Conclusions

 

Level 1

Treatment with anthracycline-containing chemotherapy reduces the RR of death from breast cancer by approximately 38% per year for women under 50 years of age and approximately 20% per year for   women who are 50-69 years.

These anthracycline-containing chemotherapy schedules are more effective than CMF regimes and result in a significant reduction in the chance of a recurrence and death compared to the CMF   schedule.

 

A1        EBCTCG 2005

 

Level 2

Treatment with high-dose epirubicin (100-120 mg/m2) schedules in patients with an N+/high-risk breast cancer shows a better survival rate compared to 6 courses of typical CMF and compared to   epirubicin 50-60 mg/m2.

 

B          Piccart 2001, French epirubicin study group 2001, Bonneterre 2005

 

Level 2

Addition of a taxane to anthracycline-containing chemotherapy results in a better (disease-free)   survival of patients in early stage breast cancer.

Improvement in (disease-free) survival with addition of a taxane to anthracycline-containing chemotherapy has been demonstrated in patients with N+ and N0 breast cancer. Subgroups cannot be distinguished (ER status, HER-2 status) in which this treatment has a more or less pronounced effect.

 

B         Henderson 2003, Buzdar 2002, Mamounas 2005, Roché 2006, Martin 2005, Gianni 2005, Goldstein 2005, Martin 2010

 

Level 1

Studies (NSABP-B31, NCCTG N9831, HERA, BCIRG   006) that have researched the value of 1-year treatment with trastuzumab as part of systemic adjuvant therapy in patients with a tumour with HER-2-overexpression, all show a significant reduction in the risk of recurrence and death.

 

A2        Romond 2005, Smith 2007, Slamon 2011

 

Level 3

It has been demonstrated in multiple retrospective studies that the presence of HER-2-overexpression in small tumours (< 1 cm) is associated with a clear increase in the chance of   recurrence.

 

C         Rakkhit 2009, Joensuu 2003, Gonzalez-Angulo 2009, Curigliano 2009, Chia 2008, Tovey 2009, Black 2006, Park 2010, Oakman 2010, Amar 2010, Burstein 2009, Verma 2010, Banerjee   2010, Joerger 2011

Literature summary

Anthracycline-containing chemotherapy

Meta-analyses of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) show that chemotherapy improves the disease-free and total survival of all patients with an early stage breast cancer [EBCTCG 2005, 2008, 2010]. The therapy results in the meta-analysis are expressed in the annual reduction in RR of death and ultimate absolute ten or fifteen-year survival advantage. Treatment with 6-9 courses of anthracycline-containing chemotherapy reduces the RR of death from breast cancer, by approximately 38% per year for women under 50 years of age and approximately 20% per year for women who are 50-69 years. The reduction in RR of recurrence or death in these studies is largely independent of the hormone sensitivity of the tumour, tamoxifen use, node status and other tumour characteristics. The anthracycline-containing chemotherapy schedules are more effective than the CMF (C: Cyclophosphamide, M: Methotrexate, F: 5-Fluorouracil) regimes and resulted in a significant reduction in the recurrence rate (HR 0.89; 2p=0.0001) and death (HR 0.84; 2p<0.00001) compared to the CMF schedule [EBCTCG, 2005].

 

Adjuvant chemotherapy and hormone receptor status of the tumour

A few retrospective studies have shown that postmenopausal patients with a hormone-sensitive (HR+), early stage breast cancer (node negative (N0) and node positive (N+) patients with metastasis in 1-3 nodes), only experience a limited absolute advantage with the addition of chemotherapy to standard treatment with tamoxifen [Colleoni, 2005; Pritchard, 1997; LBCSG, 1984; Goldhirsch, 1990; Fisher, 1997; Fisher, 2004; Albain, 2004; Berry, 2006; Wils, 1999; Fargeot, 2004; Namer, 2006; Conforti, 2007; Albain, 2009]. The same finding was made in the small IBCSG 11-93 study in low-risk N+ premenopausal patients with a hormone-sensitive tumour. Addition of 4 courses of A/EC chemotherapy to tamoxifen in combination with suppression of the ovarian function did not show an improvement in survival [Thurlimann, 2009]. In a retrospective analysis, the programme Adjuvant! also overestimated the effects of chemotherapeutic treatment added to combination hormonal therapy with tamoxifen and suppression of the ovarian function in premenopausal patients with an ER+, N+, low-risk breast cancer [Paridaens, 2010; Cufer, 2008]. However, most of these studies used first or at the most second generation chemotherapy schedules.

 

Studies with neoadjuvant chemotherapy also show a negative correlation between hormone sensitivity and the effect of chemotherapy, usually expressed in percentage pathological complete remission (pCR). The difference in pCR percentages in patients with hormone-sensitive versus hormone-insensitive tumours as a result of neoadjuvant chemotherapy have also been confirmed in recent studies (up to 10% vs >20%). Unfortunately, the studies do not provide data about the level of hormone sensitivity, with the exception of Bhargava, who indicates that the pCR percentages in patients with luminal A and B tumours (corresponding with an ER score >200 vs 11-199) do not differ (1.8 vs 1.4%). A consistent relationship between the presence or absence of the progesterone receptor and the effect of (neo)adjuvant chemotherapy has not been shown.

