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Adjuvant therapy
ADJUVANT TREATMENT
Adjuvant therapy
drug choice is primarily dependent on the patient’s menopausal status. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) found that 5 years of adjuvant tamoxifen reduced the 15-year breast cancer mortality by a third (34.8% versus 25.6%).1 However, there is increasing evidence that extending treatment up to 10 years in pre/perimenopausal women can further improve survival rates2 and this is now becoming standard practice. Aromatase inhibitors are a newer class of hormone therapy that can only be used for postmenopausal women. Trials to date have shown a significant benefit over tamoxifen in prolonging disease-free survival, and reducing both the risk of recurrence and 10 year breast cancer mortality3,4 (Figure 1). The optimal
Rhiannon Evans Jake Tanguay
Abstract Adjuvant therapy is used following radical treatment to reduce the risk of cancer recurrence and improve survival. The rationale for its use is its potential to treat local and/or distal occult microscopic disease. However, it can be associated with significant adverse effects. The potential benefit of treatment must therefore be assessed on an individual basis, considering both tumour and patient characteristics. This article discusses the basic principles of adjuvant and neoadjuvant therapy, focussing on breast and colorectal cancer. We also discuss some of the adverse effects of therapy and look at potential future developments.
a 50
9885 women, 1791 events RR=0·80 (95% CI 0·73–0·88)
40
Keywords breast cancer; chemotherapy; colorectal cancer; horRecurrence (%)
mone therapy; neoadjuvant; radiotherapy
Introduction Adjuvant therapy is used following primary radical treatment to reduce the risk of cancer recurrence. While the initial treatment targets the primary tumour with the aim of removing all macroscopic disease, adjuvant therapy can be given either to improve local tumour control (e.g. by radiotherapy) or to target micro-metastases using systemic therapy. As most recurrences are thought to be due to occult microscopic disease present at the time of diagnosis, and as most patients are no longer curable once relapse has occurred, the importance of adjuvant therapy should not be underestimated. However, not all patients benefit from adjuvant treatment and it can be associated with substantial adverse effects. An assessment of the risk of recurrence is therefore essential, and is dependent on factors such as tumour histology, site and stage. Patient comorbidity, performance status and preferences are also important. Adjuvant therapy may include chemotherapy, radiotherapy, hormone therapy and/or targeted therapy. They can be given individually or in combination, and are well established forms of treatment in the management of common malignancies such as breast and colorectal cancer.
10-year gain 3·6% (95% CI 1·7 to 5·4) Log-rank 2p<0·00001 30 Tamoxifen 22·7% 20
AI 19·1% 12·1%
10 9·0%
0 0 5 10 Recurrence rate/year (%), events/woman-years and log-rank statistics Allocation AI Tamoxifen Rate ratio (95% CI) from (O-E)/V
Years 0–1 1·62 (157/9691) 2·41 (230/9542) 0·64 (0·52–0·78) –41·1/92·8
Years 2–4 2·14 (285/13336) 2·62 (338/12906) 0·80 (0·68–0·93) –34·1/149·0
Years 5–9 2·33 (365/15648) 2·48 (372/14985) 0·92 (0·79−1·06) −15·5/177·2
Year 10+ 3·23 (20/619) 4·54 (24/529) 0·72 (0·39−1·30) −3·6/10·7
b
Breast cancer mortality (%)
50
9885 women, 1066 deaths RR=0·85 (95% CI 0·75–0·96)
40 10-year gain 2·1% (95% CI 0·5 to 3·7) Log-rank 2p=0·009 30
20 Tamoxifen 14·2% 10 5·8%
AI 12·1%
4·5%
Breast cancer
0 0 5 10 Death rates (%/year: total rate minus rate in women without recurrence) and log-rank
Hormone therapy Adjuvant hormone therapy is effective and appropriate for most patients with oestrogen receptor (ER)-positive breast cancer, but
Allocation Years 0–1 AI 0·52 (0·39−0·66) Tamoxifen 0·51 (0·39−0·67) Rate ratio (95% CI)0·98 (0·66−1·46) from (O-E)/V −0·4/24·3
Years 2–4 1·23 (1·05−1·41) 1·60 (1·38−1·83) 0·74 (0·60−0·91) −27·2/90·7
Years 5–9 1·66 (1·46−1·86) 1·81 (1·60−2·02) 0·90 (0·76−1·07) −13·6/129·4
Year 10+ 1·93 (0·88−2·99) 1·88 (0·77−2·99) 1·01 (0·45−2·33) 0·1/5·6
RR =rate ratio (with 95% confidence interval). AI=aromatase inhibitor. O-E=observed minus expected. V=variance of O-E.
