Current first-line treatment options: reassessing the evidence

1. Current first-line treatment options: reassessing the evidence Martin Stockler Sydney Cancer CentreNHMRC Clinical Trials Centre, University of SydneyAustralia New Zealand Breast Cancer Trials Group

2. Options for first-line chemotherapy in HER2-negative metastatic breast cancer (MBC) At the present time, treatment options for the first-line treatment of metastatic breast cancer (MBC) include both established therapies (e.g. anthracycline-, taxane- and Xeloda-based regimens) CMF, and investigational therapies (e.g. gemcitabine or vinorelbine). First line options for women with HER2-negative MBC include proven regimens based on anthracyclines, taxanes, Xeloda and CMF, or investigational regimens based on drugs like gemcitabine or vinorelbine. During this presentation the evidence supporting various first-line treatment choices will be reviewed, highlighting clinical trials data on efficacy and safety. As well as efficacy and safety, patient needs and characteristics must also be considered when deciding which treatment should be administered, e.g. age, performance status, comorbidities, personal circumstances and preferences) fitter patients with good performance status and rapidly progressing disease or visceral metastases might derive most benefit from more intensive combinations whereas less fit patients or those with more indolent disease might derive more benefit from single-agents. At the present time, treatment options for the first-line treatment of metastatic breast cancer (MBC) include both established therapies (e.g. anthracycline-, taxane- and Xeloda-based regimens) CMF, and investigational therapies (e.g. gemcitabine or vinorelbine). First line options for women with HER2-negative MBC include proven regimens based on anthracyclines, taxanes, Xeloda and CMF, or investigational regimens based on drugs like gemcitabine or vinorelbine. During this presentation the evidence supporting various first-line treatment choices will be reviewed, highlighting clinical trials data on efficacy and safety. As well as efficacy and safety, patient needs and characteristics must also be considered when deciding which treatment should be administered, e.g. age, performance status, comorbidities, personal circumstances and preferences) fitter patients with good performance status and rapidly progressing disease or visceral metastases might derive most benefit from more intensive combinations whereas less fit patients or those with more indolent disease might derive more benefit from single-agents.

3. Limited evidence to support anthracycline re-use in metastatic setting Anthracycline-based therapy for MBC:after adjuvant anthracyclines versus no adjuvant anthracyclines lower response rates shorter time to treatment failure Anthracyclines, and increasingly taxanes, are commonly used in the adjuvant setting. Women who recur after adjuvant anthracyclines are less likely to respond to anthracyclines for metastatic disease, because their cumulative dose will reach toxic levels after only a few cycles. Evidence from clinical trials indicates that retreatment with anthracyclines after relapse provides poor outcomes, indicating that a change in treatment strategy is required. In a randomised study, univariate analysis demonstrated a significantly lower probability of response to combination chemotherapy with cyclophosphamide, epirubicin and 5-FU (CEF) chemotherapy for those patients who had received prior adjuvant therapy (CMF- or anthracycline-based) compared with those patients who had received no prior adjuvant therapy (43 versus 58%; p=0.02) [1]. In another trial, liposomal doxorubicin failed to achieve any objective responses in anthracycline-pretreated patients [2]. Anthracycline treatment of MBC also achieves shorter progression-free survival in patients pretreated with anthracycline-based adjuvant treatment (10.2 months compared with 12.5 months in chemona�ve patients) [3]. Randomised trials have also demonstrated poorer outcomes after anthracycline reuse in relapsed patients treated with prior anthracycline-containing adjuvant therapy, with overall survival times of 16�20 months compared with 21�28 months for those patients who had received no prior adjuvant therapy [1,3]. 1. Venturini M et al. J Clin Oncol 1996;14:764�73. 2. Rivera E et al. Cancer Chemother Pharmacol 2002;49:299�302. 3. Gennari A et al. Br J Cancer 2004;90:962�7.Anthracyclines, and increasingly taxanes, are commonly used in the adjuvant setting. Women who recur after adjuvant anthracyclines are less likely to respond to anthracyclines for metastatic disease, because their cumulative dose will reach toxic levels after only a few cycles. Evidence from clinical trials indicates that retreatment with anthracyclines after relapse provides poor outcomes, indicating that a change in treatment strategy is required. In a randomised study, univariate analysis demonstrated a significantly lower probability of response to combination chemotherapy with cyclophosphamide, epirubicin and 5-FU (CEF) chemotherapy for those patients who had received prior adjuvant therapy (CMF- or anthracycline-based) compared with those patients who had received no prior adjuvant therapy (43 versus 58%; p=0.02) [1]. In another trial, liposomal doxorubicin failed to achieve any objective responses in anthracycline-pretreated patients [2]. Anthracycline treatment of MBC also achieves shorter progression-free survival in patients pretreated with anthracycline-based adjuvant treatment (10.2 months compared with 12.5 months in chemona�ve patients) [3]. Randomised trials have also demonstrated poorer outcomes after anthracycline reuse in relapsed patients treated with prior anthracycline-containing adjuvant therapy, with overall survival times of 16�20 months compared with 21�28 months for those patients who had received no prior adjuvant therapy [1,3]. 1. Venturini M et al. J Clin Oncol 1996;14:764�73. 2. Rivera E et al. Cancer Chemother Pharmacol 2002;49:299�302. 3. Gennari A et al. Br J Cancer 2004;90:962�7.

4. Unpredictable safety of anthracyclines Cumulative toxicity, particularly after use in adjuvant setting Cardiovascular complications are unpredictable and potentially fatal (3%)1 symptomatic CHF in 2�18% at doses below typical maximum cumulative dose1�4 doxorubicin 550mg/m2, epirubicin 900mg/m2 significant LVEF impairment can occur early and variably3,4 High incidence of febrile neutropenia (16%)1 Complete alopecia in majority (>90%)1 One of the major drawbacks of anthracyclines is that they are associated with both acute and chronic cardiac toxicity. In addition to compromised efficacy, the usefulness of anthracycline rechallenge in patients relapsing after adjuvant anthracyclines is limited by cumulative toxicity associated with this class of agents. Chronic toxicity is due to anthracyclines producing a dose-dependent cardiac myopathy that often leads to congestive heart failure. Cardiotoxicity is of great concern because of the unpredictable and potentially fatal consequences: symptomatic congestive heart failure is observed in 2�18% patients at cumulative doses below the MTD (doxorubicin 550mg/m2, epirubicin 900mg/m2) [1�8] additionally, left ventricular failure can occur unpredictably with anthracycline therapy anthracycline-related cardiotoxicity is also potentiated by prior local radiation therapy. Myelosuppression is the main dose-limiting acute toxicity associated with anthracycline. Febrile neutropenia occurs in up to 16% of patients receiving doxorubicin. Complete alopecia also occurs in the majority of patients receiving anthracyclines [1]. 1. Chan S et al. J Clin Oncol 1999;17:2341�54. 2. French Epirubicin Study Group. J Clin Oncol 1988;6:679�88. 3. Jain KK et al. J Clin Oncol 1985;3:818�26. 4. Brambilla C et al. Cancer Treat Rep 1986;70:261�6. 5. Hortobagyi GN et al. Am J Clin Oncol 1989;12:57�62. 6. Italian Multicentre Breast Study with Epirubicin. J Clin Oncol 1988;6:976�82. 7. Gasparini G et al. Am J Clin Oncol 1991;14:38�44. 8. Perez DJ et al. J Clin Oncol 1991;9:2148�52. One of the major drawbacks of anthracyclines is that they are associated with both acute and chronic cardiac toxicity. In addition to compromised efficacy, the usefulness of anthracycline rechallenge in patients relapsing after adjuvant anthracyclines is limited by cumulative toxicity associated with this class of agents. Chronic toxicity is due to anthracyclines producing a dose-dependent cardiac myopathy that often leads to congestive heart failure. Cardiotoxicity is of great concern because of the unpredictable and potentially fatal consequences: symptomatic congestive heart failure is observed in 2�18% patients at cumulative doses below the MTD (doxorubicin 550mg/m2, epirubicin 900mg/m2) [1�8] additionally, left ventricular failure can occur unpredictably with anthracycline therapy anthracycline-related cardiotoxicity is also potentiated by prior local radiation therapy. Myelosuppression is the main dose-limiting acute toxicity associated with anthracycline. Febrile neutropenia occurs in up to 16% of patients receiving doxorubicin. Complete alopecia also occurs in the majority of patients receiving anthracyclines [1]. 1. Chan S et al. J Clin Oncol 1999;17:2341�54. 2. French Epirubicin Study Group. J Clin Oncol 1988;6:679�88. 3. Jain KK et al. J Clin Oncol 1985;3:818�26. 4. Brambilla C et al. Cancer Treat Rep 1986;70:261�6. 5. Hortobagyi GN et al. Am J Clin Oncol 1989;12:57�62. 6. Italian Multicentre Breast Study with Epirubicin. J Clin Oncol 1988;6:976�82. 7. Gasparini G et al. Am J Clin Oncol 1991;14:38�44. 8. Perez DJ et al. J Clin Oncol 1991;9:2148�52.

