or treatment characteristics
There were no significant variations in treatment effects on death according to age or hormonal receptors when these covariates were considered separately, as shown in Table 4. When we analyzed these covariates simultaneously, the only subgroup that seemed to benefit from ovarian suppression was that of patients <40 years of age with an estrogen receptor-positive tumor. The test of interaction comparing the treatment effect among the four subgroups was significant (P=0.01). When a multivariate analysis was performed, adjusting for tumor size, histological grade and number of involved lymph nodes, the relative risk of recurrence or death was 0.49 (95% CI 0.30–0.81), with a P value of 0.005 in the subgroup of patients < 40 years of age and with estrogen receptor-positive tumors.


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Table 4. Risk of recurrence or death associated with ovarian suppression, according to hormonal receptors and age at randomization

 
The effect of definitive radiation-induced ovarian suppression did not differ from that of transitory triptorelin-induced amenorrhea. The relative risks of recurrence or death were 1.1 (95% CI 0.8–1.4) and 1.0 (95% CI 0.8–1.3), respectively (P=0.87 for treatment interaction).

Other treatment effects
The maximal body weight recorded was 66.3 kg in the control arm versus 67.4 kg in the ovarian suppression arm (P=0.32). The incidence of reported hot flashes was 38% in the control arm and 48% in the ovarian suppression arm (P <10–3).

Finally, there were seven normal pregnancies after treatment in the study, four in the control arm and three in the ovarian suppression (triptorelin) arm.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this trial do not favor the use of adjuvant ovarian suppression after adjuvant chemotherapy in patients with early breast cancer, after at least 10 years of follow-up. In the Early Breast Cancer Trialists' Collaborative Group overview [3Go], which included five trials totalling 933 patients in whom ovarian suppression was evaluated in the presence of chemotherapy, the reduction in the risk of death was only 8%, and not statistically significant (P >0.10). This latter result is consistent with that of our trial, which is one of the largest published on this particular subject.

The recently published International Breast Cancer Study Group (IBCSG) trial VIII [12Go] included 1063 patients in three adjuvant treatment arms: goserelin for 2 years versus six classic CMF [6Go] versus six CMF followed by goserelin for 1.5 years. Results in terms of DFS and overall survival were not significantly different. However, when the analysis was restricted to the 88 patients <40 years of age and with estrogen receptor-positive tumors, a benefit was observed with the combined sequential treatment (P=0.02). This result, observed in a subgroup of patients, was also found for the 124 patients in our trial who were defined according to the same characteristics (Table 4). The age effect may be due to a higher probability of recovering menses after an anthracycline-based chemotherapy in younger patients. Indeed, in the control arm, 59% of patients <40 years old recovered their menses in the first 3 years, compared with 19% in patients aged ≥40 years.

The Eastern Cooperative Oncology Group trial E5188–INT-0101 was also presented recently [13Go]. The study included 1504 patients in three arms: CAF chemotherapy alone versus CAF and goserelin for 5 years versus CAF, goserelin and tamoxifen for 5 years. Adding goserelin did not significantly reduce the recurrence rate (P=0.25), whereas adding both goserelin and tamoxifen did (P <0.01). However, the effects on survival were not significant with a median follow-up of almost 10 years.

In the next overview round, results concerning >5000 patients will probably be available about the role of adjuvant ovarian suppression in the presence of chemotherapy. More information will also be available regarding the hormonal receptor status for each patient.

Ovarian suppression (with or without tamoxifen) has been shown to be as effective as adjuvant chemotherapy, mostly CMF-like regimens (only one trial used an anthracycline containing regimen), in at least seven randomized trials totaling almost 5000 patients [14Go–20Go]. Thus, ovarian suppression seems a good alternative to adjuvant chemotherapy at least in patients with hormone receptor-positive tumors. However, unlike tamoxifen [21Go], ovarian suppression does not seem to add a benefit to adjuvant chemotherapy. A plausible hypothesis would be that ovarian suppression and adjuvant chemotherapy yield a treatment benefit through similar mechanisms in premenopausal patients [15Go, 16Go, 22Go] and that their sequential use in these patients is pointless. Another interesting finding in the present trial is that among the patients in the control arm who were considered premenopausal at the time of inclusion, 63% (including the 17 patients who had ovarian suppression because of a protocol violation) became menopausal within 3 years of follow-up. This finding suggests that adjuvant chemotherapy may have a delayed estrogen blockade effect that varies according to age.