Rhiannon Evans MRCP is a Specialist Registrar on the South Wales Clinical Oncology Training Programme, Swansea, UK. Competing interests: none declared.
(From http://www.sciencedirect.com/science/article/pii/S0140673615610741. Available under the terms of the Creative Commons Attribution Licence (CC BY).)
Jake Tanguay MRCP FRCR is a Consultant Clinical Oncologist at Velindre Cancer Centre, Cardiff, UK. Competing interests: none declared.
MEDICINE --:-
Figure 1 Disease recurrence and breast cancer mortality rates for oestrogen receptor-positive patients given 5 years of tamoxifen compared with 5 years of aromatase inhibitor.
1
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Evans R, Tanguay J, Adjuvant therapy, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.015
ADJUVANT TREATMENT
a
b
(a) Image of oestrogen receptor-positive breast cancer cells. Cells are stained by immunohistochemistry using an antibody against the oestrogen receptor. In this example, the nuclei show strong reactivity (seen as brown staining), indicating a high chance of response to hormone therapy. (b) Image of HER-2 fluorescence in-situ hybridization analysis. The number of copies of the HER-2 gene in the tumour cell nucleus is assessed using fluorescence microscopy. The number of signals (red dots) is compared with the signal for chromosome 17 (green dots); a ratio of >2.2 is considered positive. Images courtesy of Professor Jasani, Cardiff University. Figure 2
duration of treatment with aromatase inhibitors is currently unclear, with ongoing clinical trials evaluating its use beyond 5 years.
trastuzumab with chemotherapy for HER-2-positive patients significantly reduces the risk of recurrence and death from breast cancer, at the cost of a small increased risk of cardiac dysfunction.4
Chemotherapy The benefit of adjuvant chemotherapy is dependent on several factors, and systems such as Adjuvant! Online (http://www. adjuvantonline.com) can provide an estimation of benefit using both patient and tumour characteristics. The EBCTCG overview found that adjuvant chemotherapy reduced 15-year mortality by 10% among those aged less than 50 years, compared with 3% among those aged 50e69 years.1 Its benefit is also more pronounced in node-positive or ER-negative disease. Anthracyclineand/or taxane-containing regimens are most frequently used, and sequential rather than concurrent use of these drugs has been found to be more effective.4 Further evaluation of the benefit of adjuvant chemotherapy can be gained by gene profiling. Tests such as Oncotype DXÒ measure the expression of certain genes in an individual’s breast cancer tissue to predict their risk of recurrence. This can be particularly useful when the decision of whether to offer chemotherapy is otherwise uncertain, for example in those with early-stage ER-positive, HER-2 negative, node-negative disease. Trastuzumab is a humanized monoclonal antibody that inhibits the HER-2/neu receptor, which is overexpressed on the breast cancer cell surface in 20% of patients. The combination of
Radiotherapy Adjuvant breast radiotherapy is standard treatment for patients following breast-conserving surgery and those at high risk of recurrence (N2 disease or positive resection margins) following mastectomy. There is also increasing evidence to support its use for those at intermediate risk of recurrence following mastectomy.5 In all groups, it has been found to reduce any recurrence (loco-regional or distant), and breast cancer mortality,5,6 suggesting that achieving good local control can prevent the spread of disease (Box 1).
MEDICINE --:-
Colorectal cancer Chemotherapy Adjuvant chemotherapy has an important role in stage III disease (tumour with spread to regional nodes), where there is an absolute survival benefit of 10e13% compared with surgery alone.7 In stage II disease, guidelines recommend chemotherapy for those with high-risk features8 such as T4 disease or vascular invasion only. Combination therapy with oxaliplatin and fluorouracil/folinic acid (or oral alternatives) is used as first-line treatment and is usually given for 6 months.
