Prophylactic supraclavicular fossa radiotherapy in early breast cancer: Is it worthwhile

Clinical Oncology (1994) 6:22%231 © 1994 The Royal College of Radiologists

Clinical Oncology

Original Article Prophylactic Supraclavicular Fossa Radiotherapy in Early Breast Cancer: Is it Worthwhile? D. J. Fairlamb 1 and D. Machin2 ~Radiotherapy Department, The Royal Hospital, Wolverhampton and 2MRC Cancer Trials Office, Cambridge, UK

Abstract. A total of 291 consecutive patients with early breast cancer who did not receive any supraclavicular prophylactic irradiation of the ipsilateral fossa have been followed for a minimum of 5 years. Isolated relapse in that site occurred in 4.5% of patients and was controlled by radical radiotherapy with a post-relapse 5-year survival of 33%. Relapse with co-existing distant metastases occurred in a further 7% and no patient survived to 3 years. Supraclavicular fossa irradiation contributes to morbidity, does not improve survival and should be abandoned in favour of delayed treatment for proven recurrence.

Keywords: Breast cancer; Lymphoedema; Radical radiotherapy; Recurrence of disease; Supraclavicular fossa irradiation

INTRODUCTION

The cure rate for early breast cancer has remained largely unaltered despite many changes in treatment policy. Radical and supraradical mastectomy with the aim of improving cure rates by removing 'at risk' lymph nodes did not succeed and this aggressive surgery has given way to a conservative approach of lumpectomy and radiotherapy being considered as standard treatment. If surgical removal of 'at risk' nodes failed, why do so many radiotherapists, both in trials and in routine practice, insist on techniques that include the supraclavicular fossa when treating a patient with early breast cancer? It is known that radiotherapy reduces the incidence of relapse at that site, but to be set against that there is a definite treatment related morbidity. The prospective study was based on the assumption that routine irradiation confers no overall benefit to the patient and that surveillance with delayed treatment for those who relapse is appropriate. Correspondence and offprint requests to: Dr D. J. Fairlamb, Radiotherapy Department, The Royal Hospital, Cleveland Road, Wolverhampton WV2 1BT, UK.

METHODS Patients This study includes all female breast cancer patients referred to one of us (DJF) over a 3.5-year period commencing January 1981 whose practice covers part of the West Midlands. Patients were those women whose cancer was confined to the breast and/or chest wall and axilla. Those with metastases or supraclavicular node involvement at presentation were not included.

Surgery This was undertaken by several surgeons and the procedures were determined before referral for radiotherapy. Various operative techniques were used including modified radical mastectomy, simple mastectomy, lumpectomy or biopsy alone. Axillary node sampling was undertaken at the surgeon's discretion.

Pathology Every patient had histologically confirmed breast cancer and involvement of the axillary nodes was recorded as positive, negative or unknown. This latter group comprises those patients in whom no nodes were found or no axillary node sampling was undertaken.

Radiotherapy A standard breast bridge technique was employed, using 4 MV X-rays. Hence, radiotherapy was essentially treating the chest wall and/or breast and the majority of the axillary contents, but missing the supraclavicular fossa nodes. No axillary boost was given, The field size was 20 cm x 10 cm running along the sterno-xiphysternal mid-line, with the fixed constant point being the suprasternal notch. The arm was abducted, with the palm of the hand on the forehead. Tumour dose was either the radiobiologically equivalent of 50 Gy in 25 daily fractions,

228

D . J . Fairlamb and D. Machin

(range 36-58), but information available on these patients is included in this analysis. The overall survival of these patients (Fig. 1) indicates a median survival of approximately 6 years. Approximately half the patients were free of their disease at 4 years (Fig. 2), which was dependent on T stage (Fig. 3a) and nodal status (Fig. 3b) with, for example, those with No disease at presentation having a median disease free interval of 6 years compared with 4 years for those with N1-2 disease.

or 40 Gy in 10 fractions 3 times weekly, with a cumulative radiation effect of 1541 and 1606 Gy respectively (JW Hopewell, personal communication); full bolus was used. This latter practice has now been discontinued.