5. The changing treatment landscape Most patients with metastatic disease are now anthracycline pretreated Options for anthracycline-pretreated patients docetaxel or paclitaxel XT gemcitabine / paclitaxel Xeloda monotherapy CMF other What is the evidence for these options? Most patients with MBC are anthracycline-, and increasingly taxane-pretreated. The established treatment options in anthracycline-pretreated patients include: a taxane, either Taxotere or paclitaxel combination therapy with Xeloda and Taxotere (XT) or gemcitabine and paclitaxel (GP) Xeloda monotherapy CMF.Most patients with MBC are anthracycline-, and increasingly taxane-pretreated. The established treatment options in anthracycline-pretreated patients include: a taxane, either Taxotere or paclitaxel combination therapy with Xeloda and Taxotere (XT) or gemcitabine and paclitaxel (GP) Xeloda monotherapy CMF.

6. Docetaxel is more effective than paclitaxel . . . Recently reported results from a randomised trial showed that docetaxel is more effective that paclitaxel. The trial directly compared the approved 3-weekly doses of Taxotere (100mg/m2) and paclitaxel (175mg/m2) in anthracycline-pretreated patients with MBC [1] patients had received anthracyclines in the adjuvant or metastatic (first-line) setting study treatment was administered in a first-or second-line setting. The intent-to-treat analysis showed that compared with paclitaxel, docetaxel achieved: a higher response rate, but the difference was not statistically significant significantly superior TTP (p<0.0001) significantly superior overall survival (p<0.03). The analysis of the 388 patients evaluable for response demonstrated that compared with paclitaxel, Taxotere achieved: a significantly superior response rate (37.4 vs 26.4%; p=0.02), as well as significantly superior TTP and survival. Jones S et al. Breast Cancer Res Treat 2003;82 (Suppl. 1):S9�10.Recently reported results from a randomised trial showed that docetaxel is more effective that paclitaxel. The trial directly compared the approved 3-weekly doses of Taxotere (100mg/m2) and paclitaxel (175mg/m2) in anthracycline-pretreated patients with MBC [1] patients had received anthracyclines in the adjuvant or metastatic (first-line) setting study treatment was administered in a first-or second-line setting. The intent-to-treat analysis showed that compared with paclitaxel, docetaxel achieved: a higher response rate, but the difference was not statistically significant significantly superior TTP (p<0.0001) significantly superior overall survival (p<0.03). The analysis of the 388 patients evaluable for response demonstrated that compared with paclitaxel, Taxotere achieved: a significantly superior response rate (37.4 vs 26.4%; p=0.02), as well as significantly superior TTP and survival. Jones S et al. Breast Cancer Res Treat 2003;82 (Suppl. 1):S9�10.

7. . . . but is significantly more toxic The superior efficacy of docetaxel compared with paclitaxel was, however, afforded at the cost of increased toxicity. The frequency of grade 3/4 adverse events was increased with docetaxel compared with paclitaxel notably, grade 3/4 neutropenia was observed in 93% of patients treated with docetaxel versus only 55% with paclitaxel, leading to significantly higher incidences of febrile neutropenia (15 vs 2%) and infection (10 vs 2%). Jones S et al. Breast Cancer Res Treat 2003; 82 (Suppl 1):S9�10. The superior efficacy of docetaxel compared with paclitaxel was, however, afforded at the cost of increased toxicity. The frequency of grade 3/4 adverse events was increased with docetaxel compared with paclitaxel notably, grade 3/4 neutropenia was observed in 93% of patients treated with docetaxel versus only 55% with paclitaxel, leading to significantly higher incidences of febrile neutropenia (15 vs 2%) and infection (10 vs 2%). Jones S et al. Breast Cancer Res Treat 2003; 82 (Suppl 1):S9�10.

8. XT: extending survival in MBC Only cytotoxic combination to improve survival over Taxotere monotherapy in patients with pretreated MBC Phase III trial comparing 3-weekly cycles of XT versus Taxotere XT (X 1 250mg/m2 twice daily, days 1�14 plus T 75mg/m2, day 1) (n=255) Taxotere (100mg/m2, day 1) (n=256) One-third of patients were treated in first line An international, randomised, phase III trial has compared the XT combination regimen with Taxotere monotherapy in patients with anthracycline-pretreated MBC [1]. Patients were excluded if they had received prior Taxotere, but prior paclitaxel was permitted approximately one-third of patients in each group received study therapy as first-line treatment for metastatic disease (35% in the combination arm and 31% in the single-agent arm). The primary objective of the study was to show superior TTP with the combination regimen compared with Taxotere monotherapy secondary objectives included comparison between the two treatment groups of additional efficacy parameters, safety profiles and medical resource use. In total, 511 patients were stratified according to previous exposure to paclitaxel and randomised to receive 3-weekly cycles of either oral Xeloda 1 250mg/m2 twice daily, days 1�14, plus i.v. Taxotere 75mg/m2, day 1 (n=255), or i.v. Taxotere 100mg/m2, day 1 (n=256). Patients achieving a complete or partial response or stable disease after six weeks of therapy continued treatment until disease progression or unacceptable toxicity. Forty-five patients (18%) in the combination arm discontinued Taxotere therapy but continued to receive Xeloda alone for a median of 3.2 months. The baseline characteristics of the patients were well balanced, with similar sites of metastases and treatment histories. The most frequently involved metastatic sites were the lymph nodes, liver, bone and lung, and around two-thirds of patients in each group had at least three tumour sites. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23. An international, randomised, phase III trial has compared the XT combination regimen with Taxotere monotherapy in patients with anthracycline-pretreated MBC [1]. Patients were excluded if they had received prior Taxotere, but prior paclitaxel was permitted approximately one-third of patients in each group received study therapy as first-line treatment for metastatic disease (35% in the combination arm and 31% in the single-agent arm). The primary objective of the study was to show superior TTP with the combination regimen compared with Taxotere monotherapy secondary objectives included comparison between the two treatment groups of additional efficacy parameters, safety profiles and medical resource use. In total, 511 patients were stratified according to previous exposure to paclitaxel and randomised to receive 3-weekly cycles of either oral Xeloda 1 250mg/m2 twice daily, days 1�14, plus i.v. Taxotere 75mg/m2, day 1 (n=255), or i.v. Taxotere 100mg/m2, day 1 (n=256). Patients achieving a complete or partial response or stable disease after six weeks of therapy continued treatment until disease progression or unacceptable toxicity. Forty-five patients (18%) in the combination arm discontinued Taxotere therapy but continued to receive Xeloda alone for a median of 3.2 months. The baseline characteristics of the patients were well balanced, with similar sites of metastases and treatment histories. The most frequently involved metastatic sites were the lymph nodes, liver, bone and lung, and around two-thirds of patients in each group had at least three tumour sites. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.

