Adjuvant Therapy for Breast Cancer (eBook)

Cancer Treatment and Research 3
Acknowledgments 6
Contents 7
Contributors 10
Introduction 13
Part 1: Basics 15
History of Adjuvant Therapy 16
The Guiding Principles of Adjuvant Therapy 17
Trials with Endocrine Therapy 18
Trials of Chemoendocrine Therapy 19
Trials with Chemotherapy 20
Concluding Remarks 22
References 24
Prognostic and Predictive Factors 26
Prognostic Factors 26
Age 26
Tumor Size 27
Axillary Nodes 27
Tumor Grade 28
HER2/neu Status 28
Peritumoral Vascular Invasion 28
Others 28
Predictive Factors 29
Predictive Markers for Adjuvant Hormonal Therapy 30
Predictive Markers for Adjuvant Chemotherapy 33
HER-2 as a Predictive Marker 33
Topoisomerase II Alpha (Topo IIalpha) 35
Markers Predicting the Activity of Taxane-Based Regimens 37
Markers Predicting the Activity of Anti-HER-2 Therapies 38
Conclusions 39
References 39
New Perspectives for Therapy Choice 44
Introduction 44
‘‘Omics’’ in Cancer Diagnosis and Prognosis 45
Gene Expression Profiling: Genomics and Transcriptomics 45
Protein Profiling: Proteomics 46
Profiling of Metabolic Endproducts: Metabolomics 49
Nano-Particles in Diagnosis and Therapy 50
Perspectives 51
References 52
Pathology Role in Adjuvant Setting 54
Introduction 54
Examination of Pathology Specimens 54
Core Needle Biopsy - Preoperative Diagnosis 54
Surgical Specimens 55
Frozen Sections 56
Tissue Banks 56
Tumor Classification 57
Histopathologic Prognostic Factors 57
Tumor and Axillary Lymph Node Staging 57
Lymph and Blood Vessel Invasion 59
Tumor Size 60
Tumor Grading 61
Immunhistochemical Assays 62
Steroid Hormone Receptors 63
HER-2/neu 65
HER-2 Immunohistochemistry 65
HER-2 FISH 66
Interpretation and Scoring 66
Immunohistochemistry 66
FISH 67
Which Score to Be Used? 68
Future Aspects 68
Microarray Technology 68
References 70
Guidelines, Consensus Conferences and Overviews (Meta-analysis) 75
Introduction 75
Meta-analysis or Overviews 76
Consensus Meetings and Documents 84
Clinical Practice Guidelines 85
Summary 87
References 87
Statistical Issues and Challenges 89
Learning from the Past 90
Planning for the Future 97
References 101
Part 2: Treatments 103
Multidisciplinary Care: Optimising Team Performance 104
Introduction 104
Sharing Goals and Strategies 105
Effective Team Meetings 105
Troubleshooting 106
Development and Coaching 106
Inspirational Leadership 107
Strengthening Commitment 108
Managing Conflict and Poor Performance 108
Preventing Burnout 109
Improving Communication with Patients 110
Conclusions 110
References 111
Preoperative Chemo- and Endocrine Therapy 113
Primary Systemic Therapy: Rationale and State of the Art 113
The Role pf pCR 115
Anthracyclines and Taxanes: Which is the Gold Standard? 117
Primary Treatment of Endocrine Responsive Tumours 120
Open Issues 123
Identifying Powerful Predictors of Response 123
Beyond pCR 124
Integrating Targeted Agents 124
Conclusions 126
References 126
Adjuvant Chemotherapy 131
Anthracyclines in Adjuvant Therapy 132
Duration of treatment 134
Dose Intensity 135
Randomized Studies of High-Dose Adjuvant Chemotherapy with Hematopoietic Stem Cell Transplantation 135
Sequential Regimens 135
Taxanes in the Adjuvant Setting 136
Paclitaxel 137
Other Drugs in Adjuvant Setting 139
Late Adverse Effects of Breast Cancer Adjuvant Chemotherapy 140
Cardiac Toxicity 140
Hematological Complications - Acute Myeloid Leukemia and Myelodysplastic Syndrome 140
Pulmonary Toxicity 141
Gonadal Dysfunction 141
Quality of Life 141
Recommendations for the Use of Adjuvant Chemotherapy 142
Conclusions 143
References 143
Postoperative Endocrine Therapy for Invasive Breast Cancer 148