It has become clear through research on the genetic profile of the tumour that these hormone-sensitive breast cancers belong to a heterogeneous group, in which the spectrum spans from extremely low risk for which chemotherapy is not worthwhile, to a clearly increased risk of recurrence for which treatment with chemotherapy is justified [Soteriou, 2009; Bonnefoi, 2009; Albain, 2009; Albain, 2010].

 

Aside from adequate hormonal treatment, conventional adjuvant and neoadjuvant chemotherapy is of limited significance in patients with hormone-sensitive tumours.The favourable contribution of chemotherapy reduces with age.Third generation chemotherapy schedules appear to be more effective. There is a demonstrated reverse correlation between the effect of (neo)adjuvant chemotherapy and hormone sensitivity. However, a cut-off value for receptor activity on the basis of which chemotherapy should (not) be recommended within the hormone-sensitive group is not known.

An indication for (neo)adjuvant treatment with chemotherapy may be strengthened or weakened by other factors (such as an extremely low concentration of hormone receptors, age, condition, contraindications, grading, HER-2 etc.).If feasible , a third generation schedule is preferable.

 

Adjuvant chemotherapy in the elderly

There is little known about the effect of adjuvant chemotherapy in  patients from 70 years of age. Two randomised studies have looked at  the effect of adjuvant chemotherapy in patients 65 years and older [Fargeot, 2004; Muss, 2009]. The study by Fargeot randomised between treatment with tamoxifen with(out) 6 courses epirubicin weekly, and in the  study by Muss the patients in the control arm were treated with 6 courses of CMF  or 4 courses AC ( standard treatment) or with  6 courses of capecitabine  (experimental arm) . The addition of epirubicin to tamoxifen resulted in a 6-year disease-free survival advantage of 3.3%, without a  survival advantage. Standard CMF and AC resulted in a significantly better (disease-free) survival after 3 years compared to capecitabine, especially in patients with a tumour with negative hormone receptors. Toxicity was limited in the weekly epirubicin group but substantial in the CMF treated group, with the consequence that only 62% of the patients received the planned 6 courses.

 

Optimal duration of adjuvant anthracycline-containing chemotherapy

While anthracycline-containing schedules are considered standard adjuvant chemotherapy, optimal duration and dose of this treatment have not been studied sufficiently. Indirect data suggests that 6-9 cycles of anthracycline-containing chemotherapy is more effective than 4 cycles. The arguments for this are:

  • The meta-analysis of 2005 shows if the data for the 4 studies in which 4 or less cycles of AC or EC (C: cyclophosphamide, A: doxorubicin, E: epirubicin) were administered are omitted, this results in an increase in survival advantage provided by anthracycline-containing chemotherapy compared to chemotherapy not containing anthracycline. Treatment with 6 to 9 cycles of anthracycline-containing chemotherapy results in an approximately 25% annual reduction in RR of death compared to CMF regimes [EBCTCG, 2005].
  • Three studies in which 4 cycles of AC/EC were compared with 6 cycles of typical CMF showed comparable outcomes [Fisher, 1990; Fisher, 2001; Galligioni 2000], while 6 cycles CE120F was more effective than 6 cycles of typical CMF [Levine, 2005].
  • Six cycles FEC resulted in a better survival than 3 cycles FEC in premenopausal patients with an N+ breast cancer [Fumoleau 2003].

Based on these arguments, it is generally accepted that 6 cycles of intravenous FAC/CAF or FEC/CEF are considered standard adjuvant anthracycline-containing chemotherapy.

 

Optimal dose of adjuvant anthracycline-containing chemotherapy

Dose escalation

Seven studies researched the effect of dose escalation of doxorubicin, cyclophosphamide and epirubicin as adjuvant chemotherapy [Galligioni, 2000; Levine, 2005; Henderson, 2003; Budman, 1998; Fisher, 1997; Fisher, 1999; Piccart, 2001; FASG, 2001; Bonneterre, 2005]. In the CALGB 9344 study, treatment with a higher than standard dose of doxorubicin (60 mg/m2) for 4 courses did not result in a better survival [Henderson, 2003]. In CALGB 8541 however, treatment with a cumulative dose of doxorubicin lower than 240 mg/m2 was found to be less effective [Budman, 1998]. In the NSABP B-22 and B-25 study, dose escalation of cyclophosphamide did not result in a better survival, except for the subgroup of women under 50 years with at least 4 tumour positive axillary nodes [Fisher, 1999]. Dose escalation of doxorubicin above a standard dose (of 60 mg/m2/course) did not result in a better clinical effect, while there did appear to be a cumulative threshold value under which the effectiveness decreased [Burdette-Radoux, 2003]. Three of the four studies on the effect of high-dose epirubicin (100-120 mg/m2) schedules in patients with an N+/high-risk breast cancer showed a better survival compared to 6 courses of typical CMF and compared to epirubicin 50-60 mg/m2 [Galligioni, 2000; Piccart, 2001; FASG, 2001; Bonneterre, 2005].

No studies have been performed in which 4-6 cycles of (F)A60C were compared with 6 cycles of (F)E100-120C.

