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Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853
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Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853 Jean-Pierre Julien, Nina Bijker, Ian S Fentiman, Johannes L Peterse, Vincenzo Delledonne, Philippe Rouanet, Antoine Avril, Richard Sylvester, Françoise Mignolet, Harry Bartelink, Joop A Van Dongen, on behalf of the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group
Summary Background Ductal carcinoma in situ (DCIS) of the breast is a disorder that has become more common since it may manifest as microcalcifications that can be detected by screening mammography. Since selected women with invasive cancer can be treated safely with breast-conservation therapy it is paradoxical that total mastectomy has remained the standard treatment for DCIS. We did a randomised phase III clinical trial to investigate the role of radiotherapy after complete local excision of DCIS. Methods Between 1986 and 1996, women with clinically or mammographically detected DCIS measuring less than or equal to 5 cm were treated by complete local excision of the lesion and then randomly assigned to either no further treatment (n=503) or to radiotherapy (n=507; 50 Gy in 5 weeks to the whole breast). The median duration of follow-up was 4·25 years (maximum 12·0 years). All analyses were by intention to treat. Findings 500 patients were followed up in the no further treatment group and 502 in the radiotherapy group. In the no further treatment group 83 women had local recurrence (44 recurrences of DCIS, and 40 invasive breast cancer). In the radiotherapy group 53 women had local recurrences (29 recurrences of DCIS, and 24 invasive breast cancer). The 4year local relapse-free was 84% in the group treated with local excision alone compared with 91% in the women treated by local excision plus radiotherapy (log rank p=0·005; hazard ratio 0·62). Similar reductions in the risk of invasive (40%, p=0·04) and non-invasive (35%, p=0·06) local recurrence were seen. Conclusions Radiotherapy after local excision for DCIS, as compared with local excision alone, reduced the overall number of both invasive and non-invasive recurrences in the ipsilateral breast at a median follow-up of 4·25 years. Lancet 2000; 355: 528–33 See Commentary page ???
Department of Surgery, Centre Henri Becquerel, Rue D’Amiens 1, 76038 Rouen, France (J-P Julien MD); Department of Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands (N Bijker MD, J L Peterse MD); Guy’s Hospital, Clinical Oncology Unit, London SE1 9RT, UK (Ian S Fentiman FRCS); Department of Surgery, Istituto Nazionale dei Tumori, 20133 Milan, Italy (V Delledonne MD); Department of Surgery, CRLC Val D’Aurelle, 34094 Montpellier, France (P Rouanet MD); Department of Surgery, Institut Bergonié, 33076 Bordeaux, France (A Avril MD); EORTC Data Center, 1200 Brussels, Belgium (R Sylvester ScD, F Mignolet); Department of Radiotherapy (H Bartelink MD); and Department of Surgery (J A Van Dongen MD), 1066 CX Amsterdam, The Netherlands Correspondence to: Dr Jean-Pierre Julien (e-mail: [email protected])
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Introduction Breast-conserving treatment for patients with ductal carcinoma in situ (DCIS) is a relatively new treatment option. Until a decade ago total mastectomy was the standard treatment for women with DCIS. At that time DCIS was a rare disease, comprising only 2–5% of all breast cancers presenting clinically as a palpable mass, bloody nipple discharge, or Paget’s disease of the nipple. An almost 100% cure rate could be achieved with ablative treatment. Rare exceptions were cases labelled as DCIS but with histologically undetected microinvasion from which tumour emboli emerged and gave rise to distant metastases. With the widespread use of mammographic screening, the incidence of DCIS has increased, such that these lesions now comprise 15–20% of all breast cancers detected in population screening programmes. Most of these cases are clinically occult and detected because of microcalcifications on mammograms. For selected women with invasive breast carcinoma, breast-conserving therapy has already proved to be as effective as mastectomy.1–4 Hence it is paradoxical that DCIS, a non-invasive lesion, is generally treated by more extensive surgery than is invasive breast cancer. But whereas mastectomy for DCIS can almost invariably cure, breast-conserving treatment in DCIS could increase the risk of residual disease, which might recur and progress into invasive carcinoma, thereby increasing the risk of death from metastatic disease. In the mid-eighties several randomised clinical trials were started to find out what is the best breast-conserving treatment for patients with DCIS.5 We report the initial results of a phase III randomised study done between 1986 and 1996 to examine the effect of radiotherapy after local excision of DCIS.
Methods Participants Women with DCIS of the breast were randomly assigned radiotherapy, or no further treatment after histological confirmation that the lesion had been completely excised. Extent of free margins was not specified other than that DCIS should not be present at the margin of the sample. Patients gave informed consent according to the institute’s regulations. Patients with lesions with a diameter up to 5 cm, without evidence of invasive carcinoma or Paget’s disease of the nipple, were eligible for the study. Size was determined by either clinical measurement or from the extent of microcalcifications on the mammograms. Axillary dissection was not required or advised but, if done, the axillary lymph nodes had to be free of metastases. Patients were excluded who were more than 70 years of age, were pregnant, or had a past or concomitant malignant disease other than adequately treated basal-cell carcinoma of the skin or conebiopsied carcinoma in situ of the cervix. Those with a performance status of greater than or equal to 2 according to the WHO criteria, or with a mental condition or social situation precluding long-term follow-up, were also excluded.
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1010 women randomised
503 assigned no further treatment
507 assigned radiotherapy
3 lost to follow-up
5 lost to follow-up
500 analysed
502 analysed
Figure 1: Trial profile
Study design Patients were centrally randomised at the EORTC Data Center. Randomisation was done by minimisation and was stratified for institution. The primary endpoints were invasive and non-invasive recurrence in the treated breast. Secondary endpoints included regional recurrence, metastasis, death, and contralateral breast cancer. Recurrence-free intervals were defined as the time between the date of randomisation and the date of recurrence of the disease. All analyses were by intent to treat. All randomised patients for whom information was available were included. The time-torecurrence curves were calculated with the Kaplan-Meier analysis6 and compared by means of a two-sided log-rank test. Size of the treatment difference was calculated on the basis of the hazards ratio and its 95% CI. All patients underwent wide resection of the portion of the mammary gland harbouring the lesion. The resection was intended to remove the whole lesion or the entire area with microcalcifications. The cutaneous incision, depending on the tumour site and size, was radial or curvilinear to obtain the best cosmetic result. The surgical samples were sent to the pathologist to have the margins inked and to get information on histology and margin status. If the DCIS was incompletely excised at the first attempt, a second operation was done. External-beam radiotherapy had to be started within 12 weeks after surgery. The patient was irradiated in the supine position with immobilisation of the ipsilateral arm. The target area had to encompass the chest wall. The breast was irradiated by means of medial and tangential portals. The medial border was drawn at the midline, and the upper border was drawn between the first and second intercostal spaces and laterally to the soft tissue of the central axilla. The dorsal border was at the midaxillary line or 1–2 cm beyond, depending on breast tissue. The lower border was 1 cm below the inframammary sulcus. In addition, the margin had to be at least 2 cm clear of any incision. Correction for divergence had to be made by a slight angulation of the beam to obtain a flat dorsal plane. In this way, unnecessary irradiation of lung tissue No further treatment (n=503) Median (range) age (years) Clinical signs Palpable lesion Mean diameter of palpable lesion (mm) Nipple discharge Mammographic lesion only Mean diameter of mammographic abnormality (mm) Surgery Number of operations One Two Three Axillary dissection done Radiotherapy Boost received*
53 (25–76)
Radiotherapy (n=507) 53 (27–74)
Total (n=1010) 53 (25–76)
109 (22%) 22 40 (8%) 350 (70%) 20
99 (19%) 21 34 (7%) 372 (73%) 20
208 (21%) 21 74 (7%) 722 (71%) 20
321 (64%) 178 (35%) 1 (<1%) 98 (19%)
336 (66%) 158 (31%) 6 (1%) 104 (21%)
657 (65%) 336 (33%) 7 (1%) 202 (20%)
··
26 (5%)
··
All data are number of patients (%) unless where indicated. *Median dose 10 Gy.