Follow-Up This was undertaken at 3-monthly intervals for a minimum of 24 months and then at 6-monthly intervals to 5 years; thereafter, follow-up visits were at the patient's discretion. In the event of supraclavicular fossa relapse (SFR) re-staging was undertaken to include full blood count, liver function tests, chest radiograph and bone scan. If the relapse was isolated, then radical radiotherapy was given as 35-40 Gy in 10 fractions over 21 days, as a single direct field with build up. If metastatic disease co-existed, then systemic therapy with hormones or cytotoxic drugs was instituted and radiotherapy used for palliation of local symptoms.

~ 80 "~ 70

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Po ~ g 50 ~ 4o o~ 30 20

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10

Statistical Methods

1

The Kaplan-Meier method and associated confidence intervals for survival curves were calculated as described by Machin and Gardner [1].

2

3

4

5

6

7

8

9

10

11

12

T i m e (years) N u m b e r s at risk

291

271

234

213

171

143

116

87

70

49

26

9

Fig. 1. Life table estimate of survival of 291 women with early breast cancer.

RESULTS In all, 291 women were seen over the period January 1981 to June 1984, of which 59 were premenopausal and 232 postmenopausal. The mean age at presentation was 59 years (range 21-84). The TNM stage at presentation is shown in Table 1; the largest group of 160 (55%) patients were T2N0. A total of 225 (73%) patients had a simple mastectomy, 80 (26%) a lumpectomy or biopsy alone and 4 (1%) a modified radical mastectomy. Axillary node sampling was done in 176 (60%) patients. Bilateral disease developed synchronously in three patients and in 15 metachronously. Minimum follow-up after diagnosis is 5 years and the maximum 11 years. A total of 23 patients have been lost to follow-up after an average of 45 months

'11. . . . . . . . 0

1

2

3

4

5

6

7

8

9

10

11

12

T i m e (years) Numbers at risk

291

250

203

161

124

102

74

55

41

23

11

4

Fig. 2. Life table estimate of disease free interval of 291 women with early breast cancer.

Table 1. Presenting TNM Stage (UICC 1992 4th revision) with the number of patients with supraclavicular fossa (SFR) with or without distant metastases Nodal status

SFR

Nodal status

No

N1

Nz

Total

To-1 T2 T3 T4 Total SFR Distant metastases absent (%) Distant metastases present (%)

24 160 24 16 224

2 31 16 12 61

0 1 3 2 6

26 192 43 30 291

9 16

(4.0) (7.1)

3 (4.9) 5 (8.2)

1 (16.7) 1 (16.7)

Distant metastases absent (%)

Distant metastases present (%)

0 (0) 12 (6.3) 0 (0) 1 (3.3)

1 (3.8) 12 (6.3) 5 (11.6) 4 (13,3)

13 (4.5) 22 (7,6)

Prophylactic Supraclavicular Fossa Radiotherapy in Early Breast Cancer: Is it Worthwhile? a

=~ , 90

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Table 2. Pathological status of the axilla in relation to nodal status, together with the number of patients with supraclavicular fossa relapse (SFR) with or without distant metastases

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,o1

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Nodal status

60

Axilla

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No N1 N2 Total SFR Distant metastases absent (%) Distant metastases present (%)

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......... L I !

I 1

2

3

4

5

6

7

8

9

10

11

Time (years) Numbers at risk 0/1 26 24 21 20 2 192 168 140 114 3 43 38 25 18 4 30 22 17 9

19 87 12 6

18 69 11 4

16 50 6 2

10 40 5

8 30 3

4 18 1

1 10

4

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1

229

2

3

4

5

6

7

8

9

10

11

Numbers at risk 0 224 196 164 134 105 88 65 48 36 21 10 0/2 67 54 39 27 19 14 9 7 5 2 1

3

12

Time (years)

Fig. 3. Life table estimate of disease free interval of 291 women with early breast cancer by (a) T stage and (h) nodal status.