The different ovarian suppression modalities seem to have a similar therapeutic effect. The radiotherapy doses must be sufficient (equivalent to 12 Gy in four fractions), as shown at the Institut Gustave-Roussy in the 1960s [23Go]. Indeed, lower total doses (4.5 Gy), as delivered in the Christie trial [2Go], may result in a high proportion of treatment failures. Ultrasound localization of both ovaries is recommended before radiotherapy [24Go]. However, we managed to achieve definitive amenorrhea in all irradiated patients without ultrasound localization of the ovaries. Similarly, the use of luteinizing hormone–releasing hormone analogs has been shown to induce a transitory hormonal blockade [25Go]. As laparocopic oophorectomy is now performed for ovarian ablation, morbidity and treatment costs are significantly decreased [26Go]. In the present trial, there was no difference in the effect of ovarian suppression according to the modality used. Two-thirds of the patients who stopped taking triptorelin had developed a tumor recurrence during treatment and received salvage chemotherapy, which resulted in a high amenorrhea rate at 3 years of follow-up.

Side-effects of ovarian suppression such as vaginal dryness, hot flashes [15Go], the risk of coronary heart disease [27Go] and high cholesterol levels have been a cause for concern. In the present study, no severe adverse effects were documented. However, no quality of life assessment was foreseen in the protocol. The evaluation of side-effects has become a subject of major interest in adjuvant hormonal and chemotherapy trials [28Go]. Indeed, when the benefits of different adjuvant treatments are comparable, then quality of life criteria may tip the balance in deciding which is the most appropriate treatment. This issue is still more important in women younger than 40 years old, probably benefiting more from the ovarian suppression, who are at the highest risk of being hampered by prolonged estrogenic suppression.

Another issue is the role of complete estrogen blockade induced by combining ovarian suppression with tamoxifen or anti-aromatase inhibitors in patients with hormone receptor-positive tumors, especially in younger patients. This combined approach could be more effective than the adjuvant chemotherapy regimens currently used, or may even add a benefit to therapy with anti-aromatase inhibitors. An appealing possibility will be explored in a new trial [Suppression of Ovarian Function Trial (SOFT)] promoted by the IBCSG. This trial is proposed for premenopausal patients with positive hormonal receptors treated or not with adjuvant chemotherapy and who continue to menstruate; the three proposed arms are tamoxifen for 5 years (the current standard treatment) versus tamoxifen for 5 years plus ovarian suppression versus exemestane for 5 years plus ovarian suppression.

Once again, the answer to one question sparks off questions about several other related issues and it is noteworthy that ovarian suppression, which opened the way for systemic treatments in breast cancer more than a century ago, will remain in the investigational fields of oncology for several years to come.


    Acknowledgements
 
The authors thank Ms Lorna Saint-Ange for editing. We thank M. Labbé (data management), and M. G. Lê and C. Hill (biostatistics) at the Institut Gustave-Roussy. Ipsen-Biotech, France, provided DecapeptylTM for the trial, free of charge, and partially funded the updating of trial data. The data analysis was performed independently by the Biostatistics Department, Institut Gustave-Roussy.

The following institutions participated in this study: Institut Gustave-Roussy, Villejuif (R. Arriagada, F. Fontaine, T. Le Chevalier, J. Mandet, F. May-Levin, F. Rochard, M. Spielmann, D. Sarrazin, T. Tursz) (557 patients); Institut Bergonié, Bordeaux (L. Mauriac) (156 patients); Centre Oscar Lambret, Lille (J. Bonneterre) (90 patients); Centre Antoine Lacassagne, Nice (M. Namer) (28 patients); Centre François Baclesse, Caen (T. Delozier, A. Rivière) (26 patients); CHR, Clermont-Ferrand (F. Suzanne) (25 patients); Instituto Radiomedicina, Santiago, Chile (R. Arriagada) (12 patients); Clinique St Hilaire, Agen (A. Veyret) (10 patients); Hôpital d'Orléans, Orléans (N. Breteau) (eight patients); Centre d'Oncologie, Bayonne (M. Lipinski) (six patients); Clinique St Catherine, Avignon (D. Serin) (four patients); and Hôpital du Val de Grâce, Paris (J. Merrer, P. Pabot du Chatelard) (two patients).

Received for publication July 22, 2004. Revision received October 18, 2004. Accepted for publication October 25, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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