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Management of breast-cancer patients with sentinel-node micrometastases
Comment
John Greim/Science Photo Library
Management of breast-cancer patients with sentinel-node micrometastases
Published Online March 11, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70074-3 See Articles page 297
266
Formal clearance of axillary nodes in patients with suspected malignant infiltration has been a basic tenet of breast-cancer management for the past century.1,2 Non-resection of operable nodal disease with contemporaneous metastases and reliance on non-surgical modalities for eradication represents a fundamental paradigm shift in therapeutic approach. The current wave of interest in omission of completion axillary lymph node dissection (cALND) in patients who have a positive sentinel lymph-node biopsy was triggered by publication of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial3 in 2011. In this seminal study,3 almost 900 patients undergoing breast-conserving surgery with macrometastasis or micrometastases in two or fewer sentinel lymph-nodes were randomly assigned to cALND or no axillary dissection (observation group). Of note, all patients received whole-breast irradiation together with hormone therapy, chemotherapy, or both, and the trial excluded patients who underwent mastectomy. At a median follow-up of 6·3 years, 5-year rates of locoregional recurrence or overall survival did not differ between groups; specific rates of axillary recurrence were 0·5% for the cALND group and 0·9% for the observation group.3 Patients within this trial3 had a low burden of axillary disease with minimum likelihood of more than two positive nodes, thereby rendering biopsy of the sentinel lymph-node a procedure of similar therapeutic value to axillary dissection. Adjuvant treatments might have partly compensated for surgically undertreating the axilla, and precise details of radiotherapy fields are being investigated. Data available from Z00113 make it highly unlikely that any equivalence of outcomes would be overturned to reveal a clinically meaningful survival benefit in the cALND group with longer follow-up. Consensus opinion supports omission of cALND for patients undergoing breast-conserving surgery with micrometastases only in the sentinel lymph-node and perhaps macrometastases when the metastatic ratio is low—eg, one of two or two out of four nodes.4 In The Lancet Oncology, Galimberti and colleagues5 present results of a multicentre trial (IBCSG 23-01),
which specifically aims to show whether cALND is necessary in patients with minimum sentinel lymphnode involvement.5 Patients with micrometastases (>0·2 mm; ≤2 mm) in one or more sentinel lymphnodes were randomly assigned to cALND or observation only. The trial differed from Z00113 by exclusion of macrometastatic disease and inclusion of patients who underwent mastectomy (about 10%). More than 900 patients were randomly assigned to treatment groups from 27 centres, with almost two-thirds (62%) coming from one unit. As for Z0011,3 there was failure to recruit the accrual target of 1960 patients (90% power to detect nonequivalence) and the trial was closed early because of a low aggregate event rate. In IBCSG 23-01,5 both groups were well matched for patient and tumour characteristics with the majority having tumours smaller than 2 cm (around 68%), and approximately 90% of patients being positive for oestrogen receptor. About a quarter of tumours were grade III and most patients received some form of systemic treatment. Administration of radiotherapy was consistent with 90% of patients undergoing breast-conserving surgery. Immunohistochemistry was not used routinely for examination of the sentinel lymphnode and a small proportion of isolated tumour cells (≤0·2 mm) were unconventionally classified as micrometastases (two-thirds of patients had micrometastases measuring ≤1 mm). At a median follow-up of 5·0 years, 124 disease-free events had occurred with no significant difference in the primary