Introduction 148
Adjuvant Endocrine Therapy for Premenopausal Women with Early Breast Cancer 149
Tamoxifen Alone 150
Tamoxifen plus Chemotherapy 150
Ovarian Ablation/Suppression Alone 152
Ovarian Ablation/Ovarian Suppression Compared to Chemotherapy 153
Ovarian Suppression Combined with Chemotherapy 156
Ovarian Ablation Combined with Tamoxifen 157
Emerging Data Regarding Endocrine Therapy for Premenopausal Women 158
Adjuvant Endocrine Therapy in Postmenopausal Women 159
Aromatase Inhibitors Instead of Tamoxifen 160
Aromatase Inhibitors After Tamoxifen 161
Recommendations for Adjuvant Endocrine Therapy from Consensus Meetings 165
Lingering Questions, Emerging Considerations and Future Directions for Research 165
References 166
Adjuvant Therapy of Breast Cancer - Bisphosphonates 171
Adjuvant Bisphosphonate Therapy 172
Bisphosphonates and Treatment Related Bone Loss 174
Bone Health and Risk of Osteoporosis 174
Chemotherapy Induced Bone Loss and Bisphosphonates 175
Ovarian Suppression Induced Bone Loss and Bisphosphonates 177
Antiestrogens and Bisphosphonates 178
Aromatase Inhibitors Induced Fracture Risk and Bisphosphonates 179
Bisphosphonates in Prevention of Treatment Related Osteoporosis 181
Safety of Bisphosphonates 182
Summary 182
References 183
Part 3: New Wind in the Adjuvant Setting 186
Trastuzumab 187
Introduction 187
The Large Phase III Adjuvant Trastuzumab Trials 188
Trial Designs 188
National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 Trial 190
North Central Cancer Treatment Group (NCCTG) N9831 Intergroup Trial 190
Breast Cancer International Research Group (BCIRG) 006 Trial 190
Breast International Group Herceptin Adjuvant (HERA) Trial 191
Eligibility Criteria 191
Cardiac Safety and Monitoring 191
Efficacy and Safety Results 192
Disease-free Survival 192
Overall Survival 194
Other Efficacy Endpoints 194
Cardiac Safety 194
Hematologic and Nonhematologic Safety 195
Additional Adjuvant Trastuzumab Trials 195
FINHER 195
Trial Design 195
Eligibility Criteria 195
Efficacy and Safety Results 196
E2198 196
Trial Design 196
Eligibility Criteria 196
Efficacy and Safety Results 196
Impact of Trial Results on Clinical Practice 196
HER2 Testing 198
Future Directions 199
Conclusions 199
References 200
Lapatinib: New Directions in HER2 Directed Therapy for Early Stage Breast Cancer 203
Introduction 203
HER-2 Signaling 204
Mechanisms of Trastuzumab Resistance 204
Blocking Receptor-Antibody Interaction 205
Truncated HER-2 Protein 205
Insulin Growth Factor-1 Receptor Signaling 206
PTEN and AKT Signaling 206
Other Proposed Trastuzumab Resistance Mechanisms 206
Lapatinib 207
Theoretical Advantages of Lapatinib over Trastuzumab 207
Pre-Clinical Studies with Lapatinib 208
Clinical Trials Testing Lapatinib as Treatment of Advanced and Inflammatory Breast Cancer 209
Advanced Disease 209
Lapatinib Combinations 210
Inflammatory Disease 212
Toxicities of Lapatinib 212
Ongoing Lapatinib Trials for Early Stage HER2 Overexpressing Breast Cancer 214
Adjuvant Trials 214
ALLTO Trial 214
TEACH Trial 215
Neoadjuvant Trials 215
NeoALLTO Trial 215
NSABP-B41 216
CALGB 40601 216
Other Ongoing Neoadjuvant Trials 217
Concluding Remarks 217
References 217
Part 4: Special Issues 222
Supportive Care During Adjuvant Treatment 223
Background: The Context of Supportive Care During Adjuvant Therapy for Breast Cancer 223
Introduction 223
Supportive Care During Adjuvant Breast Cancer Treatment 224
The Definition Of Supportive Care 224
Distress Screening 224
Referral Pathways 225
Issues and Challenges Facing Women During Adjuvant Breast Cancer Treatment 226
Adjustment to Breast Cancer: The Psychosocial Journey 226