2
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Evans R, Tanguay J, Adjuvant therapy, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.015
ADJUVANT TREATMENT
Several biomarkers have been identified that are important for prognosis and for predicting the response to drug therapy; further research should refine the patient and tumour characteristics that influence treatment and its outcome. A
Case example A 42-year-old woman undergoes a left wide local excision of the breast and sentinel lymph node biopsy for a 29-mm grade 2 invasive ductal carcinoma that is completely excised. There is no perineural or vascular invasion, but two sentinel lymph nodes are positive for tumour. The tumour is found to be oestrogen receptor-positive by immunohistochemistry (Figure 2), and HER-2 receptor-negative (confirmed by fluorescent in-situ hybridization analysis). An axillary lymph node dissection shows that the remaining lymph nodes are clear. The patient is referred for adjuvant therapy and treatment options are discussed. Chemotherapy, using an anthracycline- and taxanebased combination, would improve her survival at 10 years by approximately 17%. Hormonal therapy alone would improve her survival by 10%. However, the combination of chemotherapy followed by hormonal therapy would improve survival by 22% (figures obtained using Adjuvant! Online).10 Upon completion of chemotherapy, radiotherapy of the left breast is offered, and tamoxifen is recommended for 10 years because the patient is premenopausal.
REFERENCES 1 Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687e717. 2 Burstein H, Temin S, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol 2014; 32: 2255e69. 3 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomized trials. Lancet [online] Available at: http://www.thelancet.com/pdfs/journals/lancet/ PIIS0140-6736(15 http://www.thelancet.com/pdfs/journals/ lancet/PIIS0140-6736(15)61074-1.pdf [Accessed 16 September 2015]. 4 Senkus E, Kyriakides S, Penault-Llorca F, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24: vi7e23. 5 Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual data for 8135 women in 22 randomised trials. Lancet 2014; 383: 2127e35. 6 Early Breast Cancer Trialists’ Collaborative Group. Effect 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: 1707e16. 7 Cunningham D, Starling N. Adjuvant chemotherapy of colorectal cancer. Lancet 2007; 370: 1980e1. 8 Jonker DJ, Spithoff K, Maroun J. Adjuvant systemic chemotherapy for stage II and III colon cancer after complete resection: an updated practice guideline. Clin Oncol 2011; 23: 314e22. 9 Sauer R, Becker H, Hohenberger W, et al. German rectal cancer study group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731e40. 10 Adjuvant! Online, http://www.adjuvantonline.com (accessed 2 May 2015).
Box 1
Neoadjuvant therapy This refers to therapy given before the primary treatment. It exposes both the primary tumour and potential micro-metastases to therapy, thereby avoiding the delay caused by surgery and recovery. The sensitivity of the primary tumour is easily assessed and a reduction in bulk may aid surgery. In the treatment of low rectal cancer, preoperative chemo-radiotherapy improves the rate of sphincter-sparing surgery,9 and locally advanced tumours that are initially unresectable may become resectable. This increases the possibility of cure and reduces the risk of local recurrence.
Deleterious effects of adjuvant therapy Adjuvant therapy involves substantial risks and it is important to weigh these against the benefits on an individual basis. The acute toxicities of chemotherapy are regime dependent, one of the most serious being neutropenic sepsis. Late complications are less well understood but are becoming more apparent as patients survive longer. For example, aromatase inhibitors increase the risk of osteoporosis by decreasing bone mineral density. Anthracyclines can cause cardiac dysfunction, and this risk is increased for those also receiving trastuzumab and left-sided breast radiotherapy. However, modern radiotherapy techniques reduce the dose to which the heart is exposed and there are ongoing trials attempting to reduce this further.
Practice points C
The future C
Further advances in adjuvant therapy will come not only from optimizing current regimens, but also from identifying novel therapies that have greater effectiveness and less toxicity. Ongoing trials are attempting to reduce the duration of adjuvant therapy for both colorectal and breast cancer to minimize toxicity while maintaining, or potentially improving, therapeutic benefit.