 

Dose intensification

Many studies have looked at the principle of dose intensification [Bonadonna, 2004; Therasse, 2003; Fetting, 1998; Linden, 2007; Nitz, 2005; Citron, 2003; Venturini, 2005; Burnell, 2010; Moebus, 2010]. However, most studies did not research the pure dose-dense principle (intensification of the chemotherapy dose by shortening the interval between administrations) but the doses in the two study arms were not identical. Two pure dose-dense studies yielded the following results. In the CALGB 9741 study, treatment with 4 courses of AC followed by 4 courses paclitaxel in a 14-day schedule resulted in a better 4-year disease-free survival (82 vs 75%) and 4-years survival (92 vs 90%) than the same 3-weekly treatment in patients with N+ breast cancer. In the Italian study in which the effect of 6 courses FE60C, administered with a 2- or 3-weekly interval, were compared, there was no significant difference in effectiveness between the two schedules [Venturini, 2005]. Two large studies were published recently that compared a dose-dense and intensified schedule with 3-weekly standard AC/EC and paclitaxel schedule [Moebus, 2010; Burnell, 2010]. The study by Burnell, conducted in 2104, N+ and high-risk N0 patients, used the Canadian CE120F schedule as the third arm. After a median follow-up of 30 months, the 3-weekly AC/paclitaxel schedule was found to be inferior to both the intensified schedule and the Canadian CE120F schema. The 3-year disease-free survival was: 85%, 89.5% and 90.1% respectively. The German study compared a standard 3-weekly EC/paclitaxel schedule with all agents given as monotherapy in a 2-weekly schedule and escalated dose; the study incorporated 1,284 patients with 4 or more positive lymph nodes. The 5-year disease-free survival was 62% vs 70% (p<0.001) and the survival was 77% vs 82% (p=0.0285) respectively. In this study, an AML or MDS developed in 4 patients treated in the intensified arm.

 

High-dose chemotherapy

A number of studies have compared the effect of high-dose chemotherapy followed by stem cell transplantation to treatment with standard adjuvant chemotherapy. In a meta-analysis of 15 studies, an absolute disease-free survival advantage of 13% was reported after a median follow-up of 6 years. There was no survival advantage, possibly partly due to therapy-related death and an increase in the occurrence of acute myeloid leukaemia and MDS in some studies. In a few retrospective subgroup analyses, high-dose chemotherapy appeared to be mainly effective for patients with an HER-2-negative tumour and for patients with a triple negative tumour [Rodenhuis, 2006; Tallman, 2003; Peters, 2005; Wilkin, 2007; Hanrahan, 2006; Zander, 2004; Leonard, 2004; Coombes, 2005; Moore, 2007; Nieto, 2009; Farquhar, 2007]. After a follow-up of 87 months, the Dutch 4+ study shows a trend in the actuarial 5-year disease-free survival in favour of the high-dose arm of 4% for the entire group (HR 0.84; p=0.076 (two-sided)). An unplanned subgroup analysis shows a significant 5-year survival advantage of 7% for the patients with a tumour without HER-2-overexpression who are treated with high-dose chemotherapy. A second analysis in a representative sample within the HER-2-negative subpopulation shows a substantial 8-year survival advantage of approximately 50% for patients with tumours with a BRCA1-like array comparative genomic hybridisation (CGH) profile when they have been treated with high-dose chemotherapy compared to standard FE90C (multivariate HR 0.12; 95%CI 0.04-0.43; 5-year recurrence-free survival 78% vs 29%), while a significant difference in (recurrence-free) survival is seen between the two treatment arms in the patient group who have a tumour without a BRCA1-like CGH profile [Vollebergh, 2010].

Taxane-containing chemotherapy

Aside from anthracyclines, taxanes (paclitaxel and docetaxel) have been found to be very effective in the treatment of breast cancer. Neither agent shows a clinical cross-resistance with anthracyclines. Results are now available for 21 trials with first-generation taxane treatment in which approximately 35,000 women were randomised between treatment with taxane-containing and taxane-free, generally anthracycline-containing, chemotherapy. Studies differ in study structure, the type of taxane used, and the simultaneous or sequential addition of taxane to the anthracycline-containing schedule. It appears from a few pooled data analyses and a meta-analysis that taxane-containing adjuvant chemotherapy results in a small advantage in disease-free survival and survival (approximately 5 vs 3% absolute advantage respectively) compared to the control arm (generally an anthracycline-containing schedule) of the studies. This finding is independent of the type of taxane, the administration schedule, the node status and hormone receptor expression [Bria, 2006; de Laurentiis, 2008; Ferguson, 2007; Bedard, 2010; Kelly, 2010]. However, the studies can be further subdivided into:

a)     studies in which the taxane-containing schedule is compared to a relatively low-dose anthracycline schedule (e.g. 4 AC or 6 FAC50) and

b)    studies in which the taxane-containing schedule is compared to a standard-dose anthracycline-containing schedule (e.g. 6 FEC90/100) in the control arm

 

First generation taxane-containing chemotherapy compared with anthracycline-containing chemotherapy