Table 1: Characteristics of patients and treatment received
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could be reduced. The second measure to limit the irradiation of unnecessary lung tissue was the adaptation of the dorsal planes of the treatment portals to the angle of the chest wall. The patient had to be irradiated each day through both tangential portals. To achieve a homogeneous dose distribution over the whole breast, a compensatory filter or wedge was used for each individual patient. The maximum allowable difference in dose distribution over the target volume in the central plane was 10%. The prescribed irradiation dose was 50 Gy in 25 fractions (2 Gy per fraction) to be given in 5 weeks. This dose was directed at the intersection of the central axis of the beams (according to the International Commission on Radiation Units and Measurements definition7), or, if this intersection was outside the target volume because of correction for divergence, the dose had to be directed in the centre of the target volume. No boost was advised nor were the adjacent lymph-node stations irradiated. Patients were followed at 6-monthly intervals until the 10th postoperative year, and then at annually intervals. Bilateral mammograms had to be done every year. Follow-up data were sent yearly at the EORTC Data Center. Suspected local or regional recurrences had to be confirmed histologically. In 1996 patients’ medical files were reviewed during site visits. 843 (84%) of the medical files were available for review. The remaining 167 files were not reviewed because the hospitals were too far away in 82 cases, 18 files were not available at time of the visit, and 67 patients were randomised after the visit. At the review further information was collected about patients, treatment, and tumour characteristics. Eligibility was checked and, if an event had occurred, detailed information was collected on methods of detection and treatment at that time. The analysis described in this paper is based on data collected during the review. In cases for which no review data were available, detailed data were requested from the local trial investigator. If there was no response to this request, the original data reported to the EORTC Data Center were used for the analysis. Data on the original diagnosis of DCIS, tumour size, and completeness of excision were derived from the report of the local pathologist.
Results Between March, 1986, and July, 1996, 1010 women were randomly assigned to no further treatment (503 patients) or to radiotherapy (507 patients) by 46 institutes from 13 different countries (figure 1). The number of randomised patients per institute varied from one to 151. The four main institutes together entered 48% of the patients. For two patients no information was available, and no follow-up data were available on another six patients. These eight patients were excluded from the analysis. 41 patients were randomised although they did not meet the criteria for entry, (25 in the no further treatment group and 16 in the radiotherapy group). 11 patients were older than 70 years, eight women had had a previous malignant disease before the diagnosis of DCIS was made, two had a histologically confirmed Paget’s disease of the nipple, and 11 had lesions larger than 5 cm. There were four cases of microinvasion (according to the local pathologist), and in seven cases the margins were affected. One patient was randomised after having undergone a mastectomy. Three patients had more than one reason for ineligibility. 11 patients who were randomised to the no further treatment group received radiotherapy, and 19 patients randomised to radiotherapy did not receive radiotherapy. Five patients assigned radiotherapy received it in more than 12 weeks following the last date of surgery. The analyses were done twice, once including all randomised patients and once excluding the ineligible cases. Because the two analyses yielded the same conclusions (data not shown), the results presented here include all randomised patients. Analysis on the basis of the
529
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Number of events
4-year recurrencefree rates
Hazard ratio (95% CI)
p
All local recurrence No treatment Treatment
83 53
84% 91%
0·62 (0·44–0·87)
0·005
DCIS recurrence* No treatment Treatment
44 29
92% 95%
0·65 (0·41–1·03)
0·06
Invasive recurrence* No treatment Treatment
40 24
92% 96%
0·60 (0·37–0·97)
Distant metastasis No treatment Treatment
12 12
98% 99%
0·98 (0·44–2·18)
Death No treatment Treatment
12 12
99% 99%
0·97 (0·44–2·16)
0·94
Contralateral breast cancer No treatment Treatment
8 21
99% 97%
2·57 (1·24–5·33)
0·01
Event-free survival No treatment Treatment
93 78
82% 86%
0·82 (0·61–1·10)
90 80 70 0·04
60 0·96
0 Numbers at risk No further treatment Radiotherapy
381
232
125
45
10
413
243
115
52
16
395
252
137
51
13
420
254
127
61
19
DCIS recurrence
0·20
Table 2: Recurrence-free intervals and hazard ratios according to treatment
treatment actually given also yielded similar results (data not shown). Characteristics of patients according to treatment group are listed in table 1. All factors are well balanced between the two groups. The cut-off date for this analysis was July 1998, when the median duration of follow-up was 4·25 years (maximum 12·0 years). There were 136 patients with local recurrences, 83 in the no further treatment group and 53 in the radiotherapy group. The local recurrence-free interval was significantly longer in the radiotherapy than in the no further treatment group (p=0·005). The 4-year local recurrence-free rates were 91% and 84%, respectively (table 2). 73 patients (44 in no further treatment group, 29 in radiotherapy group) had recurrences of DCIS, and 64 patients (40 vs 24) developed invasive breast cancer. Figure 2 shows the local, DCIS, and invasive recurrence-free intervals. There were 24 patients who developed distant metastases. Figure 3 shows the time to distant metastasis. The 4-year metastasis-free rate was similar in the two groups: 98% in the no further treatment group and 99% in the radiotherapy group. Three patients developed distant metastasis without a prior local or contralateral event, three patients following a contralateral event, one after a bilateral invasive recurrence, and 16 because of an invasive local recurrence. Only one patient in the no further treatment group had an isolated axillary lymph-node metastasis without evidence of local recurrence; she developed distant metastasis as well. There were 24 deaths. 11 patients died from ipsilateral breast recurrence (seven in the no further treatment group and four in the radiotherapy group), one patient in the no further treatment group died after an invasive contralateral breast cancer, four because of another malignant disease (one patient in the no further treatment group had bladder cancer, three in the radiotherapy group had mediastinal lymphoma, carcinoma of the sinus ethmoidalis region, or acute myeloid leukaemia). Two patients died of cardiovascular disease (one in the radiotherapy group and one in the no further treatment group), one from postoperative bleeding for another surgery (in the radiotherapy group), and three from metastases as first
Patients without events (%)
100
*1 patient with recurrence of DCIS had a second local recurrence that was invasive.
530
Local recurrence 100
90 80 70 60 0
Numbers at risk No further treatment Radiotherapy
Invasive recurrence 100 90 80 70 60
Radiotherapy No further treatment
0 0
2
4
6
8
10
12
Time (years) Numbers at risk No further treatment Radiotherapy
398
253
141
54
13
426
259
126
58
17
Figure 2: Time to local, DCIS, and invasive recurrence-free intervals by treatment group
event (one in the no further treatment group, two in the radiotherapy group). For two patients the cause of death is unknown (without evidence of recurrent disease, one in the no further treatment group and one in the radiotherapy group). The 4-year overall survival rate was 99%. Overall, the number of deaths was the same in the two groups (log rank p=0·94, figure 4). 29 patients developed a contralateral breast cancer (21 [4%] of 507 in the radiotherapy group and 8 [2%] of 503 in
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Distant metastasis
100
Patients without events (%)
100 90 80 70 60
Survival
90 80 70 60 Radiotherapy No further treatment
0
0
0
2
4
Numbers at risk No further treatment Radiotherapy
Patients without events (%)
100
408
266
151
59
15
8
10
12
433
268
135
65
19
Numbers at risk No further treatment Radiotherapy
412
273
153
60
16
433
270
138
67
20
Figure 4: Survival of patients according to treatment
First event
group versus 97% in the radiotherapy group (table 2). There was a significant difference in time to contralateral recurrence (log rank p=0·01; figure 3). 171 patients had at least one event. The first events were 133 local recurrences, 26 contralateral breast cancers, one isolated regional recurrence, three distant metastases without evidence of local recurrence and eight deaths due to other causes (figure 3). The 4-year event-free survival rate was 82% in the no further treatment group versus 86% in the radiotherapy group (table 2). Six patients had both an ipsilateral and contralateral relapse. One patient had a simultaneous bilateral recurrence of DCIS, one developed an ipsilateral invasive carcinoma at the same time as a contralateral DCIS, one had an ipsilateral DCIS 3 years after a contralateral DCIS, one had an ipsilateral DCIS recurrence 4 years after a contralateral invasive breast cancer, and two developed contralateral invasive breast cancer after having had an invasive local recurrence. Three patients with a local recurrence of DCIS (two in the no further treatment group and one in the radiotherapy group) developed a second local recurrence after breast-conserving therapy for this local recurrence; one recurrence progressed to an invasive recurrence, one patient developed Paget’s disease of the nipple, and one had a second recurrence of DCIS.