MEDICINE --:-
C
3
Adjuvant therapies, such as radiotherapy and chemotherapy, are administered to eliminate micro-metastatic disease, improve local control and reduce the risk of cancer recurrence Clinical trials have shown that adjuvant treatment can significantly improve cancer outcomes in common malignancies, such as breast and colorectal cancer Although improved survival is an important endpoint for cancer treatment, consideration must be given to the acute toxicity and morbidity caused by adjuvant therapy, which may be substantial
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Evans R, Tanguay J, Adjuvant therapy, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.015
Adjuvant therapy
drug choice is primarily dependent on the patient’s menopausal status. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) found that 5 years of adjuvant tamoxifen reduced the 15-year breast cancer mortality by a third (34.8% versus 25.6%).1 However, there is increasing evidence that extending treatment up to 10 years in pre/perimenopausal women can further improve survival rates2 and this is now becoming standard practice. Aromatase inhibitors are a newer class of hormone therapy that can only be used for postmenopausal women. Trials to date have shown a significant benefit over tamoxifen in prolonging disease-free survival, and reducing both the risk of recurrence and 10 year breast cancer mortality3,4 (Figure 1). The optimal
Rhiannon Evans Jake Tanguay
Abstract Adjuvant therapy is used following radical treatment to reduce the risk of cancer recurrence and improve survival. The rationale for its use is its potential to treat local and/or distal occult microscopic disease. However, it can be associated with significant adverse effects. The potential benefit of treatment must therefore be assessed on an individual basis, considering both tumour and patient characteristics. This article discusses the basic principles of adjuvant and neoadjuvant therapy, focussing on breast and colorectal cancer. We also discuss some of the adverse effects of therapy and look at potential future developments.
a 50
9885 women, 1791 events RR=0·80 (95% CI 0·73–0·88)
40
Keywords breast cancer; chemotherapy; colorectal cancer; horRecurrence (%)
mone therapy; neoadjuvant; radiotherapy
Introduction Adjuvant therapy is used following primary radical treatment to reduce the risk of cancer recurrence. While the initial treatment targets the primary tumour with the aim of removing all macroscopic disease, adjuvant therapy can be given either to improve local tumour control (e.g. by radiotherapy) or to target micro-metastases using systemic therapy. As most recurrences are thought to be due to occult microscopic disease present at the time of diagnosis, and as most patients are no longer curable once relapse has occurred, the importance of adjuvant therapy should not be underestimated. However, not all patients benefit from adjuvant treatment and it can be associated with substantial adverse effects. An assessment of the risk of recurrence is therefore essential, and is dependent on factors such as tumour histology, site and stage. Patient comorbidity, performance status and preferences are also important. Adjuvant therapy may include chemotherapy, radiotherapy, hormone therapy and/or targeted therapy. They can be given individually or in combination, and are well established forms of treatment in the management of common malignancies such as breast and colorectal cancer.
10-year gain 3·6% (95% CI 1·7 to 5·4) Log-rank 2p<0·00001 30 Tamoxifen 22·7% 20
AI 19·1% 12·1%
10 9·0%
0 0 5 10 Recurrence rate/year (%), events/woman-years and log-rank statistics Allocation AI Tamoxifen Rate ratio (95% CI) from (O-E)/V
Years 0–1 1·62 (157/9691) 2·41 (230/9542) 0·64 (0·52–0·78) –41·1/92·8
Years 2–4 2·14 (285/13336) 2·62 (338/12906) 0·80 (0·68–0·93) –34·1/149·0
Years 5–9 2·33 (365/15648) 2·48 (372/14985) 0·92 (0·79−1·06) −15·5/177·2
Year 10+ 3·23 (20/619) 4·54 (24/529) 0·72 (0·39−1·30) −3·6/10·7
b
Breast cancer mortality (%)
50
9885 women, 1066 deaths RR=0·85 (95% CI 0·75–0·96)
40 10-year gain 2·1% (95% CI 0·5 to 3·7) Log-rank 2p=0·009 30
20 Tamoxifen 14·2% 10 5·8%
AI 12·1%
4·5%
Breast cancer
0 0 5 10 Death rates (%/year: total rate minus rate in women without recurrence) and log-rank
Hormone therapy Adjuvant hormone therapy is effective and appropriate for most patients with oestrogen receptor (ER)-positive breast cancer, but
Allocation Years 0–1 AI 0·52 (0·39−0·66) Tamoxifen 0·51 (0·39−0·67) Rate ratio (95% CI)0·98 (0·66−1·46) from (O-E)/V −0·4/24·3
Years 2–4 1·23 (1·05−1·41) 1·60 (1·38−1·83) 0·74 (0·60−0·91) −27·2/90·7
Years 5–9 1·66 (1·46−1·86) 1·81 (1·60−2·02) 0·90 (0·76−1·07) −13·6/129·4
Year 10+ 1·93 (0·88−2·99) 1·88 (0·77−2·99) 1·01 (0·45−2·33) 0·1/5·6
RR =rate ratio (with 95% confidence interval). AI=aromatase inhibitor. O-E=observed minus expected. V=variance of O-E.
