Correspondence

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5 van Wely BJ, Teerenstra S, Schinagl DA, Aufenacker TJ, de Wilt JH, Strobbe LJ. Systematic review of the eff ect of external beam radiation therapy to the breast on axillary recurrence after negative sentinel lymph node biopsy. Br J Surg 2011; 98: 326–33.

chemotherapy aff ected axillary recurrence.5 However, the rate of axillary recurrence tripled in those not receiving external beam radiotherapy (1·2% vs 0·4%). Thus, in patients who seem to be free of cancer with just sentinel nodes removed, only radiotherapy improves locoregional control. Such fi ndings imply that residual cancer remains in the nodes of patients who have not had axillary dissection for two IBCSG 23-01 groups: patients who have had mastectomy with systemic treatment only and patients who have had breast conservation where radiation treatment can miss parts of the axilla.

Together, these results suggest a potency for locoregional recurrence or metastasis that is unlikely to be captured within IBCSG 23-01’s median 5-year follow-up. The probability of increased mortality and potential future medicolegal claims from the implementation of the IBCSG 23-01 recommendations outside a trial setting or without long-term follow-up across a broader, unselected, community setting is high, especially for patients having a mastectomy. We declare that we have no confl icts of interest.

*John Boyages, Caleb Winchjohn.boyages@mq.edu.au

Macquarie University Cancer Institute, Macquarie University Hospital, Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia

1 Galimberti V, Cole BF, Zurrida S, et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 2013; 14: 297–305.

2 Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. Strategies for subtypes: dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22: 1736–47.

3 Darby S, McGale P, Correa C, et al. Eff ect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet 2011; 378: 1707–16.

4 Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 1233–41.

samples is shown in the very large 99% CI for survival after mastectomy for patients who had no axillary dissection compared with those who had axillary dissection (hazard ratio [HR] 0·09–3·02). Because the upper limit of this interval exceeds IBCSG 23-01’s boundary of non-inferiority (≤1·25), to conclude that axillary dissection is not necessary for women under-going mastectomy is inappropriate. Moreover, IBCSG 23-01 recruited selected good-prognosis patients, had poor accrual, and closed early, features that would undermine generalisation of the fi ndings to the clinic even if statistical non-inferiority was shown.

Second, maximisation of loco-regional control reduces the risk of death from breast cancer, but not within IBCSG 23-01’s 5-year timeframe. Leaving microscopic disease in lymph nodes is biologically no diff erent, in terms of outcome, to leaving it behind in the breast. A meta-analysis3 of 10 801 patients found radiotherapy to the breast, and part or all of level 1 of the axilla, reduced absolute 15-year, but not 5-year mortality, by 3·3% for node-negative and 7·8% for node-positive patients with breast cancer.

Third, many nodal recurrences do not arise until after 5 years. In the 20-year results of NSABP-B06,4 20% of nodal recurrences after lumpectomy and 24% of nodal recurrences after lumpectomy plus radiation were recorded after 5 years. On the basis these fi ndings, we expect that many recurrences in the no-axillary dissection group of the IBCSG 23-01 study, which will cause psychological and physical morbidity, have yet to occur.

Fourth, we are unconvinced that systemic treatment could achieve locoregional control in patients from the IBCSG 23-01 trial with micrometastatic breast cancer. A meta-analysis of 23 357 patients with sentinel-node negative breast cancer (median follow-up 39 months) supports this prediction: neither hormonal treatment nor

Authors’ replyWe thank Fayda and Karanlik for comm enting that IBCSG 23-01 pro-vides clear level 1 evidence for omitt-ance of axillary dissection in patients with sentinel-node micro metastatic breast cancer. Both Fayda and Karanlik, and Boyages and Winch, suggest that caution should be used in extending this conclusion to patients who have had a mastectomy. In fact, our study was restricted to patients with micrometastatic disease, and we were cautious in our conclusion and stated that: “Although numbers are small, subgroup analysis suggested that no axillary dissection might be acceptable for patients undergoing mastectomy, provided the invasive component of the breast lesion is small”.1

Fayda and Karanlik raised questions about the role of radiotherapy, rates of neuro pathy, and the eff ect of disease burden on outcome. Our study was not designed to answer the ques tion of whether radiotherapy can con trol axillary metastases in patients treated either conservatively or with mas tect-omy. Radiotherapy was usually given to the residual breast in conser vatively treated patients, and the extent of in ci dental axillary irradiation is not ascertain able. Findings from the 2005 GRISO randomised trial2 showed that axillary irradiation did not improve outcomes in patients with early breast cancer with a clinically nega tive axilla who received neither sentinel-node biopsy nor axillary dissection: after 5 years, breast cancer events, including the appearance of axillary disease, were low in both groups.

We have moved on from treatment of the axilla (with radiotherapy or surgery) to avoidance of axillary treatment in selected patients. The fi ndings of IBCSG 23-011 and Z00113 showed that this is a safe policy.