90 80 70 60 50 0
Numbers at risk No further treatment Radiotherapy
6 Time (years)
377
228
123
43
10
409
234
107
49
15
Contralateral breast cancer 100 90 80
Discussion
70 60
Radiotherapy No further treatment
0 0
2
4
6
8
10
12
Time (years) Numbers at risk No further treatment Radiotherapy
410
271
152
57
16
429
262
129
63
20
Figure 3: Time to distant metastasis, first event, and contralateral breast cancer
the no further treatment group). Eight contralateral breast tumours were DCIS (three in the no further treatment group and five in the radiotherapy group), and 21 were invasive carcinomas (five vs 16). The 4-year contralateralrecurrence-free rate was 99% in the no further treatment
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At a median follow-up of 4·25 years the results of this randomised clinical trial show that radiotherapy after local excision of DCIS of the breast gives a longer local recurrence-free interval than local excision alone. The design of our trial is similar to the National Surgical Adjuvant Breast and Bowel Project (NSABP) Trial B-17,8 which also showed a beneficial effect of radiotherapy on local control. The findings of the NSABP were unchanged in an update based on a median follow-up of 8 years.9 We compared our data with those of the NSABP B-17 data published in 1993, in view of the comparable duration of follow-up. At a median follow-up of 3·6 years, the NSABP study showed 92 local recurrences in 790 patients, a rate of 12%, with 16% in the no further treatment group and 7% in the radiotherapy group. At a median follow-up of 4·25 years in our study there were 137 local recurrences in 1002 patients, a rate of 14%, with 17% in the no further treatment group and 11% in the radiotherapy group. When the local relapses are classified as DCIS and invasive carcinomas, our study shows 531
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approximately equal reductions by radiotherapy; a reduction of DCIS recurrence from 8% to 5% (hazard ratio=0·65 [95% CI 0·41–1·03]) and a reduction from 8% to 4% (0·60 [0·37–0·97]) of invasive breast cancer. The NSABP showed a much higher reduction of invasive local recurrence after radiotherapy with a relative risk of 0·20 compared with local excision alone. Although the overall local-recurrence rates do not seem to differ much between the two studies, our study does not confirm a similar magnitude of reduction of invasive local recurrence due to radiotherapy as found in the NSABP B-17; after 4 years, even with radiotherapy, 4% of the patients developed invasive breast cancer in our study after a relatively short follow-up period. In two other large, non-randomised studies, half of the reported local relapses after local excision plus radiotherapy were invasive breast cancers.10,11 The results of our study accord with these findings. When all first events are included, there was no significant difference in event-free survival rates for the radiotherapy group (86%) compared with the no further treatment group (82%; p=0·20). This is caused by a significantly higher rate of contralateral breast cancers in the treatment group. We have no adequate explanation for this phenomenon. Studies investigating the induction of breast cancer after radiotherapy for Hodgkin’s disease have shown intervals of at least 8 years between the primary treatment and presentation of subsequent breast cancer. The first analysis of the NSABP B-17 did not report a difference in the occurrence of contralateral breast cancer, although in their 8-year update a higher, but non-significant rate of contralateral breast cancer in the treatment group was found when only those contralateral breast cancers occuring as first events (13 in the no further treatment group vs 19 in the radiotherapy group) were included. However, when all contralateral breast cancers were included in the analysis, this difference disappeared (18 vs 20).9 Studies investigating breast-conserving therapy for invasive breast cancer have not reported an increased rate of contralateral breast cancer. Although our results may have occurred by chance we will monitor this finding, because if the increase is due to radiotherapy, it will decrease the overall value of this form of therapy for DCIS patients. Silverstein and colleagues12 reported a large nonrandomised study of 333 patients with DCIS treated with breast-conserving treatment and examined factors associated with the development of a local recurrence. Three factors—DCIS classification (based on nuclear grade and presence of necrosis), size, and margin status—were combined in a prognostic index. Based on the score of this prognostic index a treatment recommendation was made. It was suggested that lesions with a low score (that is, low grade, small lesions excised with a wide free margin), could be treated conservatively without radiotherapy, with a very low risk of local recurrence. Recently, the same investigators argued that in the same group of patients the margin width is the most important prognostic factor for local recurrence in breast-conserving treatment for DCIS.13 Lesions that were excised with a margin of 10 mm or more had an excellent local recurrence-free survival rate, and postoperative radiotherapy did not lower the recurrence rate in this group. However, our study has not confirmed the theory of subgroups requiring different treatments. The number of events is still too small in our study for identification of subgroups of patients who will benefit to different degrees from radiotherapy. The results of a centrally coordinated histology review are forthcoming.
532
At a median follow-up of 4·25 years, similar rates of distant metastases and death were observed in the two groups. However, these numbers are (fortunately) still very small. The risk of eventually dying from breast cancer when DCIS is treated with breast-conserving treatment is still not clear. In this study 15 patients died from breast cancer. Although this does not seem a high rate, the follow-up time was relatively short. A few of these deaths would probably have occurred even if the patients had initially had a mastectomy. However, given the number of invasive local recurrences, a significant number will probably die from metastatic disease. Longer follow-up is needed to investigate whether the beneficial effect of radiotherapy on local control will improve survival rates. Although mastectomy for DCIS results in a virtually 100% cure rate, the disease can occassionally recur.14 Also, missed invasive foci in mastectomy samples possibly account for a few deaths from breast cancer. Although a randomised study comparing mastectomy with breastconserving treatment for DCIS has never been done, several non-randomised studies have shown that survival rates after mastectomy do not reach 100%.15 Other options, apart from ablative treatment followed by reconstruction, include the use of hormonal therapy such as tamoxifen. The results of the NSABPB-24 showed a significant decrease in the risk of breast-cancer events in patients treated with local excision, radiotherapy, and tamoxifen, compared with local excision and radiotherapy alone.16 Patients with an unacceptably high risk of local recurrence despite breast-conserving surgery plus radiotherapy (and tamoxifen) need to be identified so that they can be offered mastectomy. Also, patients should be identified who have a very low risk of local recurrence, and whose benefit from adjuvant therapy is so small that they may be offered the option of local excision alone. Contributors (identified according to EORTC co-authorship rules) J-P Julien and I S Fentiman coordinated the trial, wrote the protocol, and monitored the trial. N Bijker did the review on site, prepared the database for analysis, and wrote the paper. J L Peterse reviewed the histological material and wrote the protocol. V Delledonne, P Rouanet, and A Avril contributed 10% or more of all patients entered. R Sylvester did the statistical analysis. F Mignolet was the data manager. H Bartelink and J A van Dongen wrote the protocol.