Rhiannon Evans MRCP is a Specialist Registrar on the South Wales Clinical Oncology Training Programme, Swansea, UK. Competing interests: none declared.
(From http://www.sciencedirect.com/science/article/pii/S0140673615610741. Available under the terms of the Creative Commons Attribution Licence (CC BY).)
Jake Tanguay MRCP FRCR is a Consultant Clinical Oncologist at Velindre Cancer Centre, Cardiff, UK. Competing interests: none declared.
MEDICINE --:-
Figure 1 Disease recurrence and breast cancer mortality rates for oestrogen receptor-positive patients given 5 years of tamoxifen compared with 5 years of aromatase inhibitor.
1
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Evans R, Tanguay J, Adjuvant therapy, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.015
ADJUVANT TREATMENT
a
b
(a) Image of oestrogen receptor-positive breast cancer cells. Cells are stained by immunohistochemistry using an antibody against the oestrogen receptor. In this example, the nuclei show strong reactivity (seen as brown staining), indicating a high chance of response to hormone therapy. (b) Image of HER-2 fluorescence in-situ hybridization analysis. The number of copies of the HER-2 gene in the tumour cell nucleus is assessed using fluorescence microscopy. The number of signals (red dots) is compared with the signal for chromosome 17 (green dots); a ratio of >2.2 is considered positive. Images courtesy of Professor Jasani, Cardiff University. Figure 2
duration of treatment with aromatase inhibitors is currently unclear, with ongoing clinical trials evaluating its use beyond 5 years.
trastuzumab with chemotherapy for HER-2-positive patients significantly reduces the risk of recurrence and death from breast cancer, at the cost of a small increased risk of cardiac dysfunction.4
Chemotherapy The benefit of adjuvant chemotherapy is dependent on several factors, and systems such as Adjuvant! Online (http://www. adjuvantonline.com) can provide an estimation of benefit using both patient and tumour characteristics. The EBCTCG overview found that adjuvant chemotherapy reduced 15-year mortality by 10% among those aged less than 50 years, compared with 3% among those aged 50e69 years.1 Its benefit is also more pronounced in node-positive or ER-negative disease. Anthracyclineand/or taxane-containing regimens are most frequently used, and sequential rather than concurrent use of these drugs has been found to be more effective.4 Further evaluation of the benefit of adjuvant chemotherapy can be gained by gene profiling. Tests such as Oncotype DXÒ measure the expression of certain genes in an individual’s breast cancer tissue to predict their risk of recurrence. This can be particularly useful when the decision of whether to offer chemotherapy is otherwise uncertain, for example in those with early-stage ER-positive, HER-2 negative, node-negative disease. Trastuzumab is a humanized monoclonal antibody that inhibits the HER-2/neu receptor, which is overexpressed on the breast cancer cell surface in 20% of patients. The combination of
Radiotherapy Adjuvant breast radiotherapy is standard treatment for patients following breast-conserving surgery and those at high risk of recurrence (N2 disease or positive resection margins) following mastectomy. There is also increasing evidence to support its use for those at intermediate risk of recurrence following mastectomy.5 In all groups, it has been found to reduce any recurrence (loco-regional or distant), and breast cancer mortality,5,6 suggesting that achieving good local control can prevent the spread of disease (Box 1).
MEDICINE --:-
Colorectal cancer Chemotherapy Adjuvant chemotherapy has an important role in stage III disease (tumour with spread to regional nodes), where there is an absolute survival benefit of 10e13% compared with surgery alone.7 In stage II disease, guidelines recommend chemotherapy for those with high-risk features8 such as T4 disease or vascular invasion only. Combination therapy with oxaliplatin and fluorouracil/folinic acid (or oral alternatives) is used as first-line treatment and is usually given for 6 months.