The results are available for nine first-generation taxane studies in which the taxane-containing schedule is compared with an anthracycline-containing schedule. There are 17,000 patients in these studies. The PACS 01 study included N+ patients and found a significant improvement in the five-year disease-free survival and survival (HR 0.82 and 0.73 respectively) after treatment with 3 courses FEC100 followed by 3 courses docetaxel compared to 6 courses FEC100 [Roche, 2006]. The GEICAM 9906 trial found an improvement in the 5-year disease-free survival (HR 0.74) of N+ patients in favour of the group treated with 3 courses of FEC90 followed by 8-weekly administrations of paclitaxel compared to 6 courses FEC90 [Martin, 2008]. In the ECTO study with N0 and N+ patients, the effect of treatment with 4 courses doxorubicin in combination with paclitaxel followed by 4 courses CMF iv. was compared to the effect of 4 courses doxorubicin monotherapy prior to 4 courses CMF iv. The hazard ratio for disease-free survival and for survival was 0.73 (p=0.027) and 0.80 respectively after more than 6 years, in favour of the arm without paclitaxel [Gianni, 2009]. Both the 4-arm BIG 02-98 and Taxit 216 studies showed a better disease-free survival in patients with an N+ breast cancer, with a hazard ratio of 0.79 and 0.82 respectively for the taxane-containing study arm. The combination of 4 courses epirubicin/cyclophosphamide followed by 4 courses docetaxel was found to provide a significantly better disease-free survival compared to 6 courses FEC100 or 6 courses CMF (iv day 1 and 8 schedule) in the WGSG/AGO study [Nitz 2008]. The HeCOG 10/97 compared an unconventional dose-dense schedule, namely 3 courses CMF with a dose-dense schedule of 4 courses epirubicin and 4 courses CMF. While the taxane regimen was not found to provide a statistically significant advantage, the study had insufficient power to show a difference in survival. In the GEICAM 98-05 study, TAC was found to be more effective than FAC50 after a follow-up of more than 6 years in high-risk N0 patients. The hazard ratio for the recurrence rate was 0.68 (p=0.01). A significant difference in survival has not (yet) been demonstrated (HR 0.76); however, the number of patients in the study who died is still very low (TAC: 26, FAC: 34) [Martin, 2010]. In two studies, the NCIC MA 21 and the UK TACT, no advantage was found in the addition of a taxane to a standard anthracycline schedule. In both studies, the anthracycline regime was superior to the typical CMF as has been found earlier in head-to-head comparisons (CEF and E-CMF) [Fountzilas, 2005; Burnell, 2009; Ellis, 2007]. From the recent (as yet unpublished) meta-analysis of the EBCTCG 2010, it appears that the combination of a taxane- plus anthracycline-containing schedule versus the same or a high dose anthraycline-containing schedule results in a reduction in breast cancer mortality of approximately 12% (RR 0.88; p=0.00001; n=44,000). Subdivided in the anthracycline strength of the studies, the RR is 0.87 (p=0.001; n=11,000) if the taxane-anthracycline schedule is compared with the same dose anthracycline in the control arm; however, if the dose of the non-taxane arm was doubled, the advantage of treatment with a taxane was lost (RR=0.95±0.06, p=0.4; n=10,000).

 

Second generation taxane studies

The second generation taxane studies directly compare different taxane-containing regimes in order to determine the optimal dose and the optimal schedule and type of taxanes in the adjuvant setting. CALGB 9741 tested the dose-dense hypothesis (see dose intensification). There was a clear advantage for the experimental schedule in the 4-year disease-free survival (HR 0.80). After a follow-up of almost 6 years, the risk of recurrence is still significantly lower in favour of the dose-dense arm, but the difference in survival is not significant (HR 0.85, p=0.12). The as yet unpublished BCIRG 005 study compares the effect of 6 courses TAC with 4 courses AC followed by 4 courses docetaxel in N+ patients. After a follow-up of 60 months, there is no difference in (disease-free) survival between the two study arms [Eiermann, 2008].

It appears from the results of the ECOG 1199 study that the taxane schedule may be of importance. This study randomised almost 5,000 patients with N+ breast cancer into 4 different taxane schedules according to a 2-by-2 factorial design. After 4 courses adjuvant AC, patients were randomised between 4 courses three-weekly paclitaxel or 12 courses weekly paclitaxel, 4 courses three-weekly docetaxel or 12 courses weekly docetaxel. A disease-free survival advantage was found in the study arms in which the patients were treated with weekly paclitaxel or three-weekly docetaxel, while a survival advantage was only found in the arm with the weekly paclitaxel schedule [Sparano, 2008]. Six small (neo)adjuvant studies researched the optimal sequence of anthracyclines and taxanes [Cardoso, 2001; Miller, 2005; Piedbois, 2007; Puhalla, 2008; Wildiers, 2009; Earl, 2009]. In three of the four adjuvant studies, the relative dose intensity was found to be higher in the sequence taxane followed by anthracycline. A higher pCR percentage was achieved in the two neoadjuvant studies with the taxane followed by anthracycline schedule. Data on the effectiveness in the adjuvant setting are not yet known. The optimal schedule taxane/anthracycline-containing chemotherapy is not yet known because only preliminary results of most studies have been published.