The European Organization for Research and Treatment of Cancer (EORTC) Investigators Istituto Nazionale Dei Tumori, Milano, Italy (B Salvadori, V Delledonne), Institut Bergonié, Bordeaux, France (A Avril), Center Henri Becquerel, Rouen, France (J-P Julien), CRCL Val D’Aurelle, Montpellier, France (xx Rouanet), Institut Jules Bordet, Brussels, Belgium (M Coibion), University Hospital Gasthuisberg, Leuven, Belgium (J Wildiers), Radiotherapeutisch Instituut, Arnhem, Netherlands (W J B M Huls), The Netherlands Cancer Institute, Amserdam, Netherlands (E J T Rutgers), Rotterdam Radiotherapeutisch Institut, Netherlands (P C M Koper, C Griwp), Dr Bernard Verbeeten Instituut, Tilberg, Netherlands (H P Hamers), Ospedale Civile, Genova, Italy (G Canavese), Integraal Kankercentrum West, Leiden, Netherlands (M B Lagaaij), Policlinico di Careggi, Florence, Italy (L Cataliotti), University Hospital Leiden, Netherlands (J W H Leer), Radiotherapeutisch Instituut Limburg, Heerlen, Netherlands (J J Jager), Guy’s Hospital, London, England (I S Fentiman), St Radboud Ziekenhuis, Nijmegen, Netherlands (T Wobbes), Integraal Kankercentrum West, Amsterdam, Netherlands (H W Siebbeles), Academisch Ziekenhuis Utrecht, Netherlands (H Struikmans), Center Eugéne Marquis, Rennes, France (C Chenal), St Savas Hospital, Athens, Greece (I Karydas), I P O, Porto, Portugal (J Cardoso da Silva), Western General Hospital, Edinburgh, Scotland (U Chetty, H J Stewart), Istituto Europea di Oncologia, Milano, Italy (V Sacchini), Center Georges-François Leclerc, Dijon, France (J C Horiot), Hôpital Jean Minjoz, Besançon, France (S Schraub, J F Bosset), Academisch Medisch Centrum, Amsterdam, Netherlands (C W Taat), Istituto de Ginecologia e Ostetrica, Torino, Italy (D Katsaros), Universitätsklinik für Chirurgie, Graz, Austria (M G L Smola), Marika Eliadi Hospital, Athens, Greece (S Vassilaros), I Universitäts Klinik für Chirurgie, Innsbruck, Austria (M Duenser), Radiotherapeutisch Instituut Friesland, Leeuwarden, Netherlands
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ARTICLES (G Botke), Policlinico di Borgo Roma, Verona, Italy (S Modena), Ospedale de Noale, Italy (M Bari). Instituto Oncologia San Sebastian, Spain (J A Alberro), Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands (K J Roozendael), Diakonessenhuis, Utrecht, Netherlands (J W R Nortier), Ninewells Hospital, Dundee, Scotland (P E Preece), Dijkzight Ziekenhuis, Rotterdam, Netherlands (T A W Splinter), Andreas Ziekenhuis, Amsterdam, Netherlands (R Weller), Streekziekenhuizen Gooi-Noord, Blaricum, Netherlands (M A N Gerrits), Universitätsklinik, Göttingen, Germany (H Rauschecker), Hôpital Cantonal de Genève, Switzerland (L Perey), Tygerberg Hospital, South Africa (J Van Zijl), Rambam Medical Centre, Haïfa, Israël (A Kuten), C H U Vaudois, Lausanne, Switzerland (R Mirimanoff).
5 6 7 8
9
Acknowledgments This trial was supported by grants number 2U10 CA11488–16 through 5U10 CA11488–28 from the National Cancer Institute (Bethesda, Maryland, USA). The contents are solely the responsibility of the investigators and do not necessarily represent the official views of the National Cancer Institute.
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3
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comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995; 332: 907–11. Recht A, Rutgers EJTh, Fentiman IS, et al. The fourth EORTC DCIS consensus meeting: conference report. Eur J Cancer 1998; 34: 1664–69. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81. Shiragai A. A proposal concerning the absorbed dose conversion factor. Phys Med Biol 1978; 23: 245–52. Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993; 328: 1581–86. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from national surgical adjuvant breast and bowel project B-17. J Clin Oncol 1998; 16: 441–52. Solin LJ, Kurtz J, Fourquet A, et al. Fifteen-year results of breastconserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol 1996; 14: 754–63. Silverstein MJ, Barth A, Poller DN, et al. Ten-year results comparing mastectomy to excision and radiation therapy for ductal carcinoma in situ of the breast. Eur J Cancer 1995; 31A: 1425–27. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996; 77: 2267–74. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 1999; 340: 1455–61. De Jong E, Peterse JL, Van Dongen JA. Recurrence after breast ablation for ductal carcinoma in situ. Eur J Surg Oncol 1992; 18: 64–66. Schnitt SJ, Silen W, Sadowski NL, Connolly JL, Harris JR. Ductal carcinoma in situ (intraductal carcinoma) of the breast. N Engl J Med 1988; 318: 898–903. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999; 353: 1993–2000.
Stress and psychiatric disorder in healthcare professionals and hospital staff Ashley Weinberg, Francis Creed
Summary Background Previous studies of stress in healthcare staff have indicated a probable high prevalence of distress. Whether this distress can be attributed to the stressful nature of the work situation is not clear. No previous study has used a detailed interview method to ascertain the link between stress in and outside of work and anxiety and depressive disorders. Methods Doctors, nurses, and administrative and ancillary staff were screened using the general health questionnaire (GHQ). High scorers (GHQ>4) and matched individuals with low GHQ scores were interviewed by means of the clinical interview schedule to ascertain definite anxiety and depressive disorders (cases). Cases and controls, matched for age, sex, and occupational group were interviewed with the life events and difficulties schedule classification and an objective measure of work stress to find out the amount of stress at work and outside of work. Sociodemographic and stress variables were entered into a logistic-regression analysis to find out the variables associated with anxiety and depressive disorders. Findings 64 cases and 64 controls were matched. Cases and controls did not differ on demographic variables but cases were less likely to have a confidant (odds ratio 0·09 [95% CI 0·01–0·79]) and more likely to have had a previous episode of
psychiatric disorder (3·07 [1·10–8·57]). Cases and controls worked similar hours and had similar responsibility but cases had a greater number of objective stressful situations both in and out of work (severe event or substantial difficulty in and out of work—45 cases vs 18 controls 6·05 [2·81–13·00], p<0·001; severe chronic difficulty outside of work—27 vs 8, 5·12 [2·09–12·46], p<0·001). Cases had significantly more objective work problems than controls (median 6 vs 4, z=3·81, p<0·001). The logistic-regression analyses indicated that even after the effects of personal vulnerability to psychiatric disorder and ongoing social stress outside of work had been taken into account, stressful situations at work contributed to anxiety and depressive disorders. Interpretation Both stress at work and outside of work contribute to the anxiety and depressive disorders experienced by healthcare staff. Our findings suggest that the best way to decrease the prevalence of these disorders is individual treatment, which may focus on personal difficulties outside of work, combined with organisational attempts to reduce work stress. The latter may involve more assistance for staff who have a conflict between their managerial role and clinical role. Lancet 2000; 355: 533–37
Introduction Faculty of Health Care and Social Work Studies, University of Salford, Allerton Building, Salford M6 6PU, UK (A Weinberg PhD, Prof F Creed MD) Correspondence to: Dr Ashley Weinberg (e-mail: [email protected])
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Numerous studies have shown high amounts of psychological distress in doctors, nurses, and other healthcare professionals working in various situations.1–8 In the UK, 20 reports have indicated that a quarter to a half of the National Health Service (NHS) staff report distress,9 which may be a higher
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Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853 Jean-Pierre Julien, Nina Bijker, Ian S Fentiman, Johannes L Peterse, Vincenzo Delledonne, Philippe Rouanet, Antoine Avril, Richard Sylvester, Françoise Mignolet, Harry Bartelink, Joop A Van Dongen, on behalf of the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group
Summary Background Ductal carcinoma in situ (DCIS) of the breast is a disorder that has become more common since it may manifest as microcalcifications that can be detected by screening mammography. Since selected women with invasive cancer can be treated safely with breast-conservation therapy it is paradoxical that total mastectomy has remained the standard treatment for DCIS. We did a randomised phase III clinical trial to investigate the role of radiotherapy after complete local excision of DCIS. Methods Between 1986 and 1996, women with clinically or mammographically detected DCIS measuring less than or equal to 5 cm were treated by complete local excision of the lesion and then randomly assigned to either no further treatment (n=503) or to radiotherapy (n=507; 50 Gy in 5 weeks to the whole breast). The median duration of follow-up was 4·25 years (maximum 12·0 years). All analyses were by intention to treat. Findings 500 patients were followed up in the no further treatment group and 502 in the radiotherapy group. In the no further treatment group 83 women had local recurrence (44 recurrences of DCIS, and 40 invasive breast cancer). In the radiotherapy group 53 women had local recurrences (29 recurrences of DCIS, and 24 invasive breast cancer). The 4year local relapse-free was 84% in the group treated with local excision alone compared with 91% in the women treated by local excision plus radiotherapy (log rank p=0·005; hazard ratio 0·62). Similar reductions in the risk of invasive (40%, p=0·04) and non-invasive (35%, p=0·06) local recurrence were seen. Conclusions Radiotherapy after local excision for DCIS, as compared with local excision alone, reduced the overall number of both invasive and non-invasive recurrences in the ipsilateral breast at a median follow-up of 4·25 years. Lancet 2000; 355: 528–33 See Commentary page ???