endpoint of disease-free survival, thus satisfying the criteria for non-inferiority, which was predefined as a HR of less than 1·25 (p=0·004). Furthermore, overall survival was almost identical for the observation (97·5%) and cALND (97·6%) groups and rates of axillary recurrence were very low (1·1% for the observation group and 0·2% for cALND). These results of IBCSG 23-015 are practice-changing when co-interpreted with those of Z0011.3 It should be noted that 13% of patients in the cALND group had metastases in non-sentinel lymph nodes, for some of whom radiation exposure of lower www.thelancet.com/oncology Vol 14 April 2013
Comment
axillary nodes was precluded (namely, patients who underwent mastectomy and intra-operative breast irradiation). However, no conclusive evidence exists that incidental irradiation of the axilla in the patients of the Z0011 study3 contributed to low rates of axillary recurrence, and, indeed, almost half the patients in the observation group had micrometastases only in the sentinel lymph-node(s). It must be assumed that systemic treatments, and possibly immune mechanisms, can eliminate these low volumes of residual axillary disease, which accords with modern concepts of tumour biology and efficacy of multimodality therapy in terms of both distant micrometastatic disease and loco-regional control.6 Occult nodal metastases detected with immunohistochemical and other non-standard methods have minimum impact on distant disease-free survival, disease-free survival, and overall survival.7,8 These clinically insignificant differences (1·2% magnitude difference for overall survival in the NSABP B-32 trial7) should not influence treatment decisions. In the aftermath of Z0011,3 many breast cancer centres have already abandoned cALND for patients positive for sentinel lymph-node biopsy with micrometastatic foci only; results from IBCSG 1-235 support this change in practice and provide justification for omission of cALND in selected patients who undergo mastectomy. The proposed UK POSNOC (POsitive Sentinel Lymph Node:
Observation vs Clearance) trial9 will be a logical sequel to Z00113 and IBCSG 1-23,5 and will randomly assign to observation only or cALND both patients who undergo breast-conserving surgery and those who undergo mastectomy with one or two sentinel lymph-nodes containing macrometastases. John R Benson Cambridge University Teaching Hospitals Trust, Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK [email protected] I declare that I have no conflicts of interest. 1 2 3
4
5
6 7 8
9
Jatoi I. The natural history of breast cancer. Surg Clin North Am 1999; 79: 949–60. Hellman S. Stopping metastases at their source. N Eng J Med 1997; 337: 996–97. Giuliano AE, Hunt K, Ballman K, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastases: a randomized clinical trial. JAMA 2011; 305: 569. Toi M, Winer EP, Inamoto T, et al. Identifying gaps in the locoregional management of early breast cancer: Highlights from the Kyoto Consensus Conference. Ann Surg Oncol 2011; 18: 2885–92. Galimberti V, Cole BF, Zurrida S, et al, for the International Breast Cancer Study Group trial 23-01 investigators. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastasis (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 2013; published online March 11. http://dx.doi.org/10.1016/S14702045(13)70035-4. Morrow M, Harris JR, Schnitt SJ. Surgical margins in lumpectomy for breast cancer—bigger is not better. N Eng J Med 2012; 367: 79–82. Weaver DL, Ashikaga T, Krag DN, et al. Effect of occult metastases on survival in node-negative breast cancer. N Eng J Med 2011; 364: 412–21. Hansen NM, Gribe B, Ye X, et al. Impact of micrometastases in the sentinel node of patients with invasive breast cancer. J Clin Oncol 2009; 27: 4679–84. Goyal A. POSNOC Trial (Positive Sentinel lymph node: Observation vs Clearance): a randomized trial of axillary lymph node dissection in women with T1 or T2N0M0 breast cancer who have a positive sentinel node. London: Association of Breast Surgery, 2012: 72–73.