 

Taxane-containing, non-anthracycline-containing chemotherapy versus anthracycline-containing chemotherapy

A large randomised study compared the effectiveness of taxane-containing chemotherapy with that of anthracycline-containing chemotherapy [Jones, 2006]. In this study, 1,016 patients (N+ and N0) were randomised between treatment with 4 courses AC or 4 courses TC (docetaxel/cyclophosphamide). After a median follow-up of 5.5 years, there was a significantly longer disease-free survival for TC (HR 0.67).

Chemotherapy in combination with trastuzumab

Six randomised studies have researched the value of 1-year treatment with trastuzumab as part of the medication-based adjuvant therapy in patients with a tumour with HER-2-overexpression [Piccart, 2005; Romond, 2005; Smith, 2007; Slamon, 2007; Spielman, 2009; Joensuu, 2009].In NSABP-B31, N+ patients were treated with 4 courses AC, followed by 4 courses paclitaxel (175 mg/m2/3 weeks) versus the same chemotherapy to which 1-year treatment with trastuzumab was added, to be started simultaneously with paclitaxel. In the three-arm NCCTG N9831 study, N+ (after an amendment also N0) patients were treated with 4 courses AC, followed by 12-weekly courses of paclitaxel (80 mg/m2) as monotherapy or in combination with weekly trastuzumab for a duration of 1 year or followed by weekly trastuzumab for a duration of 1 year (sequential trastuzumab). After treatment with adequate adjuvant chemotherapy, N0 and N+ patients were randomised for treatment with 0, 1 or 2 year trastuzumab in a 3-weekly schedule in the three-arm HERA study [Piccart, 2005; Smith, 2007]. In the three-arm BCIRG 006 study, N+ and high-risk N0 patients in arm 1 and 2 were treated with 4 courses AC followed by 4 courses docetaxel (AC-T) as monotherapy or in combination with trastuzumab (AC-TH) for a duration of 1 year (weekly during chemotherapy, thereafter three-weekly). In the third arm, treatment consisted of 6 courses docetaxel plus carboplatin (TCH) in combination with trastuzumab for a duration of 1 year (weekly during chemotherapy, thereafter three-weekly [Slamon, 2011]. In the PACS04 study, N+ patients with a tumour with HER-2-overexpression were randomised between treatment with 6 courses FEC100 or epirubicin/docetaxel followed by a second randomisation between observation or treatment with trastuzumab for a duration of 1 year. In the FinHer study, patients were randomised for 3 courses docetaxel or vinorelbine followed by 3 courses FEC, in which patients with HER-2-overexpression were also randomised between receiving or not receiving treatment with trastuzumab for a duration of 9 weeks during vinorelbine or docetaxel treatment [Joensuu, 2006; 2009].

 

The design and therapeutic interventions of the NSABP-B31 and NCCTG N9831 studies were so similar that it was decided to evaluate the studies together in relation to the arms in which the trastuzumab was administered simultaneously with paclitaxel [Romond, 2005] After a median follow-up of 2.9 years, the hazard ratio for disease-free survival was 0.49 for patients treated with trastuzumab (p<0.0001). The 4-year disease-free survival for the trastuzumab group was 85.9% versus 73.1% for the control group. In the trastuzumab arm, 92.6% percent of patients were still alive after 4 years compared to 89.4% in the control arm. After a median follow-up of 4 years so far, a significant effect is seen on survival (HR 0.63; p=0.0004). In an unplanned interim analysis with still relatively few events, the results of the sequential trastuzumab treatment in the NCCTG N9831 study did not show significant advantage for the sequence 4 AC – 4 paclitaxel – trastuzumab compared to 4 AC – 4 paclitaxel with a hazard ratio of 0.87 for the 2-year disease-free survival.

 

The first results of the HERA study concern the comparison of no trastuzumab treatment vs 1 year treatment with the agent. After a median follow-up of 2 years, there was a significant survival advantage for the trastuzumab arm with a hazard ratio for disease-free survival of 0.63 (p<0.0001) and 0.63 for survival (p=0.0051). The three-year disease-free survival in the trastuzumab arm was 80.6% versus 74.3% for the control arm and the corresponding survival was 92.4% versus 89.7%. In the FinHer study, the three-year disease-free survival was also significantly better for the group of patients in the trastuzumab arm (89% vs 78%, p=0.01). There was also a trend for a better survival (96% vs 90%, p=0.07). In the BCIRG 006 study, both trastuzumab-containing treatment arms (TCH and AC-TH) showed a significant improvement in disease-free survival after a median follow-up of 3 years compared to the AC-T schedule (HR 0.67 en 0.61; p=0.0003 and p<0.0001). The 3-year disease-free survival was 87% for AC-TH, 86% for TCH and 81% for AC-T. There was also a significant improvement in survival by both TCH and AC-TH compared to AC-T (HR 0.66 and 0.59; p=0.017 and p=0.004). Only the PACS 04 study showed no improvement in (disease-free) survival as a result of the addition of trastuzumab [Spielmann, 2009].

It is still unclear what the most effective form of administering trastuzumab is: after or simultaneously with chemotherapy. There are indications that the simultaneous administration of trastuzumab with a taxane is more effective than sequential administration. This can be seen from the comparison in risk reductions that are better in the studies in which trastuzumab was administered in combination with a taxane (NSABP B-31/NCCTG N9831 and BCIRG 006).