Department of Surgery, Centre Henri Becquerel, Rue D’Amiens 1, 76038 Rouen, France (J-P Julien MD); Department of Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands (N Bijker MD, J L Peterse MD); Guy’s Hospital, Clinical Oncology Unit, London SE1 9RT, UK (Ian S Fentiman FRCS); Department of Surgery, Istituto Nazionale dei Tumori, 20133 Milan, Italy (V Delledonne MD); Department of Surgery, CRLC Val D’Aurelle, 34094 Montpellier, France (P Rouanet MD); Department of Surgery, Institut Bergonié, 33076 Bordeaux, France (A Avril MD); EORTC Data Center, 1200 Brussels, Belgium (R Sylvester ScD, F Mignolet); Department of Radiotherapy (H Bartelink MD); and Department of Surgery (J A Van Dongen MD), 1066 CX Amsterdam, The Netherlands Correspondence to: Dr Jean-Pierre Julien (e-mail: [email protected])
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Introduction Breast-conserving treatment for patients with ductal carcinoma in situ (DCIS) is a relatively new treatment option. Until a decade ago total mastectomy was the standard treatment for women with DCIS. At that time DCIS was a rare disease, comprising only 2–5% of all breast cancers presenting clinically as a palpable mass, bloody nipple discharge, or Paget’s disease of the nipple. An almost 100% cure rate could be achieved with ablative treatment. Rare exceptions were cases labelled as DCIS but with histologically undetected microinvasion from which tumour emboli emerged and gave rise to distant metastases. With the widespread use of mammographic screening, the incidence of DCIS has increased, such that these lesions now comprise 15–20% of all breast cancers detected in population screening programmes. Most of these cases are clinically occult and detected because of microcalcifications on mammograms. For selected women with invasive breast carcinoma, breast-conserving therapy has already proved to be as effective as mastectomy.1–4 Hence it is paradoxical that DCIS, a non-invasive lesion, is generally treated by more extensive surgery than is invasive breast cancer. But whereas mastectomy for DCIS can almost invariably cure, breast-conserving treatment in DCIS could increase the risk of residual disease, which might recur and progress into invasive carcinoma, thereby increasing the risk of death from metastatic disease. In the mid-eighties several randomised clinical trials were started to find out what is the best breast-conserving treatment for patients with DCIS.5 We report the initial results of a phase III randomised study done between 1986 and 1996 to examine the effect of radiotherapy after local excision of DCIS.
Methods Participants Women with DCIS of the breast were randomly assigned radiotherapy, or no further treatment after histological confirmation that the lesion had been completely excised. Extent of free margins was not specified other than that DCIS should not be present at the margin of the sample. Patients gave informed consent according to the institute’s regulations. Patients with lesions with a diameter up to 5 cm, without evidence of invasive carcinoma or Paget’s disease of the nipple, were eligible for the study. Size was determined by either clinical measurement or from the extent of microcalcifications on the mammograms. Axillary dissection was not required or advised but, if done, the axillary lymph nodes had to be free of metastases. Patients were excluded who were more than 70 years of age, were pregnant, or had a past or concomitant malignant disease other than adequately treated basal-cell carcinoma of the skin or conebiopsied carcinoma in situ of the cervix. Those with a performance status of greater than or equal to 2 according to the WHO criteria, or with a mental condition or social situation precluding long-term follow-up, were also excluded.
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1010 women randomised
503 assigned no further treatment
507 assigned radiotherapy
3 lost to follow-up
5 lost to follow-up
500 analysed
502 analysed
Figure 1: Trial profile
Study design Patients were centrally randomised at the EORTC Data Center. Randomisation was done by minimisation and was stratified for institution. The primary endpoints were invasive and non-invasive recurrence in the treated breast. Secondary endpoints included regional recurrence, metastasis, death, and contralateral breast cancer. Recurrence-free intervals were defined as the time between the date of randomisation and the date of recurrence of the disease. All analyses were by intent to treat. All randomised patients for whom information was available were included. The time-torecurrence curves were calculated with the Kaplan-Meier analysis6 and compared by means of a two-sided log-rank test. Size of the treatment difference was calculated on the basis of the hazards ratio and its 95% CI. All patients underwent wide resection of the portion of the mammary gland harbouring the lesion. The resection was intended to remove the whole lesion or the entire area with microcalcifications. The cutaneous incision, depending on the tumour site and size, was radial or curvilinear to obtain the best cosmetic result. The surgical samples were sent to the pathologist to have the margins inked and to get information on histology and margin status. If the DCIS was incompletely excised at the first attempt, a second operation was done. External-beam radiotherapy had to be started within 12 weeks after surgery. The patient was irradiated in the supine position with immobilisation of the ipsilateral arm. The target area had to encompass the chest wall. The breast was irradiated by means of medial and tangential portals. The medial border was drawn at the midline, and the upper border was drawn between the first and second intercostal spaces and laterally to the soft tissue of the central axilla. The dorsal border was at the midaxillary line or 1–2 cm beyond, depending on breast tissue. The lower border was 1 cm below the inframammary sulcus. In addition, the margin had to be at least 2 cm clear of any incision. Correction for divergence had to be made by a slight angulation of the beam to obtain a flat dorsal plane. In this way, unnecessary irradiation of lung tissue No further treatment (n=503) Median (range) age (years) Clinical signs Palpable lesion Mean diameter of palpable lesion (mm) Nipple discharge Mammographic lesion only Mean diameter of mammographic abnormality (mm) Surgery Number of operations One Two Three Axillary dissection done Radiotherapy Boost received*
53 (25–76)
Radiotherapy (n=507) 53 (27–74)
Total (n=1010) 53 (25–76)
109 (22%) 22 40 (8%) 350 (70%) 20
99 (19%) 21 34 (7%) 372 (73%) 20
208 (21%) 21 74 (7%) 722 (71%) 20
321 (64%) 178 (35%) 1 (<1%) 98 (19%)
336 (66%) 158 (31%) 6 (1%) 104 (21%)
657 (65%) 336 (33%) 7 (1%) 202 (20%)
··
26 (5%)
··
All data are number of patients (%) unless where indicated. *Median dose 10 Gy.