9. XT: superior response rate and TTP Tumour responses were assessed based on World Health Organization (WHO) criteria at 6-week intervals until week 48, and then at 12-week intervals until disease progression. The investigator-assessed tumour response rate was significantly superior in patients treated with XT (42%) compared with those receiving Taxotere monotherapy (30%, p=0.006) [1]. The rates of disease stabilisation were similar in the two treatment arms (38% vs 44%, respectively). The significantly superior response rate according to investigator assessment was supported by the Independent Review Committee assessment (p=0.025). TTP, defined as the time from randomisation to progressive disease or to death in patients with no evidence of disease progression, was significantly superior with the combination regimen (log-rank p=0.0001, hazard ratio=0.652; 95% CI: 0.545�0.780) [1]. The hazard ratio of 0.652 means that the risk of disease progression is reduced by 35% in patients treated with XT combination therapy compared with those receiving Taxotere monotherapy. Furthermore, the curves separated early and maintained a clear separation over time, indicating that at almost all time points, a larger proportion of patients in the combination arm than in the monotherapy arm remained disease free. Median TTP was 6.1 months (95% CI: 5.4�6.5) in the combination arm and 4.2 months (95% CI: 3.4�4.5) in the Taxotere monotherapy arm. The primary objective of the study, which was to demonstrate that treatment with the XT combination regimen results in superior TTP in patients with MBC compared with Taxotere monotherapy, was clearly met. �1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.Tumour responses were assessed based on World Health Organization (WHO) criteria at 6-week intervals until week 48, and then at 12-week intervals until disease progression. The investigator-assessed tumour response rate was significantly superior in patients treated with XT (42%) compared with those receiving Taxotere monotherapy (30%, p=0.006) [1]. The rates of disease stabilisation were similar in the two treatment arms (38% vs 44%, respectively). The significantly superior response rate according to investigator assessment was supported by the Independent Review Committee assessment (p=0.025). TTP, defined as the time from randomisation to progressive disease or to death in patients with no evidence of disease progression, was significantly superior with the combination regimen (log-rank p=0.0001, hazard ratio=0.652; 95% CI: 0.545�0.780) [1]. The hazard ratio of 0.652 means that the risk of disease progression is reduced by 35% in patients treated with XT combination therapy compared with those receiving Taxotere monotherapy. Furthermore, the curves separated early and maintained a clear separation over time, indicating that at almost all time points, a larger proportion of patients in the combination arm than in the monotherapy arm remained disease free. Median TTP was 6.1 months (95% CI: 5.4�6.5) in the combination arm and 4.2 months (95% CI: 3.4�4.5) in the Taxotere monotherapy arm. The primary objective of the study, which was to demonstrate that treatment with the XT combination regimen results in superior TTP in patients with MBC compared with Taxotere monotherapy, was clearly met. �1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.

10. Addition of Xeloda to Taxotere extends survival Most importantly, overall survival was significantly superior in patients receiving XT compared with Taxotere monotherapy (log-rank p=0.0126, hazard ratio = 0.775; 95% CI: 0.634�0.947) [1]. This means that patients receiving XT were 23% less likely to die during the study period than those receiving monotherapy. Median survival was 14.5 months (95% CI: 12.3�16.3) with the combination regimen and 11.5 months (95% CI: 9.8�12.7) with Taxotere monotherapy. The 12-month survival rate was 57% in the combination arm and 47% in the monotherapy arm. This multicentre, phase III study is the first and only clinical trial in which a cytotoxic combination regimen has provided a significant survival advantage over a standard monotherapy regimen in this patient population. The survival benefit with XT was seen early in the course of treatment, with the curves clearly separating at an early stage. This indicates that almost all patients benefited from the superior efficacy of the combination and lived longer than if they had been treated with Taxotere monotherapy. Since patients in the combination arm received a lower dose of Taxotere compared with those receiving Taxotere monotherapy, the survival benefit with the combination regimen can be attributed to the addition of Xeloda. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.Most importantly, overall survival was significantly superior in patients receiving XT compared with Taxotere monotherapy (log-rank p=0.0126, hazard ratio = 0.775; 95% CI: 0.634�0.947) [1]. This means that patients receiving XT were 23% less likely to die during the study period than those receiving monotherapy. Median survival was 14.5 months (95% CI: 12.3�16.3) with the combination regimen and 11.5 months (95% CI: 9.8�12.7) with Taxotere monotherapy. The 12-month survival rate was 57% in the combination arm and 47% in the monotherapy arm. This multicentre, phase III study is the first and only clinical trial in which a cytotoxic combination regimen has provided a significant survival advantage over a standard monotherapy regimen in this patient population. The survival benefit with XT was seen early in the course of treatment, with the curves clearly separating at an early stage. This indicates that almost all patients benefited from the superior efficacy of the combination and lived longer than if they had been treated with Taxotere monotherapy. Since patients in the combination arm received a lower dose of Taxotere compared with those receiving Taxotere monotherapy, the survival benefit with the combination regimen can be attributed to the addition of Xeloda. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.

11. Similar overall survival in patients relapsing �2 years after adjuvant anthracyclines Similarly, the clear survival benefit derived from the addition of Xeloda to Taxotere was maintained in the subgroup of patients who relapsed within 2 years of receiving adjuvant anthracyclines: median overall survival of 14.4 months with XT (n=67) median overall survival of 12.0 months with Taxotere (n=66). 1. F Hoffmann-La Roche, data on file.Similarly, the clear survival benefit derived from the addition of Xeloda to Taxotere was maintained in the subgroup of patients who relapsed within 2 years of receiving adjuvant anthracyclines: median overall survival of 14.4 months with XT (n=67) median overall survival of 12.0 months with Taxotere (n=66). 1. F Hoffmann-La Roche, data on file.