Decision Making, Informational Needs, and Communication 226
Psychosocial Variables in Breast Cancer 229
Psychological Impact of Treatment Related Side Effects 232
Reproductive and Endocrine Effects 232
Body Image and Self Esteem 233
Weight Gain 234
Neuropsychological Effects 234
Fatigue 235
Survivorship Issues 235
Summary 236
Case Study 236
References 237
Dose in (Adjuvant) Chemotherapy of Breast Cancer 243
Introduction 243
Theoretical Background 243
The Skipper Schabel Model 243
Norton Simon Hypothesis 244
Clinical Data 244
Retrospective Analyses of the Role of Dose Intensity (Dose per Week) from Levine 244
Prospective Randomized Clinical Trials 245
Conventional Dose Range 246
Escalation of Single Dose and Total Dose of One Compound Within a Standard Regimen Cyclophosphamide Within NSABP AC x 4 q3w 246
(Epi) - Doxorubicin Within French Fluorouracil/Epirubicin/Cyclophosphamide (FEC) x 6 q3w/ NSABP AC x 4 q3w 246
Fasg 05 246
Calgb 9344 [8] 247
Taxanes 247
Paclitaxel/Docetaxel 247
Escalation of Single Dose and Total Doses of Standard Regimens (CMF, EC, FAC) 247
CMF (Cyclophosphamide, Methotrexate, Fluorouracil) 247
Epirubicin/Cyclophosphamide (EC) Combinations 248
FAC Combinations 248
Escalation of Single Dose with Constant Total Dose (AC vs ArarrC) 248
Scheduling (Taxane/Anthracycline Based Regimens) 249
Total Dose Constant (Dose Density) 249
Total Dose Inconstant 249
Taxanes - Sequential vs Combination 249
Taxanes 2 Weekly (q3w) vs Weekly (q1w) 251
Beyond Conventional Dose Range. . . . 251
High Dose Chemotherapy with Growth Factor Support 251
High Dose Chemotherapy with Stem Cell Support 252
Conclusion 255
Conventional Dose Range 255
References 255
Timing of Adjuvant Therapy 258
Timing of Risk and Benefit 258
Timing of Surgery 259
Timing of Sentinel Node Biopsy 260
Timing of Pathology 260
Timing of Radiotherapy 261
Radiotherapy Initiation and Duration 261
Radiotherapy in Combination with Systemic Treatments 261
Timing of Adjuvant Systemic Therapy 262
Preoperative (Neoadjuvant) Systemic Therapy 263
Primary Endocrine Therapy 264
Primary Chemotherapy 264
Duration of Preoperative Systemic Treatment 264
Postoperative (Adjuvant) Systemic Therapy 264
Chemoendocrine Treatment 264
Chemotherapy (CT) 266
CT Initiation 266
CT Duration 267
Endocrine Treatment 269
Ovarian Function Ablation/Suppression (OFS) 269
Selective ER Modulators (SERMS): Tamoxifen 270
Aromatase Inhibitors (AIs) 272
Targeted Therapies 274
Conclusion 275
References 275
Sequencing of Systemic Treatment and Radiotherapy 283
Introduction 283
Efficacy of Radiotherapy in the Concept of Treatment of Early Breast Cancer 283
Current Practice of Combined Modality Treatment Including Radiotherapy Outside of Clinical Trials 284
Are There Reasons to Re-investigate Current Practice of Radiotherapy? 284
Potential Impact of Delay of Radiotherapy on Outcome 284
Concomitant Chemo- and Radiotherapy 285
Randomized Trials on Sequencing of Postoperative Concomitant Adjuvant Radiotherapy and Systemic Polychemotherapy Treatment 286
Open Questions 287
Conclusion 287
References 287
Part 5: Special Populations 290
Young Patients with Breast Cancer 291
Incidence and Prognosis 291
Endocrine Considerations 291
Loco-regional Therapy 295
Pregnancy, Fertility and Menopause 295
Genetic Considerations 296
Psycho-social Considerations 297
Conclusions 297
References 297
Special Populations: Elderly Patients 299
Introduction 299
Assessment of Older Patients 300
Biological Aspects 303
Treatment 304
Surgery 304
Radiotherapy 305
Hormonal Treatment 306
Chemotherapy 308
Conclusions and Future Perspectives 310
References 311