Table 1: Characteristics of patients and treatment received
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could be reduced. The second measure to limit the irradiation of unnecessary lung tissue was the adaptation of the dorsal planes of the treatment portals to the angle of the chest wall. The patient had to be irradiated each day through both tangential portals. To achieve a homogeneous dose distribution over the whole breast, a compensatory filter or wedge was used for each individual patient. The maximum allowable difference in dose distribution over the target volume in the central plane was 10%. The prescribed irradiation dose was 50 Gy in 25 fractions (2 Gy per fraction) to be given in 5 weeks. This dose was directed at the intersection of the central axis of the beams (according to the International Commission on Radiation Units and Measurements definition7), or, if this intersection was outside the target volume because of correction for divergence, the dose had to be directed in the centre of the target volume. No boost was advised nor were the adjacent lymph-node stations irradiated. Patients were followed at 6-monthly intervals until the 10th postoperative year, and then at annually intervals. Bilateral mammograms had to be done every year. Follow-up data were sent yearly at the EORTC Data Center. Suspected local or regional recurrences had to be confirmed histologically. In 1996 patients’ medical files were reviewed during site visits. 843 (84%) of the medical files were available for review. The remaining 167 files were not reviewed because the hospitals were too far away in 82 cases, 18 files were not available at time of the visit, and 67 patients were randomised after the visit. At the review further information was collected about patients, treatment, and tumour characteristics. Eligibility was checked and, if an event had occurred, detailed information was collected on methods of detection and treatment at that time. The analysis described in this paper is based on data collected during the review. In cases for which no review data were available, detailed data were requested from the local trial investigator. If there was no response to this request, the original data reported to the EORTC Data Center were used for the analysis. Data on the original diagnosis of DCIS, tumour size, and completeness of excision were derived from the report of the local pathologist.
Results Between March, 1986, and July, 1996, 1010 women were randomly assigned to no further treatment (503 patients) or to radiotherapy (507 patients) by 46 institutes from 13 different countries (figure 1). The number of randomised patients per institute varied from one to 151. The four main institutes together entered 48% of the patients. For two patients no information was available, and no follow-up data were available on another six patients. These eight patients were excluded from the analysis. 41 patients were randomised although they did not meet the criteria for entry, (25 in the no further treatment group and 16 in the radiotherapy group). 11 patients were older than 70 years, eight women had had a previous malignant disease before the diagnosis of DCIS was made, two had a histologically confirmed Paget’s disease of the nipple, and 11 had lesions larger than 5 cm. There were four cases of microinvasion (according to the local pathologist), and in seven cases the margins were affected. One patient was randomised after having undergone a mastectomy. Three patients had more than one reason for ineligibility. 11 patients who were randomised to the no further treatment group received radiotherapy, and 19 patients randomised to radiotherapy did not receive radiotherapy. Five patients assigned radiotherapy received it in more than 12 weeks following the last date of surgery. The analyses were done twice, once including all randomised patients and once excluding the ineligible cases. Because the two analyses yielded the same conclusions (data not shown), the results presented here include all randomised patients. Analysis on the basis of the
529
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Number of events
4-year recurrencefree rates
Hazard ratio (95% CI)
p
All local recurrence No treatment Treatment
83 53
84% 91%
0·62 (0·44–0·87)
0·005
DCIS recurrence* No treatment Treatment
44 29
92% 95%
0·65 (0·41–1·03)
0·06
Invasive recurrence* No treatment Treatment
40 24
92% 96%
0·60 (0·37–0·97)
Distant metastasis No treatment Treatment
12 12
98% 99%
0·98 (0·44–2·18)
Death No treatment Treatment
12 12
99% 99%
0·97 (0·44–2·16)
0·94
Contralateral breast cancer No treatment Treatment
8 21
99% 97%
2·57 (1·24–5·33)
0·01
Event-free survival No treatment Treatment
93 78
82% 86%
0·82 (0·61–1·10)
90 80 70 0·04
60 0·96
0 Numbers at risk No further treatment Radiotherapy
381
232
125
45
10
413
243
115
52
16
395
252
137
51
13
420
254
127
61
19
DCIS recurrence
0·20
Table 2: Recurrence-free intervals and hazard ratios according to treatment
treatment actually given also yielded similar results (data not shown). Characteristics of patients according to treatment group are listed in table 1. All factors are well balanced between the two groups. The cut-off date for this analysis was July 1998, when the median duration of follow-up was 4·25 years (maximum 12·0 years). There were 136 patients with local recurrences, 83 in the no further treatment group and 53 in the radiotherapy group. The local recurrence-free interval was significantly longer in the radiotherapy than in the no further treatment group (p=0·005). The 4-year local recurrence-free rates were 91% and 84%, respectively (table 2). 73 patients (44 in no further treatment group, 29 in radiotherapy group) had recurrences of DCIS, and 64 patients (40 vs 24) developed invasive breast cancer. Figure 2 shows the local, DCIS, and invasive recurrence-free intervals. There were 24 patients who developed distant metastases. Figure 3 shows the time to distant metastasis. The 4-year metastasis-free rate was similar in the two groups: 98% in the no further treatment group and 99% in the radiotherapy group. Three patients developed distant metastasis without a prior local or contralateral event, three patients following a contralateral event, one after a bilateral invasive recurrence, and 16 because of an invasive local recurrence. Only one patient in the no further treatment group had an isolated axillary lymph-node metastasis without evidence of local recurrence; she developed distant metastasis as well. There were 24 deaths. 11 patients died from ipsilateral breast recurrence (seven in the no further treatment group and four in the radiotherapy group), one patient in the no further treatment group died after an invasive contralateral breast cancer, four because of another malignant disease (one patient in the no further treatment group had bladder cancer, three in the radiotherapy group had mediastinal lymphoma, carcinoma of the sinus ethmoidalis region, or acute myeloid leukaemia). Two patients died of cardiovascular disease (one in the radiotherapy group and one in the no further treatment group), one from postoperative bleeding for another surgery (in the radiotherapy group), and three from metastases as first
Patients without events (%)
100
*1 patient with recurrence of DCIS had a second local recurrence that was invasive.
530
Local recurrence 100
90 80 70 60 0
Numbers at risk No further treatment Radiotherapy
Invasive recurrence 100 90 80 70 60
Radiotherapy No further treatment
0 0
2
4
6
8
10
12
Time (years) Numbers at risk No further treatment Radiotherapy
398
253
141
54
13
426
259
126
58
17
Figure 2: Time to local, DCIS, and invasive recurrence-free intervals by treatment group
event (one in the no further treatment group, two in the radiotherapy group). For two patients the cause of death is unknown (without evidence of recurrent disease, one in the no further treatment group and one in the radiotherapy group). The 4-year overall survival rate was 99%. Overall, the number of deaths was the same in the two groups (log rank p=0·94, figure 4). 29 patients developed a contralateral breast cancer (21 [4%] of 507 in the radiotherapy group and 8 [2%] of 503 in
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Distant metastasis
100
Patients without events (%)
100 90 80 70 60
Survival
90 80 70 60 Radiotherapy No further treatment
0
0
0
2
4
Numbers at risk No further treatment Radiotherapy
Patients without events (%)
100
408
266
151
59
15
8
10
12
433
268
135
65
19
Numbers at risk No further treatment Radiotherapy
412
273
153
60
16
433
270
138
67
20
Figure 4: Survival of patients according to treatment
First event
group versus 97% in the radiotherapy group (table 2). There was a significant difference in time to contralateral recurrence (log rank p=0·01; figure 3). 171 patients had at least one event. The first events were 133 local recurrences, 26 contralateral breast cancers, one isolated regional recurrence, three distant metastases without evidence of local recurrence and eight deaths due to other causes (figure 3). The 4-year event-free survival rate was 82% in the no further treatment group versus 86% in the radiotherapy group (table 2). Six patients had both an ipsilateral and contralateral relapse. One patient had a simultaneous bilateral recurrence of DCIS, one developed an ipsilateral invasive carcinoma at the same time as a contralateral DCIS, one had an ipsilateral DCIS 3 years after a contralateral DCIS, one had an ipsilateral DCIS recurrence 4 years after a contralateral invasive breast cancer, and two developed contralateral invasive breast cancer after having had an invasive local recurrence. Three patients with a local recurrence of DCIS (two in the no further treatment group and one in the radiotherapy group) developed a second local recurrence after breast-conserving therapy for this local recurrence; one recurrence progressed to an invasive recurrence, one patient developed Paget’s disease of the nipple, and one had a second recurrence of DCIS.