 

Trastuzumab with small (< 1 cm) N0 tumours with HER-2-overexpression.

The majority of patients with stage I breast cancer have an excellent prognosis. It appears from multiple retrospective studies that the presence of HER-2-overexpression in this small tumour is associated with a clear increase in the recurrence rate [Rakkhit, 2009; Joensuu, 2003; Gonzalez-Angulo, 2009; Curigliano, 2009; Chia, 2008; Tovey, 2009; Black, 2006; Park, 2010; Oakman, 2010; Amar, 2010; Burstein, 2009; Verma, 2010; Banerjee, 2010; Joerger, 2011]. However, interpretation of these studies is hampered by the fact that the studies differ in relation to the endpoint chosen, the duration in follow-up, and whether or not adjuvant systemic therapy was used. No prospective study has demonstrated that treatment with trastuzumab reduces the recurrence rate with these small tumours. In a small retrospective study in the Netherlands with a short follow-up, the 70-gene profile in tumours with an ER and PR of ≥ 50% resulted in a small subgroup with a good prognosis despite HER-2-overexpression [Knauer, 2010]. The St. Gallen guideline of 2011 poses that even with the small T1b tumours there may be a role for treatment with trastuzumab. For this category, the National Comprehensive Cancer Network (NCCN) guideline of 2011 recommends considering treatment with chemotherapy and trastuzumab for hormone-receptor negative tumours from T1bN0. For hormone-receptor positive tumours, the NCCN recommends treating these patients with hormonal therapy and trastuzumab, possibly in combination with chemotherapy. However, the treatment of these small tumours must be weighed up against the possible cardiotoxicity and uncertain absolute advantage provided by trastuzumab.

It appears from these retrospective studies that often contain small absolute numbers of patients that this group of small tumours with HER-2-overexpression is heterogenous; as a rule of thumb, the relative risk of death after 10 years as calculated with the adjuvant-on-line programme can be multiplied by a factor of 2.5.

 

Adjuvant treatment of the triple negative breast cancer

Approximately 15-20% of the breast cancers are so-called triple negative tumours [Perez, 2010]. This subgroup of the breast cancer is characterised by the absence of both the ER and PR and  HER-2-overexpression. The tumour occurs more often at a young age, is high-grade and on presentation is often already substantial in size and metastasised to the axillary  lymph nodes. The tumours have a poorer prognosis with rapid recurrences, frequent brain metastasis, and a short survival after a recurrence develops.Various  neoadjuvant phase II studies have found that these tumours respond better to standard neoadjuvant chemotherapy with anthracyclines and taxanes compared to other tumour types; however, if complete remission is not achieved, there is no improvement in survival [Parker, 2009; Tan, 2008; Wang, 2009; Hugh, 2009; Sorlie, 2009; Tan, 2009; Liedtke, 2008]. In a subgroup analysis of the CALGB9741 study, doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 and paclitaxel 175 mg/m2 every 2 weeks with G-CSF provided a risk reduction of 24% (95%CI 1-42%) in recurrence and 28% (95%CI 1-47%) in death compared to the same agents once every three weeks in the ER negative subgroup. The HER-2 status was left out of consideration in this analysis [Berry, 2006]. Research is underway on the effect of treatment with platinum analogues, intensified alkylating therapy, anti-tubulins, angiogenesis inhibitors and poly(ADP)ribose polymerase (PARP) inhibitors in this subgroup of mammary tumours. However, there is currently insufficient data to treat this group of breast cancers (outside a research context) different to the other types of breast cancer.

Toxicity

Secondary haematological malignancies

Patients treated with radiotherapy, alkylating chemotherapeutic agents and topoisomerase inhibitors have an increased chance of developing an acute myeloid leukaemia or myelodysplasia (AML/MDS). In a retrospective study with the data from six NSABP studies, there was an increase in the incidence of AML/MDS in the AC regimens with intensified doses cyclophosphamide, in which GCS-F support was required (Smith, 2003). The same observation has been described by Herschman (2007) with the use of GCS-F with AC chemotherapy, amongst others. In a review with data from nineteen randomised studies, Praga (2005) concluded that the chance of developing a secondary AML/MDS was 0.37% with cumulative doses of ≤ 720 mg/m2 epirubicin and ≤ 6.300 mg/m2 cyclophosphamide. Higher doses resulted in a 4.97% cumulative rate of AML/MDS after 8 years.

The chance of developing therapy-induced leukaemia is limited with the current standard regimes, and the (disease-free) survival advantage resulting from adjuvant treatment of breast cancer with anthracyclines and cyclophosphamide is many times greater than the loss of lives through AML/MDS.