Radiotherapy was not given to 70 patients for a variety of reasons: 24 patients w e r e TI_2N 0 node negative and 29 were post-mastectomy and had already commenced adjuvant hormonal therapy or chemotherapy; others included too great an interval

Positive

Negative

Unknown

Total

88 43 3 134

40 2 0 42

96 16 3 115

224 61 6 291

11 (8.2)

1 (2.4)

1 (0.9)

13 (4.5)

13 (9.7)

1 (2.4)

8 (7.0)

22 (7.6)

from surgery to referral for radiotherapy, refusal of radiation by the patient and general medical contraindications. There was an excess of node negative patients in this group which was otherwise comparable with the X-ray treated patients with respect to TNM classification and age. The relationship between clinical and pathological (axillary) node status is shown in Table 2; however, there was a large group of patients in which the status of the axilla was not known. SFR occurred in 35 patients (12.0%). The risks of SFR by T stage, N stage and pathological status of the axilla are shown in Tables 1 and 2. Clinical assessments of the primary tumour and the axilla were not good determinants of SFR except for the smallest tumours, To-], and grossly involved axillary nodes, N2. Thirteen patients (4.5%) relapsed with supraclavicular node metastases, but no distant deposits. Of these, 11 had positive axillary nodes, one was negative, and One was of unknown axillary node status (Table 3). Those with nodal recurrence only required radical radiotherapy, which controlled the recurrence in 12 of 13 patients. Twenty-two patients developed SFR with co-exist-

Table 3. Outcome for patients experiencing SFR in the absence of distant metastases

Patient status no.

Pathological axillary status

DFR (months)

Local control

Survival after recurrence (months

Overall survival (months)

1 2 3 4 5 6 7 8 9 10 11 12 13

Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Neg Unknown Pos

49 60 7 54 20 36 48 32 6 20 26 72 42

Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes

68 77a 54 56 8 14 80a 12 34 21 64 64 22

117 137~ 61 100 28 50 128" 44 40 41 90 136 64

T2N 1 T2No T2No T2No T2No TeN0 T2N0 T2No T2N2 T2N0 T2No T4No T2Na

DFI, disease free interval. aIndicates patient still alive at the last follow-up.

230

D.J. Fairlamb and D. Machin

Table 4. Number of patients (%) having arm lymphoedema by treatment with axillary surgery and/or radiotherapy Radiotherapy

No Yes Total

Axillarysurgery

Total

No

Yes

0/27 (0.0) 2/92 (2.2) 2/119 (1.7)

0/43 (0.0) 0/70 (0.0) 14/129(10.8) 16-221(7.2) 14/172(8.1) 16/291(5.5)

ing distant metastases. Palliative radiotherapy was given to the nodes in 12 of these patients; this controlled the disease in eight. The ten patients who did not receive any radiotherapy had generalized symptoms which required systemic treatment as a priority; of these, SFR was controlled in five. Persisting recurrence until death occurred in ten patients. However, local symptoms were present in only five patients; three experienced pain and two had fungation. Survival after recurrence was markedly in favour of patients who relapsed without metastases, with a median of 45 months, compared with 12 months in those with metastases. Similarly, overall survival favoured nodal relapse only, with a median of 80 months against 29 months for the other patients. No patient relapsing with distant metastases survived beyond 3 years after the relapse. Lymphoedema in the absence of axiUary recurrence was detected in sixteen (5.5%) patients, all of whom had received radiotherapy (Table 4). Although the numbers are small, lymphoedema was more prevalent amongst those who had had axillary surgery in this group. Persistent symptomatic radiation pneumonitis, brachial plexus neuritis and osteoradionecrosis of the chest wall and or humeral head were not seen. 'Matchline' fibrosis and problems relating to keying fields were avoided.

DISCUSSION Prophylactic irradiation of the chest wall and nodal areas following the initial surgical intervention, whether mastectomy or lumpectomy, is well established in clinical practice. There is no doubt that it reduces the local recurrence rate but has no effect on survival. [24]. Techniques of field arrangements vary considerably from department to department, but the aim is usually to include the breast (or chest wall), axilla and supraclavicular fossa, with optional fields for the internal mammary chain of nodes. The supraclavicular fossa is not always included, as some departments treat this only if the axillary nodes are involved. The practice is nonetheless widely recommended in clinical papers [5-7], editorials [8], text books [9-12] and clinical trials, both old [13,14] and currently open such as the Cancer Research Campaign trials on radiotherapy and adjuvant tamoxifen in Stage I and II breast cancer (launched 1985) and adjuvant therapy for patients over the age of 50 (launched in 1986). Indeed there is a planning teaching video that commends the use of supraclavicular fields [15]. Alternatively, selective avoidance of any lymphatic irradiation in early breast cancer has been proposed [16].