90 80 70 60 50 0
Numbers at risk No further treatment Radiotherapy
6 Time (years)
377
228
123
43
10
409
234
107
49
15
Contralateral breast cancer 100 90 80
Discussion
70 60
Radiotherapy No further treatment
0 0
2
4
6
8
10
12
Time (years) Numbers at risk No further treatment Radiotherapy
410
271
152
57
16
429
262
129
63
20
Figure 3: Time to distant metastasis, first event, and contralateral breast cancer
the no further treatment group). Eight contralateral breast tumours were DCIS (three in the no further treatment group and five in the radiotherapy group), and 21 were invasive carcinomas (five vs 16). The 4-year contralateralrecurrence-free rate was 99% in the no further treatment
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At a median follow-up of 4·25 years the results of this randomised clinical trial show that radiotherapy after local excision of DCIS of the breast gives a longer local recurrence-free interval than local excision alone. The design of our trial is similar to the National Surgical Adjuvant Breast and Bowel Project (NSABP) Trial B-17,8 which also showed a beneficial effect of radiotherapy on local control. The findings of the NSABP were unchanged in an update based on a median follow-up of 8 years.9 We compared our data with those of the NSABP B-17 data published in 1993, in view of the comparable duration of follow-up. At a median follow-up of 3·6 years, the NSABP study showed 92 local recurrences in 790 patients, a rate of 12%, with 16% in the no further treatment group and 7% in the radiotherapy group. At a median follow-up of 4·25 years in our study there were 137 local recurrences in 1002 patients, a rate of 14%, with 17% in the no further treatment group and 11% in the radiotherapy group. When the local relapses are classified as DCIS and invasive carcinomas, our study shows 531
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approximately equal reductions by radiotherapy; a reduction of DCIS recurrence from 8% to 5% (hazard ratio=0·65 [95% CI 0·41–1·03]) and a reduction from 8% to 4% (0·60 [0·37–0·97]) of invasive breast cancer. The NSABP showed a much higher reduction of invasive local recurrence after radiotherapy with a relative risk of 0·20 compared with local excision alone. Although the overall local-recurrence rates do not seem to differ much between the two studies, our study does not confirm a similar magnitude of reduction of invasive local recurrence due to radiotherapy as found in the NSABP B-17; after 4 years, even with radiotherapy, 4% of the patients developed invasive breast cancer in our study after a relatively short follow-up period. In two other large, non-randomised studies, half of the reported local relapses after local excision plus radiotherapy were invasive breast cancers.10,11 The results of our study accord with these findings. When all first events are included, there was no significant difference in event-free survival rates for the radiotherapy group (86%) compared with the no further treatment group (82%; p=0·20). This is caused by a significantly higher rate of contralateral breast cancers in the treatment group. We have no adequate explanation for this phenomenon. Studies investigating the induction of breast cancer after radiotherapy for Hodgkin’s disease have shown intervals of at least 8 years between the primary treatment and presentation of subsequent breast cancer. The first analysis of the NSABP B-17 did not report a difference in the occurrence of contralateral breast cancer, although in their 8-year update a higher, but non-significant rate of contralateral breast cancer in the treatment group was found when only those contralateral breast cancers occuring as first events (13 in the no further treatment group vs 19 in the radiotherapy group) were included. However, when all contralateral breast cancers were included in the analysis, this difference disappeared (18 vs 20).9 Studies investigating breast-conserving therapy for invasive breast cancer have not reported an increased rate of contralateral breast cancer. Although our results may have occurred by chance we will monitor this finding, because if the increase is due to radiotherapy, it will decrease the overall value of this form of therapy for DCIS patients. Silverstein and colleagues12 reported a large nonrandomised study of 333 patients with DCIS treated with breast-conserving treatment and examined factors associated with the development of a local recurrence. Three factors—DCIS classification (based on nuclear grade and presence of necrosis), size, and margin status—were combined in a prognostic index. Based on the score of this prognostic index a treatment recommendation was made. It was suggested that lesions with a low score (that is, low grade, small lesions excised with a wide free margin), could be treated conservatively without radiotherapy, with a very low risk of local recurrence. Recently, the same investigators argued that in the same group of patients the margin width is the most important prognostic factor for local recurrence in breast-conserving treatment for DCIS.13 Lesions that were excised with a margin of 10 mm or more had an excellent local recurrence-free survival rate, and postoperative radiotherapy did not lower the recurrence rate in this group. However, our study has not confirmed the theory of subgroups requiring different treatments. The number of events is still too small in our study for identification of subgroups of patients who will benefit to different degrees from radiotherapy. The results of a centrally coordinated histology review are forthcoming.
532
At a median follow-up of 4·25 years, similar rates of distant metastases and death were observed in the two groups. However, these numbers are (fortunately) still very small. The risk of eventually dying from breast cancer when DCIS is treated with breast-conserving treatment is still not clear. In this study 15 patients died from breast cancer. Although this does not seem a high rate, the follow-up time was relatively short. A few of these deaths would probably have occurred even if the patients had initially had a mastectomy. However, given the number of invasive local recurrences, a significant number will probably die from metastatic disease. Longer follow-up is needed to investigate whether the beneficial effect of radiotherapy on local control will improve survival rates. Although mastectomy for DCIS results in a virtually 100% cure rate, the disease can occassionally recur.14 Also, missed invasive foci in mastectomy samples possibly account for a few deaths from breast cancer. Although a randomised study comparing mastectomy with breastconserving treatment for DCIS has never been done, several non-randomised studies have shown that survival rates after mastectomy do not reach 100%.15 Other options, apart from ablative treatment followed by reconstruction, include the use of hormonal therapy such as tamoxifen. The results of the NSABPB-24 showed a significant decrease in the risk of breast-cancer events in patients treated with local excision, radiotherapy, and tamoxifen, compared with local excision and radiotherapy alone.16 Patients with an unacceptably high risk of local recurrence despite breast-conserving surgery plus radiotherapy (and tamoxifen) need to be identified so that they can be offered mastectomy. Also, patients should be identified who have a very low risk of local recurrence, and whose benefit from adjuvant therapy is so small that they may be offered the option of local excision alone. Contributors (identified according to EORTC co-authorship rules) J-P Julien and I S Fentiman coordinated the trial, wrote the protocol, and monitored the trial. N Bijker did the review on site, prepared the database for analysis, and wrote the paper. J L Peterse reviewed the histological material and wrote the protocol. V Delledonne, P Rouanet, and A Avril contributed 10% or more of all patients entered. R Sylvester did the statistical analysis. F Mignolet was the data manager. H Bartelink and J A van Dongen wrote the protocol.