2
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Evans R, Tanguay J, Adjuvant therapy, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.015
ADJUVANT TREATMENT
Several biomarkers have been identified that are important for prognosis and for predicting the response to drug therapy; further research should refine the patient and tumour characteristics that influence treatment and its outcome. A
Case example A 42-year-old woman undergoes a left wide local excision of the breast and sentinel lymph node biopsy for a 29-mm grade 2 invasive ductal carcinoma that is completely excised. There is no perineural or vascular invasion, but two sentinel lymph nodes are positive for tumour. The tumour is found to be oestrogen receptor-positive by immunohistochemistry (Figure 2), and HER-2 receptor-negative (confirmed by fluorescent in-situ hybridization analysis). An axillary lymph node dissection shows that the remaining lymph nodes are clear. The patient is referred for adjuvant therapy and treatment options are discussed. Chemotherapy, using an anthracycline- and taxanebased combination, would improve her survival at 10 years by approximately 17%. Hormonal therapy alone would improve her survival by 10%. However, the combination of chemotherapy followed by hormonal therapy would improve survival by 22% (figures obtained using Adjuvant! Online).10 Upon completion of chemotherapy, radiotherapy of the left breast is offered, and tamoxifen is recommended for 10 years because the patient is premenopausal.
REFERENCES 1 Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687e717. 2 Burstein H, Temin S, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol 2014; 32: 2255e69. 3 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomized trials. Lancet [online] Available at: http://www.thelancet.com/pdfs/journals/lancet/ PIIS0140-6736(15 http://www.thelancet.com/pdfs/journals/ lancet/PIIS0140-6736(15)61074-1.pdf [Accessed 16 September 2015]. 4 Senkus E, Kyriakides S, Penault-Llorca F, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24: vi7e23. 5 Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual data for 8135 women in 22 randomised trials. Lancet 2014; 383: 2127e35. 6 Early Breast Cancer Trialists’ Collaborative Group. Effect 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: 1707e16. 7 Cunningham D, Starling N. Adjuvant chemotherapy of colorectal cancer. Lancet 2007; 370: 1980e1. 8 Jonker DJ, Spithoff K, Maroun J. Adjuvant systemic chemotherapy for stage II and III colon cancer after complete resection: an updated practice guideline. Clin Oncol 2011; 23: 314e22. 9 Sauer R, Becker H, Hohenberger W, et al. German rectal cancer study group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731e40. 10 Adjuvant! Online, http://www.adjuvantonline.com (accessed 2 May 2015).
Box 1
Neoadjuvant therapy This refers to therapy given before the primary treatment. It exposes both the primary tumour and potential micro-metastases to therapy, thereby avoiding the delay caused by surgery and recovery. The sensitivity of the primary tumour is easily assessed and a reduction in bulk may aid surgery. In the treatment of low rectal cancer, preoperative chemo-radiotherapy improves the rate of sphincter-sparing surgery,9 and locally advanced tumours that are initially unresectable may become resectable. This increases the possibility of cure and reduces the risk of local recurrence.
Deleterious effects of adjuvant therapy Adjuvant therapy involves substantial risks and it is important to weigh these against the benefits on an individual basis. The acute toxicities of chemotherapy are regime dependent, one of the most serious being neutropenic sepsis. Late complications are less well understood but are becoming more apparent as patients survive longer. For example, aromatase inhibitors increase the risk of osteoporosis by decreasing bone mineral density. Anthracyclines can cause cardiac dysfunction, and this risk is increased for those also receiving trastuzumab and left-sided breast radiotherapy. However, modern radiotherapy techniques reduce the dose to which the heart is exposed and there are ongoing trials attempting to reduce this further.
Practice points C
The future C
Further advances in adjuvant therapy will come not only from optimizing current regimens, but also from identifying novel therapies that have greater effectiveness and less toxicity. Ongoing trials are attempting to reduce the duration of adjuvant therapy for both colorectal and breast cancer to minimize toxicity while maintaining, or potentially improving, therapeutic benefit.
MEDICINE --:-
C
3
Adjuvant therapies, such as radiotherapy and chemotherapy, are administered to eliminate micro-metastatic disease, improve local control and reduce the risk of cancer recurrence Clinical trials have shown that adjuvant treatment can significantly improve cancer outcomes in common malignancies, such as breast and colorectal cancer Although improved survival is an important endpoint for cancer treatment, consideration must be given to the acute toxicity and morbidity caused by adjuvant therapy, which may be substantial
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Evans R, Tanguay J, Adjuvant therapy, Medicine (2015), http://dx.doi.org/10.1016/j.mpmed.2015.10.015