12. XT: potential for overlapping toxicity Xeloda and Taxotere show some overlap of key toxicities, especially gastrointestinal side effects: nausea, vomiting, diarrhoea, and stomatitis [1�3]. Notably, myelosuppression, the key dose-limiting toxicity with Taxotere as well as many other cytotoxic agents, is infrequent with Xeloda. The minimal overlap of key toxicities with Xeloda and Taxotere, together with their demonstrated synergistic activity in preclinical evaluation [4,5], supports their use in combination. 1. O�Shaugnessy J et al. J Clin Oncol 2002;20:2812�23. 2. Nabholtz JM et al. J Clin Oncol 1999;17:1413�24. 3. Blum JL, et al. J Clin Oncol 1999;17:485�93. 4. Sawada N, et al. Clin Cancer Res 1998;4:1013�9. 5. Kurosumi M, et al. Oncol Rep 2000;7:945�8. Xeloda and Taxotere show some overlap of key toxicities, especially gastrointestinal side effects: nausea, vomiting, diarrhoea, and stomatitis [1�3]. Notably, myelosuppression, the key dose-limiting toxicity with Taxotere as well as many other cytotoxic agents, is infrequent with Xeloda. The minimal overlap of key toxicities with Xeloda and Taxotere, together with their demonstrated synergistic activity in preclinical evaluation [4,5], supports their use in combination. 1. O�Shaugnessy J et al. J Clin Oncol 2002;20:2812�23. 2. Nabholtz JM et al. J Clin Oncol 1999;17:1413�24. 3. Blum JL, et al. J Clin Oncol 1999;17:485�93. 4. Sawada N, et al. Clin Cancer Res 1998;4:1013�9. 5. Kurosumi M, et al. Oncol Rep 2000;7:945�8.

13. XT: a manageable safety profile XT demonstrated a manageable safety profile: The incidence of grade 3/4 adverse events was higher in the combination therapy group (71% vs 49%), driven primarily by hand-foot syndrome (13% incidence in cycle 2) [1]. However, hand-foot syndrome was always manageable. Grade 4 adverse events were less frequent in the combination arm than the monotherapy arm (25% vs 31%, respectively), driven primarily by the higher incidence of neutropenic fever in the Taxotere monotherapy arm. Active patient management is required to maximise benefit with from the combination. Patients need to be educated to recognise grade 1/2 hand-foot syndrome and advised to contact their doctor or nurse for further advice. Grade 1/2 hand-foot syndrome can be easily treated topically or with vitamin B6 (pyridoxine) tablets. Diarrhoea and stomatitis are also manageable side effects; diarrhoea can be managed with agents such as loperamide and stomatitis can be managed prophylactically with bicarbonate or salt mouthwashes. Anti-emetics must be given to prevent and treat nausea. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.XT demonstrated a manageable safety profile: The incidence of grade 3/4 adverse events was higher in the combination therapy group (71% vs 49%), driven primarily by hand-foot syndrome (13% incidence in cycle 2) [1]. However, hand-foot syndrome was always manageable. Grade 4 adverse events were less frequent in the combination arm than the monotherapy arm (25% vs 31%, respectively), driven primarily by the higher incidence of neutropenic fever in the Taxotere monotherapy arm. Active patient management is required to maximise benefit with from the combination. Patients need to be educated to recognise grade 1/2 hand-foot syndrome and advised to contact their doctor or nurse for further advice. Grade 1/2 hand-foot syndrome can be easily treated topically or with vitamin B6 (pyridoxine) tablets. Diarrhoea and stomatitis are also manageable side effects; diarrhoea can be managed with agents such as loperamide and stomatitis can be managed prophylactically with bicarbonate or salt mouthwashes. Anti-emetics must be given to prevent and treat nausea. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.

14. Dose reductions for side-effect management Dose reductions required by 65% in XT arm and 36% in Taxotere arm1 With XT, 78% of dose reductions were of both drugs2 Taxotere to approximately 60mg/m2 Xeloda to approximately 1 000mg/m2 twice daily Nausea, vomiting, diarrhoea and stomatitis are overlapping toxicities with Xeloda and Taxotere Neutropenia driven by Taxotere alone; rare with Xeloda3,4 In the XT trial, treatment was continued without interruption or dose reduction if patients experienced grade 1 adverse events or other adverse events considered not to be drug related or unlikely to become serious or life threatening (e.g., alopecia). Treatment-related adverse events of grade 2 or higher resulted in dose modification [1]. All safety and efficacy data, and data on the incidence, timing and causes of dose modification (treatment interruption and/or dose reduction) were collected prospectively during the study. Overall, more patients receiving the XT combination had dose reduction of one or both agents for adverse events compared with those receiving single-agent Taxotere (65% and 36%, respectively). During the whole study period, 65% of patients in the combination arm required dose reduction: both agents were reduced in the majority of patients (51%), while Xeloda only was reduced in 4% and Taxotere alone was reduced in 10%. Overall, the majority (78%) of dose reductions involved the simultaneous reduction of both Taxotere dose (to approximately 60mg/m2; range 45�65mg/m2) and Xeloda dose (to approximately 1 000mg/m2 twice daily, range 750�1 000mg/m2) [2]. Nausea, vomiting, diarrhoea and stomatitis are overlapping toxicities with Xeloda and Taxotere Neutropenia was driven by Taxotere alone, as it is a rare event with Xeloda [3,4]. 1. O�Shaughnessy J, et al. J Clin Oncol 2002;20:2812�23. 2. F. Hoffmann-La Roche data on file. 3. Nabholtz JM et al. J Clin Oncol 1999;17:1413�24. 4. Blum J et al. J Clin Oncol 1999; 17:485�93.In the XT trial, treatment was continued without interruption or dose reduction if patients experienced grade 1 adverse events or other adverse events considered not to be drug related or unlikely to become serious or life threatening (e.g., alopecia). Treatment-related adverse events of grade 2 or higher resulted in dose modification [1]. All safety and efficacy data, and data on the incidence, timing and causes of dose modification (treatment interruption and/or dose reduction) were collected prospectively during the study. Overall, more patients receiving the XT combination had dose reduction of one or both agents for adverse events compared with those receiving single-agent Taxotere (65% and 36%, respectively). During the whole study period, 65% of patients in the combination arm required dose reduction: both agents were reduced in the majority of patients (51%), while Xeloda only was reduced in 4% and Taxotere alone was reduced in 10%. Overall, the majority (78%) of dose reductions involved the simultaneous reduction of both Taxotere dose (to approximately 60mg/m2; range 45�65mg/m2) and Xeloda dose (to approximately 1 000mg/m2 twice daily, range 750�1 000mg/m2) [2]. Nausea, vomiting, diarrhoea and stomatitis are overlapping toxicities with Xeloda and Taxotere Neutropenia was driven by Taxotere alone, as it is a rare event with Xeloda [3,4]. 1. O�Shaughnessy J, et al. J Clin Oncol 2002;20:2812�23. 2. F. Hoffmann-La Roche data on file. 3. Nabholtz JM et al. J Clin Oncol 1999;17:1413�24. 4. Blum J et al. J Clin Oncol 1999; 17:485�93.

15. Fewer grade 3 / 4 adverse events afterTaxotere and Xeloda doses are reduced A retrospective analysis has investigated the impact of dose reduction on the tolerability and efficacy of the XT combination [1]. When Xeloda and Taxotere were reduced to 75% of the starting dose, the proportion of treatment cycles with grade 3/4 treatment-related adverse events was approximately halved grade 3/4 adverse events occurred in 34% of cycles administered at full dose compared with only 16% of cycles with Xeloda 1 000 mg/m2 twice daily and Taxotere 55 mg/m2 notably, grade 4 neutropenic fever occurred in association with 25 cycles with full-dose XT but during only 3 cycles with Xeloda 1000 mg/m2 twice daily and Taxotere 55 mg/m2. 1. F Hoffmann-La Roche, data on file.A retrospective analysis has investigated the impact of dose reduction on the tolerability and efficacy of the XT combination [1]. When Xeloda and Taxotere were reduced to 75% of the starting dose, the proportion of treatment cycles with grade 3/4 treatment-related adverse events was approximately halved grade 3/4 adverse events occurred in 34% of cycles administered at full dose compared with only 16% of cycles with Xeloda 1 000 mg/m2 twice daily and Taxotere 55 mg/m2 notably, grade 4 neutropenic fever occurred in association with 25 cycles with full-dose XT but during only 3 cycles with Xeloda 1000 mg/m2 twice daily and Taxotere 55 mg/m2. 1. F Hoffmann-La Roche, data on file.