Elective irradiation of the uninvolved supraclavicular fossa,reduces the local recurrence rate. This was well demonstrated over 30 years when Paterson and Russell compared two post-radical mastectomy techniques of chest wall irradiation in which one method did not include the supraclavicular fossa (peripheral versus quadrate techniques). Prophylactic irradiation reduced the incidence of SFR from 17% to 6% [17]. A later analysis, including patients who received no radiotherapy after radical mastectomy, showed a 12% SFR rate overall with 5.5% of patients with isolated relapse and 6.5% with concurrent metastases. Five-year survival in the localized group was 25%-30% when radically irradiated [18]; this was corroborated in other studies [19]. The present study confirms this in patients who have undergone lesser surgery, with an overall SFR of 11%, a 4% localized relapse rate and 7% with metastases. The crude 5-year survival for those radically treated local recurrences is 33% Histologically proven axillary nodal involvement is a good predictor of supraclavicular relapse, which occurred in 18% of patients compared with 5% in the negative axilla. Elective radiotherapy reduced this to 6%. Unfortunately radiotherapy is not without morbidity and major long term complications can be as high as 11% [20]. There is public concern about this [21,22]; in one recent year the Medical Defence Union received 43 claims concerning breast radiotherapy toxicity [23]. The incidence of arm oedema for axillary dissection or cervico-axillary radiotherapy alone is similar, but is multiplied by a factor of four if both treatments are given. Depending on definitions, the increases are from 2% to 9% [24] or 8% to 38% [25]. Radiotherapy definitely reduces shoulder movements [26,27] and is associated with irreversible brachial plexus injury in 1%-5 % [28,29]. Bone necrosis can be seen in up to 3% [30] and radiation pneumonitis in up to 16% [31,32]. Physiological and radiological lung morbidity has been reported to be the result of mediastinal and locoregional irradiation [33]. This has been quantified in a prospective study which clearly showed that radiotherapy to the chest wall was not associated with any loss of vital capacity, but the additional inclusion of locoregional node areas led to a 6% reduction of vital capacity which did not improve at 1 year posttreatment [34]. There can be little doubt that most of the toxicity is the result of the supraclavicular fossa radiotherapy (and axillary boost if used), if not always directly, then as a consequence of field matching with the inevitable occasional overlap. What about the morbidity of recurrence in the supraclavicular fossa? Radical radiotherapy controlled 92% of the local recurrences and palliative radiotherapy 66% of those with co-existing metastases. Even in the most at risk group who had involved axillary glands, symptomatic recurrence occurred in only 5% and was controlled in all but 1.5%. Persisting recurrence until death was present in 3% overall, which compared favourably with the Paterson and Russell's series of 6% [17]. What then should be the role of irradiation of the supraclavicular fossa? In order to confidently recommend supraclavicular radiotherapy, one must be