 

Cardiotoxicity

The formation of free radicals and oxidative stress that occurs during  treatment with anthracyclines can damage the heart. Anthracycline-induced cardiotoxicity is characterised by a slow progressive worsening in pump function without spontaneous improvement, and correlates strongly with the cumulative dose of anthracycline – half the dose causes half the damage [Jensen, 2006; Johnson, 2006]. There is also a clear increase in the sensitivity for heart damage with increasing age. The reduction in pump function occurs especially in the period after treatment so that monitoring of the ejection fraction during treatment is hardly effective. The individual sensitivity for anthracycline cardiotoxicity varies strongly. Shan (1996) concludes in a review that cardiac damage in some patients already occurs with cumulative doses of ≤ 300 mg/m2, while other patients tolerate doses of ≥ 1000 mg/m2 doxorubicin. An estimated cumulative percentage of clinical heart failure of 5% was found to occur in the study by Swain (2003) in patients treated with 400 mg/m2 and in 26% of patients treated with 550 mg/m2 doxorubicin. In the French adjuvant study with FE100C, clinical heart failure was observed in 2 of the 85 patients evaluated and asymptomatic left ventricle dysfunction in 18 patients [Bonneterre, 2004]. Meinardi (2002) did not observe clinical heart failure in any of the 56 patients treated in the 4+ study in the Netherlands. However, there was abnormal systolic function in 11% of patients and abnormal diastolic function in 38%, two or more years after treatment with epirubicin doses up to 450 mg/m2. For the time being, the (disease-free) survival advantage for adjuvant treatment with anthracyclines is greater than mortality  through cardiotoxicity. However, increasing use of (higher-dose) anthracycline-containing chemotherapy schedules, also at a higher age, means it is plausible that the full extent of the problem will only  become clear in coming years and caution is warranted.

 

Cardiotoxicity may also occur after   treatment with trastuzumab. This especially occurs if trastuzumab is administered closely together with anthracyclines. Well functioning HER-2 signalling is probably needed for the healing of cardiac damage induced by anthracyclines [Hudis, 2007; de Korte, 2007]. Trastuzumabas  monotherapy can also be cardiotoxic. Binding of trastuzumab to HER-2 receptors in the heart limits the response to stress. Despite strict selection of patients prior to research, cardiotoxicity was seen in the four large adjuvant studies in which patients were treated with both anthracyclines and trastuzumab. Symptomatic heart failure was observed in the HERA trial in 0.6% of patients treated with trastuzumab, and in the BCIRG trial in 1.6% of patients in the anthracycline-containing arm (AC-TH) and in 0.4% in the therapy arm without anthracycline (TCH). This percentage was 3-4% in both American studies in which the trastuzumab was administered simultaneously with paclitaxel. The definition of cardiotoxicity and the associated (temporary) cessation in treatment with asymptomatic reduction in left ventricular ejection fraction (LVEF) was not identical in the studies, which makes comparison difficult. There was an asymptomatic cardiac dysfunction in the NSABPB-31 in 34% of patients (defined as at least a one-off reduction in LVEF by ≥ 10 EF points and an LVEF of < 55%) in the group treated with trastuzumab, while at least a one-off reduction in LVEF of ≥ 10 EF points of < 50% was observed in 7% of patients treated with trastuzumab [Suter, 2007].

It is unknown to what extent the cardiotoxicity of trastuzumab will be temporary. Telli (2007) outlines that there was still a significant reduction in LVEF in a substantial number of patients with a cardiac event in both the NSABP B-31 and the BCIRG studies after ≥ 6 months follow-up.

Authorization date and validity

Last review : 13-02-2012

Last authorization : 13-02-2012

The national Breast Cancer guideline 2012 is a living guideline, in other words there is no standard term of revision. NABON continually watches at new developments and clinical problems in the areas of screening, diagnostics, treatment and aftercare, and whether this requires an update.

Initiative and authorization

Initiative : Nationaal Borstkanker Overleg Nederland

Authorized by:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Psychiatrie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie

General details

Approximately 14,000 women (and 100 men) are diagnosed with invasive breast cancer each year in the Netherlands, and about 1,900 have an in situ carcinoma. A woman's risk of having breast cancer over the course of her life is 12-13%. This means that breast cancer is the most common form of cancer in women in the Netherlands. Early detection, particularly via national breast cancer screening, combined with adjuvant therapy followed by locoregional treatment, improves the prognosis in women with breast cancer

The guideline on Breast Cancer Screening and Diagnostics, published in 2000, was updated in 2007. In 2002, the first multidisciplinary National Breast Cancer Guideline was published, it was revised in 2004, 2005 and 2006. In 2008 both guidelines were combined to Breast Cancer Guideline, which 2012 revision is now effected.

Scope and target group

This guideline is written for all the members of the professional groups that have contributed to its development.

 

This guideline is a document with recommendations and instructions to support daily practice. The guideline is based on the results of scientific research and expert opinion, with the aim of establishing good medical practice. It specifies the best general care for women with (suspected) breast cancer and for those who are eligible for screening. The guideline aims to serve as a guide for the daily practice of breast cancer screening, diagnostics, treatment and aftercare. This guideline is also used in the creation of informational materials for patients, in cooperation with the KWF (Dutch Cancer Society).

Member of workgroup

A core group consisting of a radiologist, surgeon, pathologist, medical oncologist and radiation therapist began preparing for the revision of the breast cancer practice guidelines in 2009. A multidisciplinary guideline development group was formed in early 2010 to implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society) (see list of guideline development group members). The benefits of such a multidisciplinary approach are obvious: not only does it best reflect the care, but it offers the greatest possible expertise for the guideline. In composing the development group, geographic distribution of the members, balanced representation of the various organisations and agencies concerned, and a fair distribution in academic background were taken into account as much as possible.