16. XT dose reduction does not compromise efficacy: overall survival Analyses show that early dose reduction of Xeloda and Taxotere does not compromise the efficacy of XT. Patients who received reduced doses of Xeloda and Taxotere from cycle two onwards had similar favourable overall survival as those receiving full-dose XT during cycle two [1]. The Kaplan-Meier curves for TTP were also similar in the subgroup receiving reduced doses of Xeloda and Taxotere from cycle two onwards and those receiving full-dose XT in cycle two [1]. 1. F Hoffmann-La Roche, data on file.Analyses show that early dose reduction of Xeloda and Taxotere does not compromise the efficacy of XT. Patients who received reduced doses of Xeloda and Taxotere from cycle two onwards had similar favourable overall survival as those receiving full-dose XT during cycle two [1]. The Kaplan-Meier curves for TTP were also similar in the subgroup receiving reduced doses of Xeloda and Taxotere from cycle two onwards and those receiving full-dose XT in cycle two [1]. 1. F Hoffmann-La Roche, data on file.

17. XT: the first-line standard for fitter patients with fast-progressing disease Xeloda extends survival beyond Taxotere and is the standard of care for fitter patients with fast-progressing disease Dosing flexibility allows management of XT side effects: recommended starting doses Xeloda 1 000mg/m2 twice daily, days 1�14, every 3 weeks Taxotere 60mg/m2, day 1 XT is the only cytotoxic combination providing a significant survival benefit over standard monotherapy in this setting and has been approved worldwide for the treatment of anthracycline-pretreated breast cancer XT is the standard of care for fitter patients with rapidly progressing disease. The recommended starting doses are Xeloda 1 000mg/m2 twice-daily, days 1�14, plus Taxotere 60mg/m2 day 1, every 21 days. Dose tailoring allows the management of XT side effects without loss of efficacy. Early simultaneous dose reduction of both Xeloda and Taxotere is effective in reducing the incidence and recurrence of grade 3/4 adverse events. Importantly, efficacy is maintained following early XT dose reduction. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23. XT is the only cytotoxic combination providing a significant survival benefit over standard monotherapy in this setting and has been approved worldwide for the treatment of anthracycline-pretreated breast cancer XT is the standard of care for fitter patients with rapidly progressing disease. The recommended starting doses are Xeloda 1 000mg/m2 twice-daily, days 1�14, plus Taxotere 60mg/m2 day 1, every 21 days. Dose tailoring allows the management of XT side effects without loss of efficacy. Early simultaneous dose reduction of both Xeloda and Taxotere is effective in reducing the incidence and recurrence of grade 3/4 adverse events. Importantly, efficacy is maintained following early XT dose reduction. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.

18. Goals of treatment and research in advanced breast cancer The goals of treatment in advanced breast cancer are to improve length and quality of life Recent clinical research has focused attention on whether more intensive therapy can improve outcomes for women fit enough to receive it The main goals of chemotherapy in the metastatic setting are: to relieve tumour-related symptoms (e.g. pain or shortness of breath) by inducing remission to delay disease progression while maintaining or improving patients� quality of life to prolong survival. Realistically there is little hope of cure in this setting. Recently, clinical research has been focusing attention on whether more intensive chemotherapy can improve outcomes for women with advanced breast cancer. The Xeloda/Taxotere (XT) combination is a good example of an intensive chemotherapy that is particularly suited to patients with rapidly progressing disease. XT is the only combination that extends survival compared with Taxotere monotherapy [1]. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.The main goals of chemotherapy in the metastatic setting are: to relieve tumour-related symptoms (e.g. pain or shortness of breath) by inducing remission to delay disease progression while maintaining or improving patients� quality of life to prolong survival. Realistically there is little hope of cure in this setting. Recently, clinical research has been focusing attention on whether more intensive chemotherapy can improve outcomes for women with advanced breast cancer. The Xeloda/Taxotere (XT) combination is a good example of an intensive chemotherapy that is particularly suited to patients with rapidly progressing disease. XT is the only combination that extends survival compared with Taxotere monotherapy [1]. 1. O�Shaughnessy J et al. J Clin Oncol 2002;20:2812�23.

19. Practical questions in advanced breast cancer However, many women with advanced breast cancer are unsuited to intensive therapy those with co-existing medical problems those with extensive metastatic disease the elderly those who prefer less intensive chemotherapy What is the best approach for these women? Unfortunately, many women with advanced breast cancer are not fit enough to receive intensive chemotherapy. For example patients: with co-existing medical problems, e.g. diabetes, heart disease with extensive metastatic disease who are elderly who might prefer less intensive chemotherapy (i.e. do not wish to experience many side effects, or who do not want to lose their hair). This leaves the question then, of what is the best approach for these women in terms of relieving symptoms with chemotherapy without compromising quality of life. Unfortunately, many women with advanced breast cancer are not fit enough to receive intensive chemotherapy. For example patients: with co-existing medical problems, e.g. diabetes, heart disease with extensive metastatic disease who are elderly who might prefer less intensive chemotherapy (i.e. do not wish to experience many side effects, or who do not want to lose their hair). This leaves the question then, of what is the best approach for these women in terms of relieving symptoms with chemotherapy without compromising quality of life.

20. Basis for chemotherapy regimens Intensive treatment eradication of clone high growth fraction fast doubling time low treatment to overall survival time intermittent bolus regimens i.v. combinations younger and fitter patients Palliative treatment control of clone low growth fraction slow doubling time high treatment to overall survival time continuous chronic therapy oral antimetabolites frail patients with comorbidities When administering chemotherapy regimens with curative intent, e.g. in the adjuvant setting, the following issues will impact upon the success of therapy: extent of eradication of tumour cell clones tumour cells will have a propensity to be rapidly dividing with a high growth fraction on cell cycle analysis and show a fast doubling time low treatment to overall survival time the relative benefits of intermittent bolus therapy in tumour control combination therapy with i.v. agents the ability of younger and fitter patients to withstand more intensive chemotherapy. For chemotherapy regimens administered with palliative intent, the following issues need to be considered: the ability to slow the growth of the tumour cell clones tumour cells will have a relatively low rate of growth (low growth fraction) and a slow doubling time high treatment to overall survival time continuous chronic therapy may offer the most effective control an oral treatment, such as Xeloda, which generates 5-FU preferentially in tumour, may provide effective and convenient management treatment should have a favourable safety profile, suitable for frail patients with comorbidities. When administering chemotherapy regimens with curative intent, e.g. in the adjuvant setting, the following issues will impact upon the success of therapy: extent of eradication of tumour cell clones tumour cells will have a propensity to be rapidly dividing with a high growth fraction on cell cycle analysis and show a fast doubling time low treatment to overall survival time the relative benefits of intermittent bolus therapy in tumour control combination therapy with i.v. agents the ability of younger and fitter patients to withstand more intensive chemotherapy. For chemotherapy regimens administered with palliative intent, the following issues need to be considered: the ability to slow the growth of the tumour cell clones tumour cells will have a relatively low rate of growth (low growth fraction) and a slow doubling time high treatment to overall survival time continuous chronic therapy may offer the most effective control an oral treatment, such as Xeloda, which generates 5-FU preferentially in tumour, may provide effective and convenient management treatment should have a favourable safety profile, suitable for frail patients with comorbidities.