Since the 1940s, when the hormone-dependent nature of prostate cancer was first reported, finding alternatives to surgical castration has been an active area of research. Even with its side-effects, androgendeprivation therapy (ADT) remains central to the treatment of advanced prostate cancer.1 Although ADT was first indicated for metastatic prostate cancer, use of this approach before distant metastases are seen improves overall survival,2 and early treatment has become widespread. That long-term low concentrations of prostatespecific antigen could be attained and maintained with ADT in non-metastatic prostate cancer pleased patients and treating physicians. Over the past few www.thelancet.com/oncology Vol 14 April 2013
years, however, a cost became clear that goes beyond the financial implications of medical castration. We now know that ADT causes hot flushes, loss of libido, substantial bone loss, and increased risk of fractures.3,4 A new strategic approach that involves assessment with dual-energy X-ray absorptiometry and antiresorptive agents has been proposed to prevent osteoporosis in patients receiving ADT, but it is costly and cumbersome. These adverse effects and an association with changes suggestive of metabolic syndrome5–7 have led to a notable change in how ADT is used, and growing trends for a conservative approach and intermittent use of ADT have been seen.1
Science Photo Library
The search for alternative androgen-deprivation therapies
Published Online March 4, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70057-3 See Articles page 306
267
John Greim/Science Photo Library
Management of breast-cancer patients with sentinel-node micrometastases
Published Online March 11, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70074-3 See Articles page 297
266
Formal clearance of axillary nodes in patients with suspected malignant infiltration has been a basic tenet of breast-cancer management for the past century.1,2 Non-resection of operable nodal disease with contemporaneous metastases and reliance on non-surgical modalities for eradication represents a fundamental paradigm shift in therapeutic approach. The current wave of interest in omission of completion axillary lymph node dissection (cALND) in patients who have a positive sentinel lymph-node biopsy was triggered by publication of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial3 in 2011. In this seminal study,3 almost 900 patients undergoing breast-conserving surgery with macrometastasis or micrometastases in two or fewer sentinel lymph-nodes were randomly assigned to cALND or no axillary dissection (observation group). Of note, all patients received whole-breast irradiation together with hormone therapy, chemotherapy, or both, and the trial excluded patients who underwent mastectomy. At a median follow-up of 6·3 years, 5-year rates of locoregional recurrence or overall survival did not differ between groups; specific rates of axillary recurrence were 0·5% for the cALND group and 0·9% for the observation group.3 Patients within this trial3 had a low burden of axillary disease with minimum likelihood of more than two positive nodes, thereby rendering biopsy of the sentinel lymph-node a procedure of similar therapeutic value to axillary dissection. Adjuvant treatments might have partly compensated for surgically undertreating the axilla, and precise details of radiotherapy fields are being investigated. Data available from Z00113 make it highly unlikely that any equivalence of outcomes would be overturned to reveal a clinically meaningful survival benefit in the cALND group with longer follow-up. Consensus opinion supports omission of cALND for patients undergoing breast-conserving surgery with micrometastases only in the sentinel lymph-node and perhaps macrometastases when the metastatic ratio is low—eg, one of two or two out of four nodes.4 In The Lancet Oncology, Galimberti and colleagues5 present results of a multicentre trial (IBCSG 23-01),
which specifically aims to show whether cALND is necessary in patients with minimum sentinel lymphnode involvement.5 Patients with micrometastases (>0·2 mm; ≤2 mm) in one or more sentinel lymphnodes were randomly assigned to cALND or observation only. The trial differed from Z00113 by exclusion of macrometastatic disease and inclusion of patients who underwent mastectomy (about 10%). More than 900 patients were randomly assigned to treatment groups from 27 centres, with almost two-thirds (62%) coming from one unit. As for Z0011,3 there was failure to recruit the accrual target of 1960 patients (90% power to detect nonequivalence) and the trial was closed early because of a low aggregate event rate. In IBCSG 23-01,5 both groups were well matched for patient and tumour characteristics with the majority having tumours smaller than 2 cm (around 68%), and approximately 90% of patients being positive for oestrogen receptor. About a quarter of tumours were grade III and most patients received some form of systemic treatment. Administration of radiotherapy was consistent with 90% of patients undergoing breast-conserving surgery. Immunohistochemistry was not used routinely for examination of the sentinel lymphnode and a small proportion of isolated tumour cells (≤0·2 mm) were unconventionally classified as micrometastases (two-thirds of patients had micrometastases measuring ≤1 mm). At a median follow-up of 5·0 years, 124 disease-free events had occurred with no significant difference in the primary endpoint of disease-free survival, thus satisfying the criteria for non-inferiority, which was predefined as a HR of less than 1·25 (p=0·004). Furthermore, overall survival was almost identical for the observation (97·5%) and cALND (97·6%) groups and rates of axillary recurrence were very low (1·1% for the observation group and 0·2% for cALND). These results of IBCSG 23-015 are practice-changing when co-interpreted with those of Z0011.3 It should be noted that 13% of patients in the cALND group had metastases in non-sentinel lymph nodes, for some of whom radiation exposure of lower www.thelancet.com/oncology Vol 14 April 2013