Prophylactic Supraclavicular Fossa Radiotherapy in Early Breast Cancer: Is it Worthwhile? c e r t a i n t h a t this t r e a t m e n t offers s o m e t a n g i b l e b e n e fit to t h e p a t i e n t , e n o u g h to o u t w e i g h the k n o w n t r e a t m e n t r e l a t e d m o r b i d i t y . This s t u d y c l e a r l y shows that, without prophylactic radiotherapy, isolated S F R occurs in 4 . 5 % . T h i s can b e effectively m a n a g e d b y r a d i c a l r a d i o t h e r a p y with a high c o n t r o l r a t e a n d p r o l o n g e d survival. R e c u r r e n c e in t h e p r e s e n c e of m e t a s t a t i c d i s e a s e occurs in a f u r t h e r 7 % . This has a p o o r p r o g n o s i s b u t t h e n o d a l m e t a s t a s e s can b e satisfactorily p a l l i a t e d b y a c o m b i n a t i o n o f local a n d s y s t e m i c Creatment. W h a t a b o u t p a t i e n t s with i n v o l v e m e n t o f axillary n o d e s , for this is a g o o d p r e d i c t o r o f S F R ( 1 7 . 9 % ) ? U n f o r t u n a t e l y , it is this g r o u p o f p a t i e n t s w h o will experience the worst treatment related morbidity, especially arm lymphoedema. As only 8.2% have r e c u r r e n c e solely in s u p r a c l a v i c u l a r n o d e s a n d d e f e r r e d t r e a t m e n t is effective, r a d i o t h e r a p y s h o u l d b e h e l d in a b e y a n c e so t h a t m o r b i d i t y is o n l y e x p e r i enced by those who need the treatment. Axillary n o d e i n v o l v e m e n t is a d e t e r m i n a n t o f o v e r a l l risk o f m e t a s t a t i c r e c u r r e n c e , defining t h e n e e d for a d j u v a n t s y s t e m i c t r e a t m e n t n o t s u p r a c l a v i c u l a r fossa r a d i o t h e r a p y . It s h o u l d b e n o t e d t h a t , w h e n this s t u d y was undertaken, routine adjuvant hormonal therapy/ c h e m o t h e r a p y was n o t t h e rule, a n d less t h a n 10% of the p a t i e n t s r e c e i v e d this. T h u s it m a y b e t h a t this series has o v e r e s t i m a t e d t h e r e c u r r a n c e r a t e in c u r r e n t p r a c t i c e b y a f a c t o r o f two [35]. This series shows t h a t d e l a y e d t r e a t m e n t of S F R is effective. It is o u r o p i n i o n t h a t t h e p r a c t i c e of r o u t i n e i r r a d i a t i o n o f t h e s u p r a c l a v i c u l a r fossa in e a r l y b r e a s t c a n c e r is a n a c h r o n i s t i c , uses scarce r e s o u r c e s , cont r i b u t e s significantly to t r e a t m e n t r e l a t e d m o r b i d i t y a n d s h o u l d b e a b a n d o n e d in f a v o u r o f d e l a y e d t r e a t m e n t for p r o v e n r e c u r r e n c e .

Acknowledgements. W e w o u l d like to t h a n k I r e n e F o r d ( W o l v e r h a m p t o n ) a n d Vicki C l a r k ( C a m b r i d g e ) f o r s e c r e t a r i a l assistance a n d D. J o h n M a c h i n o f t h e M R C C a n c e r Trials Office for h e l p with the statistical c o m p u t i n g .

References 1. Machin D, Gardner MJ. Calculating confidence intervals for survival time analyses. In: Gardner MJ, Altman DG, (editors). Statistics with confidence. London: British Medical Association, 1989:64-70. 2. Cancer Research Campaign Working Party. Cancer Research Campaign (Kings/Cambridge)trial for early breast cancer. A detailed update at the tenth year. Lancet 1980:ii:55-60. 3. Morgan DAL, Galea MH, Berridge J, et al. After mastectomy, high grade, node positive breast cancer patients benefit from radiotherapy [abstract]. Clin Oncol 1992;4:335. 4. Treatment of early breast cancer: Worldwide evidence 19851990, vol 1. Oxford: Oxford University Press, 1990:14. 5. Campbell IR, Green JA, Errington D, et al. Sequential chemotherapy surgery and radiotherapy in locally advanced breast cancer. Clin Radiol 1988;39:442-5. 6. Rostom AY, Pradham DG, White WF. Once weekly irradiation in breast cancer. Int J Radiat Oncol Biol Phys 1987; 13:551-5. 7. Mansfield CM. Intraoperative Ir-192 implantation for early breast cancer. Cancer 1990;66:1-5. 8. Post operative radiotherapy in breast cancer editorial. Br Med J 1981;i:1498. 9. Fletcher GH. Radiotherapy in the management of non-