21. Single-agent Xeloda: a highly active and well-tolerated first-line option Xeloda is a highly active agent for the first-line treatment of MBC. Clinical trials show that oral Xeloda is a highly effective and well-tolerated alternative to standard i.v. treatments, including paclitaxel and CMF [1,2]. There are numerous additional benefits with Xeloda, including favourable safety, improved convenience, durable pain relief and improved, or maintained, quality of life. 1. Talbot D et al. Br J Cancer 2002;86:1367�72. 2. O'Shaughnessy J et al. Ann Oncol 2001;12:1247�54. Xeloda is a highly active agent for the first-line treatment of MBC. Clinical trials show that oral Xeloda is a highly effective and well-tolerated alternative to standard i.v. treatments, including paclitaxel and CMF [1,2]. There are numerous additional benefits with Xeloda, including favourable safety, improved convenience, durable pain relief and improved, or maintained, quality of life. 1. Talbot D et al. Br J Cancer 2002;86:1367�72. 2. O'Shaughnessy J et al. Ann Oncol 2001;12:1247�54.

22. Efficacy of Xeloda compares favourably with paclitaxel This phase II randomised trial showed that Xeloda is a highly effective treatment for anthracycline-pretreated MBC. Based on the intent-to-treat analysis, an objective response rate of 36% (95% CI: 17�59%) was observed in patients receiving intermittent Xeloda, with three patients (14%) showing a complete response. In patients randomised to paclitaxel the response rate was 26% (95% CI: 9�51%), with no complete responses. The median TTP was 3.0 and 3.1 months in the Xeloda and paclitaxel groups, respectively. Overall survival was similar in the two treatment groups, with median survival of 7.6 months with Xeloda and 9.4 months with paclitaxel. 1. Talbot D et al. Br J Cancer 2002;86:1367�72. This phase II randomised trial showed that Xeloda is a highly effective treatment for anthracycline-pretreated MBC. Based on the intent-to-treat analysis, an objective response rate of 36% (95% CI: 17�59%) was observed in patients receiving intermittent Xeloda, with three patients (14%) showing a complete response. In patients randomised to paclitaxel the response rate was 26% (95% CI: 9�51%), with no complete responses. The median TTP was 3.0 and 3.1 months in the Xeloda and paclitaxel groups, respectively. Overall survival was similar in the two treatment groups, with median survival of 7.6 months with Xeloda and 9.4 months with paclitaxel. 1. Talbot D et al. Br J Cancer 2002;86:1367�72.

23. Efficacy of Xeloda compares favourably with CMF In this trial in older patients (?55 years), first-line Xeloda achieved an objective response rate of 30% (95% CI: 17�59%), with 5% of patients showing a complete response. In patients randomised to CMF the response rate was 16% (95% CI: 9�51%), with no complete responses. Xeloda compared favourably with CMF in terms of both TTP and overall survival. Xeloda and CMF were generally well tolerated alopecia and myelosuppression were rare with Xeloda, diarrhoea and hand-foot syndrome were more common there was more alopecia and slightly more nausea and stomatitis with CMF all toxicities associated with Xeloda could be adequately managed with treatment interruption and dose modification if necessary. Intravenous CMF was selected because the study was conducted in an elderly patient population. It was thought that elderly patients would not be able to tolerate the oral CMF regimen. 1. O'Shaughnessy J et al. Ann Oncol 2001;12:1247�54. In this trial in older patients (?55 years), first-line Xeloda achieved an objective response rate of 30% (95% CI: 17�59%), with 5% of patients showing a complete response. In patients randomised to CMF the response rate was 16% (95% CI: 9�51%), with no complete responses. Xeloda compared favourably with CMF in terms of both TTP and overall survival. Xeloda and CMF were generally well tolerated alopecia and myelosuppression were rare with Xeloda, diarrhoea and hand-foot syndrome were more common there was more alopecia and slightly more nausea and stomatitis with CMF all toxicities associated with Xeloda could be adequately managed with treatment interruption and dose modification if necessary. Intravenous CMF was selected because the study was conducted in an elderly patient population. It was thought that elderly patients would not be able to tolerate the oral CMF regimen. 1. O'Shaughnessy J et al. Ann Oncol 2001;12:1247�54.

24. Randomised phase III trial:oral vs i.v. CMF in advanced breast cancer The classical Bonadonna CMF (cyclophosphamide/methotrexate/5-fluorouracil) 4-weekly schedule incorporating oral cyclophosphamide was compared with a modified 3-weekly intravenous CMF schedule in postmenopausal patients (156 in each arm) with advanced breast cancer [1]. The response rate with classical CMF was 48% compared with 29% for intravenous CMF (p=0.003). Response duration was similar at 11 months, but overall survival was longer for the classical schedule than the intravenous schedule (17 versus 12 months, respectively, p=0.016). The Bonadonna CMF schedule seems to be a superior regimen to intravenous 3-weekly CMF. This can be attributed to the higher dose intensity achieved with the 4-weekly schedule. In the trial of Xeloda versus CMF [2] the modified CMF regimen was selected as a reference arm rather than the original, more dose-intense Bonadonna schedule because of the frail older patient population. 1. Engelsman E et al. Eur J Cancer 1991;27:966�70. 2. O'Shaughnessy J et al. Ann Oncol 2001;12:1247�54. The classical Bonadonna CMF (cyclophosphamide/methotrexate/5-fluorouracil) 4-weekly schedule incorporating oral cyclophosphamide was compared with a modified 3-weekly intravenous CMF schedule in postmenopausal patients (156 in each arm) with advanced breast cancer [1]. The response rate with classical CMF was 48% compared with 29% for intravenous CMF (p=0.003). Response duration was similar at 11 months, but overall survival was longer for the classical schedule than the intravenous schedule (17 versus 12 months, respectively, p=0.016). The Bonadonna CMF schedule seems to be a superior regimen to intravenous 3-weekly CMF. This can be attributed to the higher dose intensity achieved with the 4-weekly schedule. In the trial of Xeloda versus CMF [2] the modified CMF regimen was selected as a reference arm rather than the original, more dose-intense Bonadonna schedule because of the frail older patient population. 1. Engelsman E et al. Eur J Cancer 1991;27:966�70. 2. O'Shaughnessy J et al. Ann Oncol 2001;12:1247�54.