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e252 www.thelancet.com/oncology Vol 14 June 2013

Reassuringly, neuropathic events were less frequent in the no axillary dissection group, which is one of the motives for avoidance of axillary dissection. The increasing use of taxanes might increase neuropathies, but we should always distinguish between neuropathy induced by systemic treatment and neuropathy induced by axillary surgery.

With regards to the eff ect of micrometastatic disease burden on outcomes in IBCSG 23-01, univariate analysis detected no signifi cant diff er-ence in disease-free survival (DFS) for the 643 patients with sentinel-node tumours of 1 mm or smaller in size versus the 266 patients with sentinel-node tumours measuring 1·1–2·0 mm. The 5-year DFS was 86·6% (95% CI 83·6–89·6) for pat ients with 1 mm or smaller tumours and 84·8% (79·8–89·7) for patients with 1·1–2·0 mm tumours (log-rank p=0·59).

Boyages and Winch are incorrect to assert that slow enrolment and early stopping of the trial undermines our non-inferiority conclusion. Because the number of participants randomly assigned in IBCSG 23-01 (n=931) is relatively large, it is highly unlikely that an imbalance across the treatment groups biased our estimates. Moreover, the early stopping was carefully planned in consultation with an independent data and safety monitoring committee and without knowledge of the endpoint treatment comparison. We believe that with these strict scientifi c controls, the fi ndings of IBCSG 23-01 have validity to aff ect clinical practice. We are continuing to follow enrolled patients and will report longer term results. In the meantime, it is important to stress that axillary disease usually presents early after primary treatment: more than 75% of nodal recurrences are likely to have already occurred within 5 years, and the absolute numbers that might emerge later are likely to be small.4,5

We contest Boyages and Winch’s assertion that leaving microscopic

Extending the case for oestradiol in androgen-sensitive prostate cancer

The PATCH study1 by Langley and colleagues showed that transdermal oestradiol is not inferior to luteinising-hormone-releasing hormone (LHRH) agonists in terms of testosterone suppression and might even be associated with cardiovascular benefi ts.

Although not cited by Langley and co-workers, recent data on hormone replacement therapy for women are concordant with the PATCH results for men. For example, early use of oestrogen can be cardioprotective for postmenopausal women.2 Further, a recent position statement3 from the Society of Obstetricians and Gynaecologists of Canada asserts that transdermal oestradiol had no “adverse eff ects on surrogate markers of cardiovascular risk” and that “secondary benefi ts of hormone therapy for women participating in this [the KEEPS] trial were favourable eff ects on vasomotor symptoms, sexual function, quality of life, and bone mineral density”.

disease in lymph nodes is biologically no diff erent to leaving it behind in the breast in terms of outcome. Findings from several studies show that, although the false negative rate for the detection of axillary involvement by sentinel-node biopsy is about 10%, a much smaller percentage of patients undergoing no axillary dissection develop overt axillary disease, even after long follow-up.2 Metastases in the lymph node might diff er from metastases in the breast because of biological reasons too.2

Finally, Boyages and Winch cite the study of van Wely and colleagues6 to argue against our assertion that hormonal treatment and chemotherapy might reduce the occurence of axillary disease in patients who do not undergo axillary dissection. The van Wely study was a retrospective analysis of the eff ect of external beam radiation to the breast on the appearance of axillary disease (not micrometastatic axillary disease). The investigation selected papers providing data on the use of external beam radiation to the breast, and found that such irradiation signifi cantly reduced the appearance of axillary disease. However, this study was not designed to assess the eff ect of systemic treatment; studies that failed to report the percentage of patients receiving adjuvant systemic treatment were included and studies that reported on adjuvant systemic treatment but not external beam radiation were excluded. Therefore, the results of this study are unlikely to reliably indicate the eff ect of systemic treatment on the appearance of micrometastatic axillary disease. Other data suggest that systemic treatment can eliminate low-volume axillary metastasis.2

We declare that we have no confl icts of interest.

*Viviana Galimberti, Bernard F Coleviviana.galimberti@ieo.it

Molecular Senology Unit, Senology Division, European Institute of Oncology, Milan, Italy (VG); and Department of Mathematics and Statistics, College of Engineering and Mathematical Sciences, University of Vermont, Burlington, VT, USA (BFC)

1 Galimberti V, Cole BF, Zurrida S, et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 2013; 14: 297–305.

2 Veronesi U, Orecchia R, Zurrida S, et al. Avoiding axillary dissection in breast cancer surgery: a randomized trial to assess the role of axillary radiotherapy. Ann Oncol 2005; 16: 383–88.

3 Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection women with invasive breast. JAMA 2011; 305: 569–75.

4 Giuliano AE, Hawes D, Ballman KV, et al. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA 2011; 306: 385–93.

5 Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002: 347: 1233–41.

6 van Wely BJ, Teerenstra S, Schinagl DA, Aufenacker TJ, de Wilt JH, Strobbe LJ. Systematic review of the eff ect of external beam radiation therapy to the breast on axillary recurrence after negative sentinel lymph node biopsy. Br J Surg 2011; 98: 326–33.