 

The guideline development group received procedural and administrative support from IKNL (Comprehensive Cancer Centre for the Netherlands) and support on methodology from Bureau ME-TA. Partial funding was obtained from SKMS (Quality Funds Foundation of Dutch Medical Specialists). This subsidy would not have been possible without the extensive assistance provided by the NVvR (Radiological Society of the Netherlands).

Declaration of interest

Partial funding for the guideline revision was obtained from the Society of Dutch Medical Specialists in the framework of the SKMS. IKNL sponsored some of the cost. On two occasions, as well as at the beginning and end of the process, all of the members of the guideline development group were asked to fill out a statement of potential conflicts of interest, in which they stated their relationship with the pharmaceutical industry. A list of these statements of interest can be found in the appendices.

Patient involvement

In developing this guideline, four clinical questions were formulated. These questions emerge from an inventory of clinical problems collected in the field from professionals, patients and patient representatives.

 

Also, A multidisciplinary guideline development group was formed in early 2010 to create and implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society).

 

Method of development

Evidence based

Implementation

Feasibility has been taken into account in developing the guideline. This included attention to factors that could promote or hinder putting the advice into practice. Examples include the implementation of an analysis of problems, the multidisciplinary composition of the guideline development group, and making active use of support from the guideline development group members. Presenting the draft guideline to the field and communicating what, if anything, is being done with the responses, also promotes implementation. In this manner, a guideline has been developed that answers current questions in the field.

The guideline is distributed widely and is available in digital form on the Dutch Guideline Database. The guideline may also be brought to the attention of a wider audience in other periodicals or continuing education sessions, for example. To promote use of the guideline, we recommend that the regional tumour working groups and group practices, as well as scientific and professional organisations, repeatedly bring the guideline to the attention of their members. Any problems that may arise in using the guidelines can then be discussed and, when appropriate, submitted to the national guideline development group, as it is a "living" guideline. If desirable, parts of the guideline can be made more explicit by formulating regional additions or translation to the local situation in departmental and/or hospital protocols.

In principle, indicators are determined during development of the guideline that can be used to monitor implementation of the recommendations. Via a documentation project, these indicators can then be used to determine the extent of compliance with the guideline. The information from the documentation project becomes input for the revision of the guideline.

Methods and proces

This module has been evidence-based revised in 2008 and consensus based updated in 2012.

 

A revision of an existing guideline consists of revised and updated text. Revised text is new text based on an evidence-based review of the medical literature; updated text is the old guideline text which has been edited by the experts without performing a review of medical literature. Each section of the guideline states what type of revision has taken place. Each chapter of the guideline is structured according to a set format, given below. The purpose of this is to make the guideline transparent, so that each user can see on what literature and considerations the recommendations are based on.

 

Description of the literature

To the greatest extent possible, the answers to the fundamental questions (and therefore the recommendations in this guideline) were based on published scientific research. The articles selected were evaluated by an expert in methodology for their research quality, and graded in proportion to evidence using the following classification system:

 

Classification of research results based on level of evidence

A1

Research   on the effects of diagnostics on clinical outcomes in a prospectively   monitored, well-defined patient group, with a predefined policy based on the   test outcomes to be investigated, or decision analysis research into the   effects of diagnostics on clinical outcomes based on results of a study of   A2-level and sufficient consideration is given to the interdependency of   diagnostic tests.

A2

Research   relative to a reference test, where criteria for the test to be investigated   and for a reference test are predefined, with a good description of the test   and the clinical population to be investigated; this must involve a large   enough series of consecutive patients; predefined upper limits must be used,   and the results of the test and the "gold standard" must be   assessed independently. Interdependence is normally a feature of situations   involving multiple diagnostic tests, and their analysis must be adjusted   accordingly, for example using logistic regression.

B

Comparison   with a reference test, description of the test and population researched, but   without the other features mentioned in level A.

C

Non-comparative   trials

D

Opinions   of experts, such as guideline development group members

 

Conclusions

Based on the medical literature, one or more relevant conclusions are made for each section. The most important literature is listed according to the level of evidential strength, allowing conclusions to be drawn based on the level of
evidence. All the medical literature included in the conclusion is described in the bibliography.

 

Classification of conclusions based on literature analysis

1

Based   on 1 systematic review (A1) or at least 2 independent A2 reviews.

2

Based   on at least 2 independent B reviews

3

Based   on 1 level A2 of B research, or any level C research

4

Opinions   of experts, such as guideline development group members

 

Other considerations

Based on the conclusion(s), recommendations are made. However, there are other considerations that contribute to formulation of the recommendation besides literature evidence, such as safety, the patients' preferences, professional expertise, cost-effectiveness, organisational aspects and social consequences. The other considerations are mentioned separately. In this manner, it is clear how the guideline development group arrived at a particular recommendation.

 

Recommendations

The final wording of the recommendation is the result of the scientific conclusion, taking into account the other considerations. The purpose of following this procedure and drawing up the guidelines  in this format is to increase transparency.

 

References

An alphabetical list of literature references can be found at the end of the guideline.

 

All draft texts have been discussed by the guideline development group.

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.