25. Ongoing comparison: Xeloda versus CMF in first-line MBC This is the background for the ANZ Breast Cancer Trials Group�s ongoing randomised phase III trial comparing classical oral CMF with 2 different schedules of Xeloda. This trial has now recruited 245 of 465 planned patients and is the largest randomised trial of single-agent Xeloda in breast cancer, and also the largest trial comparing different regimens of single agent Xeloda in any cancer. The classical Bonadonna schedule of CMF has been the reference standard for all ANZBCTG advanced breast cancer trials, and neither we, nor others, have proved any regimen to be more effective than classical CMF in MBC. We realised early that it made more sense to start Xeloda at 1000mg/m2 twice daily in this population. We were also interested in the idea of continuous chemotherapy and the potential to develop combinations with it. The dose every three weeks is equivalent in these two arms, so this trial will also answer an important and interesting biological question about how best to deliver Xeloda. The primary endpoint for determining the preferred regimen is quality-adjusted time to progression. The primary endpoint for determining anticancer efficacy is progression free survival. Important secondary endpoints include quality of life, treatment acceptability, overall survival, tumour response rate, toxicity and cost-effectiveness. This is the background for the ANZ Breast Cancer Trials Group�s ongoing randomised phase III trial comparing classical oral CMF with 2 different schedules of Xeloda. This trial has now recruited 245 of 465 planned patients and is the largest randomised trial of single-agent Xeloda in breast cancer, and also the largest trial comparing different regimens of single agent Xeloda in any cancer. The classical Bonadonna schedule of CMF has been the reference standard for all ANZBCTG advanced breast cancer trials, and neither we, nor others, have proved any regimen to be more effective than classical CMF in MBC. We realised early that it made more sense to start Xeloda at 1000mg/m2 twice daily in this population. We were also interested in the idea of continuous chemotherapy and the potential to develop combinations with it. The dose every three weeks is equivalent in these two arms, so this trial will also answer an important and interesting biological question about how best to deliver Xeloda. The primary endpoint for determining the preferred regimen is quality-adjusted time to progression. The primary endpoint for determining anticancer efficacy is progression free survival. Important secondary endpoints include quality of life, treatment acceptability, overall survival, tumour response rate, toxicity and cost-effectiveness.

26. What troubles women starting chemotherapy for advanced breast cancer in a randomized trial? Baseline data on quality of life in ANZ0001Abstract 8144ASCO 2004 Anna Nowak, Karen Byth, Val Gebski, Akiko Fong, Alan Coates, Vernon Harvey, Martin Stockler on behalf of the ANZ Breast Cancer Trials Group

27. What troubled women before chemotherapy? Aspects that troubled women most uncertainty about the future the thought of chemotherapy anxiety, depression, tiredness problems doing vigorous activities problems doing what they wanted Aspects that troubled women least loneliness; loss of self-confidence difficulties with self-care inconvenience; problems coping with treatment;problems with tablets; needles and injections Many women with ABC are unsuited to intensive chemotherapy, but little is known about their concerns and attitudes to treatment. ANZ0001 will determine if oral Xeloda is preferable to CMF as first line chemotherapy in women with advanced breast cancer. Before starting chemotherapy, women completed four validated quality of life questionnaires (GLQ-8, LASAS, Uniscale, UBQ-C) and study specific scales assessing symptoms, functions, global ratings and treatment concerns. 148 of 150 women completed at least 1 form and 90-99% of items were completed. Mean scores for health state (6.7) and overall QL (6.6) were high with 55% rating their general health as good, very good or excellent. The five aspects rated worst before starting chemotherapy were: uncertainty about the future (4.2), the thought of chemotherapy (3.9), lack of energy (3.7), pain (3.6), feeling anxious/worried (3.0); whereas problems with needles or injections (1.5), inconvenience of treatment (0.7), problems coping with treatment (0.6), and problems taking tablets (0.3) were rated lower. More women were severely distressed (rated 7 or more) about thought of chemotherapy (23%) and uncertainty about the future (25%), than about problems with injections or needles (10%) or taking tablets (1%). Many women with ABC are unsuited to intensive chemotherapy, but little is known about their concerns and attitudes to treatment. ANZ0001 will determine if oral Xeloda is preferable to CMF as first line chemotherapy in women with advanced breast cancer. Before starting chemotherapy, women completed four validated quality of life questionnaires (GLQ-8, LASAS, Uniscale, UBQ-C) and study specific scales assessing symptoms, functions, global ratings and treatment concerns. 148 of 150 women completed at least 1 form and 90-99% of items were completed. Mean scores for health state (6.7) and overall QL (6.6) were high with 55% rating their general health as good, very good or excellent. The five aspects rated worst before starting chemotherapy were: uncertainty about the future (4.2), the thought of chemotherapy (3.9), lack of energy (3.7), pain (3.6), feeling anxious/worried (3.0); whereas problems with needles or injections (1.5), inconvenience of treatment (0.7), problems coping with treatment (0.6), and problems taking tablets (0.3) were rated lower. More women were severely distressed (rated 7 or more) about thought of chemotherapy (23%) and uncertainty about the future (25%), than about problems with injections or needles (10%) or taking tablets (1%).

28. Xeloda monotherapy in the elderly:effective and well tolerated in first-line MBC Median age: 73 years (65�89) No grade 3 / 4 myelosuppression Only one patient on 1 000mg/m2 required dose reduction Half of all breast cancer patients are elderly and many elderly patients poorly tolerate cytotoxic treatments. A phase II study assessed the efficacy and safety of Xeloda in 73 elderly patients (median age 73 years; range: 65�89 years) with locally advanced or MBC [1]. the first 30 patients received Xeloda 1250mg/m2 (twice daily, days 1�14 every 21 days) which was reduced to 1000mg/m2 for the next 43 patients following introduction of new dosing guidelines recommending 25% dose reduction in elderly, frail patients most patients had two or more disease sites and no prior cytotoxic chemotherapy in the metastatic setting. None of the patients had previously received taxane-containing therapy overall 39 patients (53%) completed the full course of treatment. Only 13 patients (18%) withdrew due to treatment-related adverse events. Xeloda showed considerable activity achieving a high rate of disease control (CR/PR + SD), with no significant differences between the lower and higher dose groups (86% with Xeloda 1000mg/m2 versus 77% with 1250mg/m2, Fisher�s Exact p=0.69). There were no significant differences in TTP achieved in the two treatment groups (Kruskall-Wallis p=0.5). Median duration of response and median TTP were 4.3 months (range 1.9�6.0 months) and 4.0 months (range 1.0�6.3 months), respectively. Xeloda at both doses demonstrated a favourable safety profile in the elderly patients: low incidence of grade 3/4 adverse events and no grade 3/4 myelosuppression. Xeloda 1000mg/m2 twice daily was well particularly well tolerated with lower incidences of grade 3/4 diarrhoea (2% vs 13%, respectively) and fewer dose reductions; 2% (one patient) vs 30% (nine patients), respectively compared with Xeloda 1250mg/m2 twice daily. Xeloda 1 000mg/m2 twice daily, days 1�14 every 21 days is a well-tolerated, effective and convenient treatment for patients ?65 years with locally advanced/metastatic BC. 1. Procopio G et al. Eur J Cancer 2003;1(Suppl. 5):S138 (Abst 451).Half of all breast cancer patients are elderly and many elderly patients poorly tolerate cytotoxic treatments. A phase II study assessed the efficacy and safety of Xeloda in 73 elderly patients (median age 73 years; range: 65�89 years) with locally advanced or MBC [1]. the first 30 patients received Xeloda 1250mg/m2 (twice daily, days 1�14 every 21 days) which was reduced to 1000mg/m2 for the next 43 patients following introduction of new dosing guidelines recommending 25% dose reduction in elderly, frail patients most patients had two or more disease sites and no prior cytotoxic chemotherapy in the metastatic setting. None of the patients had previously received taxane-containing therapy overall 39 patients (53%) completed the full course of treatment. Only 13 patients (18%) withdrew due to treatment-related adverse events. Xeloda showed considerable activity achieving a high rate of disease control (CR/PR + SD), with no significant differences between the lower and higher dose groups (86% with Xeloda 1000mg/m2 versus 77% with 1250mg/m2, Fisher�s Exact p=0.69). There were no significant differences in TTP achieved in the two treatment groups (Kruskall-Wallis p=0.5). Median duration of response and median TTP were 4.3 months (range 1.9�6.0 months) and 4.0 months (range 1.0�6.3 months), respectively. Xeloda at both doses demonstrated a favourable safety profile in the elderly patients: low incidence of grade 3/4 adverse events and no grade 3/4 myelosuppression. Xeloda 1000mg/m2 twice daily was well particularly well tolerated with lower incidences of grade 3/4 diarrhoea (2% vs 13%, respectively) and fewer dose reductions; 2% (one patient) vs 30% (nine patients), respectively compared with Xeloda 1250mg/m2 twice daily. Xeloda 1 000mg/m2 twice daily, days 1�14 every 21 days is a well-tolerated, effective and convenient treatment for patients ?65 years with locally advanced/metastatic BC. 1. Procopio G et al. Eur J Cancer 2003;1(Suppl. 5):S138 (Abst 451).