231

disseminated breast cancer. In Fletcher GH, editor. Textbook of radiotherapy. Philadelphia: Lea & Febiger 1980:572-4. 10. Levitt SH, Perez CA. Breast Cancer. In: Perez CA, Brady LW, editors. Principles of radiation oncology. Philadelphia: Lippincott 1987:754-7. 11. Keane P, Sikora K, Waxman J, et al. Breast. In: Sikora K, Halnan KE, ecitors. Treatment of cancer. 2nd ed. London: Chapman & Hall, 1992:376--7. 12. Ribeiro GG. Breast. In: Pointon RCS, editor. The radiotherapy of malignant disease. Berlin Heidelberg: Springer-Verlag, 1991:255-68. 13. Fisher B, Montague S, Redmand C, et al. Findings from NSABP Protocol B-04. Comparison of radical mastectomy with alternative treatment for primary breast cancer: 1. Radiation compliance and its relation to treatment outcome. Cancer 1980;46:1-13. 14. Cancer Research Campaign Working Party. Management of early cancer of the breast. Report on an international multi centre trial supported by the Cancer Research Campaign. Br Med J 1976;i:1035-8. 15. Spittle MF. The Breast. In: Cassoni A, editor. Site planning: The breast. Lederle Laboraties/JD Associates Visual Communications, 1992. 16. Hoskin PJ, Rayan B, Ebbs S, et al. Selective avoidance of lymphatic radiotherapy in conservative management of early breast cancer. Radiother Oncol 1992;25:83-8. 17. Paterson R, Russell MH. Clinical trials in malignant disease: Part II. Evaluation of post operative radiotherapy. J Fac Radiol 1959;10:175-80. 18. Jackson SM. Carcinoma of the breast: The significance of supraclavicular lymph node metastases. Clin Radiol 1966;17:107-14. 19. Fentiman IS, Lavelle MA, Caplan D, et al. The significance of supraclavicnlar fossa node recurrence after radical mastectomy. Cancer 1986;57:908-10. 20. Ferguson D J, Sutton HG, Dawson PS. Late effects of adjuvant radiotherapy for breast cancer. Cancer 1984;54: 2319-23. 21. The big story. Twenty Twenty Productions for Carlton TV, 16 September, 1993. 22. 150 scarred by therapy. The Daily Telegraph, 21 September, 1993:p16 cols 1-6. 23. Keddie N. Medicolegal problems in breast surgery. J Med Defence Union 1993;9:50-3. 24. Mazeron JJ, Otmezguire YY, Huart J, et al. Conservative treatment of breast cancer: Results of management of axillary lymph node area in 3353 patients. Lancet 1985;i:1387. 25. Kissin MW, Querci della Rovere G, Eaton G, et al. Risk of lymphoedema following the treatment of breast cancer. Br J Surg 1986;73:580-4. 26. Aitken RJ, Gaze MN, Rodger A, et al. Arm morbidity within a trial of mastectomy and either nodal sample with selective radiotherapy or axillary clearance. Br J Surg 1989;76:568-71. 27. Cooke J, Powell S, Parsons C. The diagosis by computed tomography of brachial plexus lesions following radiotherapy for carcinoma of the breast. Clin Radiol 1988;39:602-6. 28. Powell S, Cooke J, Parsons C. Radiation induced brachial plexus injury: Follow up of two different fractionation schedules. Radiother Oncol 1990;18:213-20. 29. Halverson KJ, Perez CA, Kuske RR. Isolated local-regional recurrence of breast cancer following mastectomy: Radiotherapeutic management. Int J Radiat Oncol Biol Phys 1990;19:851-8. 30. Price A, Jack WJL, Kerr GR, et al. Acute radiation pneumonitis after postmastectomy irradiation: Effect of fraction size. Clin Oncol 1990;2:224-9. 31. Rothwell RI, Kesby SA, Joslin CAF. Radiation pneumonitis in patients treated for breast cancer. Radiother Oncol 1985;4:%14. 32. Newman G, Bell J, Goddard P, et al. Pulmonary changes in breast cancer patients treated by three different radiotherapy techniques. Clin Oncol 1989;1:91-6. 33. Hardman PDJ, Tweeddale P, Kerr GR, et al. The effect on pulmonary function of local and locoregional irradiation for breast cancer [abstract]. Clin Oncol 1992;4:335-6. 34. Fisher B, Constantino J, Wickerham L, et al. Adjuvant therapy for node negative breast cancer: An update of NSABP findings [abstract]. Proc ASCO 1993;12:69.

Received for publication March 1993 Accepted following revision January 1994