The European Organization for Research and Treatment of Cancer (EORTC) Investigators Istituto Nazionale Dei Tumori, Milano, Italy (B Salvadori, V Delledonne), Institut Bergonié, Bordeaux, France (A Avril), Center Henri Becquerel, Rouen, France (J-P Julien), CRCL Val D’Aurelle, Montpellier, France (xx Rouanet), Institut Jules Bordet, Brussels, Belgium (M Coibion), University Hospital Gasthuisberg, Leuven, Belgium (J Wildiers), Radiotherapeutisch Instituut, Arnhem, Netherlands (W J B M Huls), The Netherlands Cancer Institute, Amserdam, Netherlands (E J T Rutgers), Rotterdam Radiotherapeutisch Institut, Netherlands (P C M Koper, C Griwp), Dr Bernard Verbeeten Instituut, Tilberg, Netherlands (H P Hamers), Ospedale Civile, Genova, Italy (G Canavese), Integraal Kankercentrum West, Leiden, Netherlands (M B Lagaaij), Policlinico di Careggi, Florence, Italy (L Cataliotti), University Hospital Leiden, Netherlands (J W H Leer), Radiotherapeutisch Instituut Limburg, Heerlen, Netherlands (J J Jager), Guy’s Hospital, London, England (I S Fentiman), St Radboud Ziekenhuis, Nijmegen, Netherlands (T Wobbes), Integraal Kankercentrum West, Amsterdam, Netherlands (H W Siebbeles), Academisch Ziekenhuis Utrecht, Netherlands (H Struikmans), Center Eugéne Marquis, Rennes, France (C Chenal), St Savas Hospital, Athens, Greece (I Karydas), I P O, Porto, Portugal (J Cardoso da Silva), Western General Hospital, Edinburgh, Scotland (U Chetty, H J Stewart), Istituto Europea di Oncologia, Milano, Italy (V Sacchini), Center Georges-François Leclerc, Dijon, France (J C Horiot), Hôpital Jean Minjoz, Besançon, France (S Schraub, J F Bosset), Academisch Medisch Centrum, Amsterdam, Netherlands (C W Taat), Istituto de Ginecologia e Ostetrica, Torino, Italy (D Katsaros), Universitätsklinik für Chirurgie, Graz, Austria (M G L Smola), Marika Eliadi Hospital, Athens, Greece (S Vassilaros), I Universitäts Klinik für Chirurgie, Innsbruck, Austria (M Duenser), Radiotherapeutisch Instituut Friesland, Leeuwarden, Netherlands
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ARTICLES (G Botke), Policlinico di Borgo Roma, Verona, Italy (S Modena), Ospedale de Noale, Italy (M Bari). Instituto Oncologia San Sebastian, Spain (J A Alberro), Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands (K J Roozendael), Diakonessenhuis, Utrecht, Netherlands (J W R Nortier), Ninewells Hospital, Dundee, Scotland (P E Preece), Dijkzight Ziekenhuis, Rotterdam, Netherlands (T A W Splinter), Andreas Ziekenhuis, Amsterdam, Netherlands (R Weller), Streekziekenhuizen Gooi-Noord, Blaricum, Netherlands (M A N Gerrits), Universitätsklinik, Göttingen, Germany (H Rauschecker), Hôpital Cantonal de Genève, Switzerland (L Perey), Tygerberg Hospital, South Africa (J Van Zijl), Rambam Medical Centre, Haïfa, Israël (A Kuten), C H U Vaudois, Lausanne, Switzerland (R Mirimanoff).
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Acknowledgments This trial was supported by grants number 2U10 CA11488–16 through 5U10 CA11488–28 from the National Cancer Institute (Bethesda, Maryland, USA). The contents are solely the responsibility of the investigators and do not necessarily represent the official views of the National Cancer Institute.
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Veronesi U, Salvadori B, Luini A, et al. Breast conservation is a safe method in patients with small cancer of the breast: long-term results of three randomised trials on 1973 patients. Eur J Cancer 1995; 31A: 1574–79. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomised clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989; 320: 822–28. Van Dongen JA, Bartelink H, Fentiman IS, et al. Factors influencing local relapse and survival and results of salvage treatment after breastconserving therapy in operable breast cancer: EORTC Trial 10801, breast conservation compared with mastectomy in TNM stage I and II breast cancer. Eur J Cancer 1992; 28A: 801–05. Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a
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comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995; 332: 907–11. Recht A, Rutgers EJTh, Fentiman IS, et al. The fourth EORTC DCIS consensus meeting: conference report. Eur J Cancer 1998; 34: 1664–69. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81. Shiragai A. A proposal concerning the absorbed dose conversion factor. Phys Med Biol 1978; 23: 245–52. Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993; 328: 1581–86. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from national surgical adjuvant breast and bowel project B-17. J Clin Oncol 1998; 16: 441–52. Solin LJ, Kurtz J, Fourquet A, et al. Fifteen-year results of breastconserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol 1996; 14: 754–63. Silverstein MJ, Barth A, Poller DN, et al. Ten-year results comparing mastectomy to excision and radiation therapy for ductal carcinoma in situ of the breast. Eur J Cancer 1995; 31A: 1425–27. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996; 77: 2267–74. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 1999; 340: 1455–61. De Jong E, Peterse JL, Van Dongen JA. Recurrence after breast ablation for ductal carcinoma in situ. Eur J Surg Oncol 1992; 18: 64–66. Schnitt SJ, Silen W, Sadowski NL, Connolly JL, Harris JR. Ductal carcinoma in situ (intraductal carcinoma) of the breast. N Engl J Med 1988; 318: 898–903. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999; 353: 1993–2000.
Stress and psychiatric disorder in healthcare professionals and hospital staff Ashley Weinberg, Francis Creed
Summary Background Previous studies of stress in healthcare staff have indicated a probable high prevalence of distress. Whether this distress can be attributed to the stressful nature of the work situation is not clear. No previous study has used a detailed interview method to ascertain the link between stress in and outside of work and anxiety and depressive disorders. Methods Doctors, nurses, and administrative and ancillary staff were screened using the general health questionnaire (GHQ). High scorers (GHQ>4) and matched individuals with low GHQ scores were interviewed by means of the clinical interview schedule to ascertain definite anxiety and depressive disorders (cases). Cases and controls, matched for age, sex, and occupational group were interviewed with the life events and difficulties schedule classification and an objective measure of work stress to find out the amount of stress at work and outside of work. Sociodemographic and stress variables were entered into a logistic-regression analysis to find out the variables associated with anxiety and depressive disorders. Findings 64 cases and 64 controls were matched. Cases and controls did not differ on demographic variables but cases were less likely to have a confidant (odds ratio 0·09 [95% CI 0·01–0·79]) and more likely to have had a previous episode of
psychiatric disorder (3·07 [1·10–8·57]). Cases and controls worked similar hours and had similar responsibility but cases had a greater number of objective stressful situations both in and out of work (severe event or substantial difficulty in and out of work—45 cases vs 18 controls 6·05 [2·81–13·00], p<0·001; severe chronic difficulty outside of work—27 vs 8, 5·12 [2·09–12·46], p<0·001). Cases had significantly more objective work problems than controls (median 6 vs 4, z=3·81, p<0·001). The logistic-regression analyses indicated that even after the effects of personal vulnerability to psychiatric disorder and ongoing social stress outside of work had been taken into account, stressful situations at work contributed to anxiety and depressive disorders. Interpretation Both stress at work and outside of work contribute to the anxiety and depressive disorders experienced by healthcare staff. Our findings suggest that the best way to decrease the prevalence of these disorders is individual treatment, which may focus on personal difficulties outside of work, combined with organisational attempts to reduce work stress. The latter may involve more assistance for staff who have a conflict between their managerial role and clinical role. Lancet 2000; 355: 533–37
Introduction Faculty of Health Care and Social Work Studies, University of Salford, Allerton Building, Salford M6 6PU, UK (A Weinberg PhD, Prof F Creed MD) Correspondence to: Dr Ashley Weinberg (e-mail: [email protected])
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Numerous studies have shown high amounts of psychological distress in doctors, nurses, and other healthcare professionals working in various situations.1–8 In the UK, 20 reports have indicated that a quarter to a half of the National Health Service (NHS) staff report distress,9 which may be a higher
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