29. Xeloda monotherapy in MBC: low incidence of grade 3 / 4 events (n=728) Xeloda has a favourable safety profile. Among more than 700 taxane-pretreated patients treated in five clinical trials, there were no treatment-related deaths [1�5]. Complete hair loss and myelosuppression were rare. The most common adverse event was hand-foot syndrome, a cutaneous side effect that is never life threatening. Grade 2 hand-foot syndrome can be treated effectively with dose interruption and, after recovery, dose modification. Patients should be educated to recognise grade 1/2 hand-foot syndrome, and contact their nurse or physician for advice immediately if this side effect appears. Emollients, with or without oral vitamin B6 preparations, are common preventative/curative measures. Gastrointestinal adverse events were the next most common side effects, but the majority of these adverse events were mild to moderate in intensity and can be effectively managed with medical intervention (e.g., loperamide and rehydration for diarrhoea, mouthwash and fluconazole for stomatitis). It is very important that patients are educated to recognise grade 1 and 2 adverse events and are instructed to stop treatment and seek medical advice if they occur. This can reduce the incidence of grade 3 or 4 adverse events. 1. Blum JL et al. Eur J Cancer 2001;37(Suppl. 6):S190 (Abst 693). 2. Blum JL et al. Cancer 2001;92:1759�68. 3. Reichardt P et al. Ann Oncol 2003;14:1227�33. 4. Fumoleau P et al. Eur J Cancer 2004;40(4):536�42 5. Maung K. Clin Breast Cancer 2003;3:375�7.Xeloda has a favourable safety profile. Among more than 700 taxane-pretreated patients treated in five clinical trials, there were no treatment-related deaths [1�5]. Complete hair loss and myelosuppression were rare. The most common adverse event was hand-foot syndrome, a cutaneous side effect that is never life threatening. Grade 2 hand-foot syndrome can be treated effectively with dose interruption and, after recovery, dose modification. Patients should be educated to recognise grade 1/2 hand-foot syndrome, and contact their nurse or physician for advice immediately if this side effect appears. Emollients, with or without oral vitamin B6 preparations, are common preventative/curative measures. Gastrointestinal adverse events were the next most common side effects, but the majority of these adverse events were mild to moderate in intensity and can be effectively managed with medical intervention (e.g., loperamide and rehydration for diarrhoea, mouthwash and fluconazole for stomatitis). It is very important that patients are educated to recognise grade 1 and 2 adverse events and are instructed to stop treatment and seek medical advice if they occur. This can reduce the incidence of grade 3 or 4 adverse events. 1. Blum JL et al. Eur J Cancer 2001;37(Suppl. 6):S190 (Abst 693). 2. Blum JL et al. Cancer 2001;92:1759�68. 3. Reichardt P et al. Ann Oncol 2003;14:1227�33. 4. Fumoleau P et al. Eur J Cancer 2004;40(4):536�42 5. Maung K. Clin Breast Cancer 2003;3:375�7.

30. Options for first-line chemotherapy in HER2-negative metastatic breast cancer (MBC) At the present time, treatment options for the first-line treatment of metastatic breast cancer (MBC) include both established therapies (e.g. anthracycline-, taxane- and Xeloda-based regimens) CMF, and investigational therapies (e.g. gemcitabine or vinorelbine). First line options for women with HER2-Negative MBC include proven regimens based on anthracyclines, taxanes, xeloda and CMF, or investigational regimens based on drugs like gemcitabine or vinorelbine. During this presentation the evidence supporting various first-line treatment choices will be reviewed, highlighting clinical trials data on efficacy and safety. As well as efficacy and safety, patient needs and characteristics must also be considered when deciding which treatment should be administered, e.g. age, performance status, comorbidities, personal circumstances and preferences) fitter patients with good performance status and rapidly progressing disease or visceral metastases might derive most benefit from more intensive combinations whereas less fit patients or those with more indolent disease might derive more benefit from single-agents. At the present time, treatment options for the first-line treatment of metastatic breast cancer (MBC) include both established therapies (e.g. anthracycline-, taxane- and Xeloda-based regimens) CMF, and investigational therapies (e.g. gemcitabine or vinorelbine). First line options for women with HER2-Negative MBC include proven regimens based on anthracyclines, taxanes, xeloda and CMF, or investigational regimens based on drugs like gemcitabine or vinorelbine. During this presentation the evidence supporting various first-line treatment choices will be reviewed, highlighting clinical trials data on efficacy and safety. As well as efficacy and safety, patient needs and characteristics must also be considered when deciding which treatment should be administered, e.g. age, performance status, comorbidities, personal circumstances and preferences) fitter patients with good performance status and rapidly progressing disease or visceral metastases might derive most benefit from more intensive combinations whereas less fit patients or those with more indolent disease might derive more benefit from single-agents.

31. Xeloda first in MBC treatment First-line Xeloda monotherapy less fit patients with slow progressing disease recommended starting dose Xeloda 1 000mg/m2 twice daily, days 1�14, every 3 weeks First-line XT is standard of care fitter patients with fast progressing disease recommended starting dose Xeloda 1 000mg/m2 twice daily, days 1�14 Taxotere 60mg/m2, day 1, every 3 weeks Xeloda has become an established component of breast cancer management. Where and how it fits should be based on each patient�s unique characteristics, circumstances and preferences. Less fit patients with more slowly progressing disease are suitable candidates for first-line treatment with Xeloda monotherapy starting at 1000mg/m2, for 14 out of every 21 days. XT is an appropriate standard of care for younger fitter patients with more rapidly progressing disease. The currently recommended starting doses are Xeloda 1000mg/m2 twice daily for 14 days, plus Taxotere 60mg/m2 on day 1 every 21-days.Xeloda has become an established component of breast cancer management. Where and how it fits should be based on each patient�s unique characteristics, circumstances and preferences. Less fit patients with more slowly progressing disease are suitable candidates for first-line treatment with Xeloda monotherapy starting at 1000mg/m2, for 14 out of every 21 days. XT is an appropriate standard of care for younger fitter patients with more rapidly progressing disease. The currently recommended starting doses are Xeloda 1000mg/m2 twice daily for 14 days, plus Taxotere 60mg/m2 on day 1 every 21-days.