Adjuvant Therapy in Patients with Breast Cancer During Pregnancy 316
Introduction 316
Systemic Therapy 317
Chemotherapy 317
Children with In Utero Exposure to Chemotherapy 319
Hormonal Therapy 320
Treatment with Trastuzumab 320
New Drugs 320
Bisphosphonates 320
Supportive Therapy 321
Summary 321
References 324
Part 6: After Breast Cancer and Treatment, Sequelae of Adjuvant Treatment Social Issues 328
Investigations After Adjuvant Therapy 329
Detection of Breast Cancer Recurrences 331
Local Complications After Breast Surgery and Radiation Therapy for Breast Cancer 337
Long-lasting Side Effects of Systemic Adjuvant Treatment for Breast Cancer 337
Psychosocial Issues 340
Coordination of Care 341
Conclusions 345
References 345
Quality of Life Issues During Adjuvant Endocrine Therapy 351
Introduction 351
How Is Quality of Life Measured? 352
Acceptability of Adjuvant Endocrine Therapy 353
QoL in the Pre-menopausal Patient 359
Patient vs Clinician Reported Side-Effects 360
Adherence 361
Conclusions 361
References 362
Fertility 364
Introduction 364
Mechanisms of Ovarian Damage 365
Chemotherapy-Related Amenorrhea with Adjuvant Regimens for Breast Cancer 366
Impact of Hormonally Based Treatments on Fertility 368
Measuring Fertility 369
Fertility Preservation Considerations in Women with Breast Cancer 370
Choice of Chemotherapy 370
Hormonal Manipulation 370
Embryo Cryopreservation 373
Oocyte Cryopreservation 374
Ovarian Tissue Cryopreservation 375
Safety of Pregnancies After Breast Cancer 376
Outcomes of Offspring 376
Maternal Outcomes 376
Conclusion 377
References 378
Cognitive Function in Breast Cancer Survivors 383
Overview of the Literature 384
Determining if Cognitive Impairment Is Present 391
Neuropsychological Tests 392
Self-Reported Cognitive Impairment 393
Incidence of Cognitive Impairment After Chemotherapy 394
Effect Sizes and Cognitive Domains Affected: Results of Meta-analyses 394
Establishing a Causal Relationship Between Chemotherapy and Cognitive Impairment 395
Animal Studies 395
Brain Imaging 396
Neurophysiological Studies 396
Chemotherapy Studies 397
Chemotherapy Regimen and Dose Related Toxicity 397
Chemotherapy Intensity and Duration 397
Chemotherapy Regimens 397
Duration of Cognitive Impairment 398
Potential Confounders 398
Fatigue 398
Anxiety, Depression and Stress 399
Hormonal Agents 399
Other Medications 400
Potential Mechanisms 400
Interventions 403
Summary 404
References 404
Costs of Adjuvant Breast Cancer Treatments 416
Introduction 416
Calendar Years of Study 417
Characteristics of the Study Population 417
Time Horizon 418
Cost Perspective 418
Methods 418
Attributable Costing 419
Microcosting 419
Types of Costs 419
Studies of Breast Cancer Treatment Costs 420
Costs of Chemotherapy 421
Costs of Endocrine Therapy 424
Costs of Supportive Care Agents 425
Chemotherapy Supportive Care Agents 425
Endocrine Therapy Supportive Care Agents 426
Costs of Targeted Therapies: Trastuzumab and Lapatinib 426
Differences in Costs by Age, Stage and Other Characteristics 427
Direct Non-medical, Indirect and Out of Pocket Costs 429
Methodologic Challenges 429
Conclusion 430
Acknowledgment 431
References 431
Social Issues: Marital Support 436
Introduction 436
Open and Healing Communication 437
Mutuality within the Relationships 440
Conclusion 442
References 443
The View and Role of Breast Cancer Advocacy 446
Breast Cancer - The Journey 446
The Meaning Of Advocacy 447
Cancer - The Fear 448
Diagnosis of Breast Cancer 449
The Personal Becomes Political 450
Advocates Join Forces 452
Advocacy and Politics 452
Final Thoughts 453
The Voice of a Special Patient 455
Reference 459
Final word 461
Index 462