Comment
axillary nodes was precluded (namely, patients who underwent mastectomy and intra-operative breast irradiation). However, no conclusive evidence exists that incidental irradiation of the axilla in the patients of the Z0011 study3 contributed to low rates of axillary recurrence, and, indeed, almost half the patients in the observation group had micrometastases only in the sentinel lymph-node(s). It must be assumed that systemic treatments, and possibly immune mechanisms, can eliminate these low volumes of residual axillary disease, which accords with modern concepts of tumour biology and efficacy of multimodality therapy in terms of both distant micrometastatic disease and loco-regional control.6 Occult nodal metastases detected with immunohistochemical and other non-standard methods have minimum impact on distant disease-free survival, disease-free survival, and overall survival.7,8 These clinically insignificant differences (1·2% magnitude difference for overall survival in the NSABP B-32 trial7) should not influence treatment decisions. In the aftermath of Z0011,3 many breast cancer centres have already abandoned cALND for patients positive for sentinel lymph-node biopsy with micrometastatic foci only; results from IBCSG 1-235 support this change in practice and provide justification for omission of cALND in selected patients who undergo mastectomy. The proposed UK POSNOC (POsitive Sentinel Lymph Node:
Observation vs Clearance) trial9 will be a logical sequel to Z00113 and IBCSG 1-23,5 and will randomly assign to observation only or cALND both patients who undergo breast-conserving surgery and those who undergo mastectomy with one or two sentinel lymph-nodes containing macrometastases. John R Benson Cambridge University Teaching Hospitals Trust, Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK [email protected] I declare that I have no conflicts of interest. 1 2 3
4
5
6 7 8
9
Jatoi I. The natural history of breast cancer. Surg Clin North Am 1999; 79: 949–60. Hellman S. Stopping metastases at their source. N Eng J Med 1997; 337: 996–97. Giuliano AE, Hunt K, Ballman K, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastases: a randomized clinical trial. JAMA 2011; 305: 569. Toi M, Winer EP, Inamoto T, et al. Identifying gaps in the locoregional management of early breast cancer: Highlights from the Kyoto Consensus Conference. Ann Surg Oncol 2011; 18: 2885–92. Galimberti V, Cole BF, Zurrida S, et al, for the International Breast Cancer Study Group trial 23-01 investigators. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastasis (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 2013; published online March 11. http://dx.doi.org/10.1016/S14702045(13)70035-4. Morrow M, Harris JR, Schnitt SJ. Surgical margins in lumpectomy for breast cancer—bigger is not better. N Eng J Med 2012; 367: 79–82. Weaver DL, Ashikaga T, Krag DN, et al. Effect of occult metastases on survival in node-negative breast cancer. N Eng J Med 2011; 364: 412–21. Hansen NM, Gribe B, Ye X, et al. Impact of micrometastases in the sentinel node of patients with invasive breast cancer. J Clin Oncol 2009; 27: 4679–84. Goyal A. POSNOC Trial (Positive Sentinel lymph node: Observation vs Clearance): a randomized trial of axillary lymph node dissection in women with T1 or T2N0M0 breast cancer who have a positive sentinel node. London: Association of Breast Surgery, 2012: 72–73.
Since the 1940s, when the hormone-dependent nature of prostate cancer was first reported, finding alternatives to surgical castration has been an active area of research. Even with its side-effects, androgendeprivation therapy (ADT) remains central to the treatment of advanced prostate cancer.1 Although ADT was first indicated for metastatic prostate cancer, use of this approach before distant metastases are seen improves overall survival,2 and early treatment has become widespread. That long-term low concentrations of prostatespecific antigen could be attained and maintained with ADT in non-metastatic prostate cancer pleased patients and treating physicians. Over the past few www.thelancet.com/oncology Vol 14 April 2013
years, however, a cost became clear that goes beyond the financial implications of medical castration. We now know that ADT causes hot flushes, loss of libido, substantial bone loss, and increased risk of fractures.3,4 A new strategic approach that involves assessment with dual-energy X-ray absorptiometry and antiresorptive agents has been proposed to prevent osteoporosis in patients receiving ADT, but it is costly and cumbersome. These adverse effects and an association with changes suggestive of metabolic syndrome5–7 have led to a notable change in how ADT is used, and growing trends for a conservative approach and intermittent use of ADT have been seen.1
Science Photo Library
The search for alternative androgen-deprivation therapies
Published Online March 4, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70057-3 See Articles page 306
267