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High Dose Chemotherapy and Autologous Bone Marrow Transplant as Adjuvant Therapy for Breast Cancer

High Dose Chemotherapy and Autologous Bone Marrow Transplant as Adjuvant Therapy for Breast Cancer. By David Martin MD February 6, 2001. Case Presentation.

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High Dose Chemotherapy and Autologous Bone Marrow Transplant as Adjuvant Therapy for Breast Cancer

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  1. High Dose Chemotherapy andAutologous Bone Marrow Transplant as Adjuvant Therapy for Breast Cancer By David Martin MD February 6, 2001

  2. Case Presentation • C.S. is a 27 year old white female with no significant past medical history who presented with a breast mass six weeks after starting a new birth control pill. • Lumpectomy revealed ductal carcinoma • Patient referred to NCBH for High dose chemotherapy and autologous bone marrow transplant

  3. Case Presentation • Past Medical History: None • Past Surgical History: Right Mastectomy 6/99 • Medications: None • Family History: Negative for breast/ovarian cancer • OB/GYN: No pregnancies. Patient has been on OCP for five years

  4. Case Presentation • Physical Exam: • T 99.1 Pulse 85 BP 123/62 • Chest: Right Mastectomy site clear, Left Breast no masses • Nodal Exam: Negative • Neurology: non-focal

  5. Case Presentation • Laboratory Data • CMP, CBC, CXR all Normal • CT Scan of Chest/Abdomen/Pelvis negative • Bone Marrow Biopsy Negative

  6. Case Presentation • Mastectomy: • Tumor 7.5 x 5.5 x 5.5 cm • 15/15 Positive Lymph nodes ER/PR + • Her-2/Neu Negative

  7. Case Presentation • Treatment • Four cycles of conventional dose chemotherapy with Cytoxan/Adriamycin • High Dose Chemotherapy Cytoxan, Thiopeta, and Carboplatin with peripheral blood stem cell rescue. • Post-chemotherapy radiation and tamoxifen.

  8. Case Presentation • Clinical Question • Patient told by friend that BMT not effective in treatment of Breast Cancer • Patient asked: • “Does high dose chemotherapy and bone marrow transplant help women with breast cancer?”

  9. Overview • Introduction • Theory Behind Bone Marrow Transplant • Political and Social Influences • Early Phase I/II Trials • Randomized Controlled Trials • Clinical Case Revisited • Conclusion

  10. Introduction • Breast Cancer develops in 1/8 American women who live to age 85 • Leading cause of death of women ages 15-54 • Prognosis inversely related to number of positive lymph nodes

  11. Introduction • 4-9 Positive Lymph Nodes • 50-60% Relapse by 10 years • 10 or more Positive Lymph Nodes • 55-87% Relapse at 5 years • 70-90% Relapse at 10 years

  12. Theory Behind Treatment • “More is Better” • Dose Response Curves • Tumor Growth Models • Cytoreduction followed by high dose chemotherapy

  13. Political and Social Influences • 1990 HDCT and ABMT • Insurance companies reluctant to cover • 1991, 60 Minutes interview • 1993 Neline Fox case

  14. Political and Social Influences • 1994 New England Journal study • 1994 and 1995 many state legislatures mandated coverage • Results: • Large increase in number of HDCT as treatment • Difficult to perform randomized controlled trials

  15. Early Phase I/II TrialsPeters et. al • 85 Patients with 10 or more axillary nodes • CAF adjuvant Therapy • High dose chemotherapy Cyclophosphamide, cisplatin, carmustine • Median age: 38 • Median Number of Lymph nodes: 14 • Follow up: 5 years

  16. Early Phase I/II TrialsPeters et. al

  17. Early Phase I/II TrialsPeters et. al • Limitations • Not RCT • Selection Bias • Different Therapies for Treatment and Control Groups • Treatment Related Mortality 12%

  18. Early Phase I/II TrialsSelection Bias • Garcia-Carbonero et. al examined DFS and OS in Patients who meet Criteria for HDCT • 171 Patients with met Criteria • > 10 Lymph nodes • age < 60 • no concomitant disease • no progression of disease during adjuvant treatment

  19. Early Phase I/II TrialsSelection Bias

  20. Early Phase I/II TrialsSelection Bias • Variables which may predict prognosis • Age • T stage • Radiotherapy • Number of Lymph nodes • HDCT Criteria

  21. Early Phase I/II TrialsSelection Bias

  22. Early Phase I/II TrialsRadiotherapy, Ragaz et. al • 318 women with node positive breast cancer randomized to chemotherapy with or without radiotherapy • Patients matched • Number Positive Lymph Nodes • Nodal Size • Age • Tumor Grade • Estrogen Receptor Status

  23. Early Phase I/II TrialsRadiotherapy, Ragaz et. al • After 15 years follow up: • Disease Free Survival improved by 33% in radiotherapy group (Relative Risk 0.67) • Overall Survival improved by 29 % (Relative Risk 0.71)

  24. Early Phase I/II TrialsRadiotherapy, Overguard et. al • 1708 women with Stage II or III breast cancer randomized • 8 Cycles with CMF + Radiotherapy • 9 Cycles CMF • Patients Matched • age • tumor size • No. of positive lymph nodes • grade of tumor

  25. Early Phase I/II TrialsRadiotherapy, Overguard et. al

  26. Early Phase I/II TrialsSummary of Phase I/II Trials

  27. Randomized Controlled Trials • M.D. Anderson Trial by Hortobagyi et. al • Netherlands Trial by Rodenhuis et. al • South African Trial by Bezwoda et. al • CALGB Trial by Peters et. al

  28. Randomized Controlled TrialsM.D. Anderson Trial by Hortobagyi et. al

  29. Randomized Controlled TrialsM.D. Anderson Trial by Hortobagyi et. al • Eligibility Criteria • Resectable tumor • >10 Lymph nodes after primary surgery • >4 Lymph nodes after 4 cycles of neoadjuvant therapy

  30. Randomized Controlled TrialsM.D. Anderson Trial by Hortobagyi et. al • Patients Matched • Age • Race • Stage • Estrogen receptor status • # of positive nodes

  31. Randomized Controlled TrialsM.D. Anderson Trial by Hortobagyi et. al • 78 patients randomized • 6 patient in HDCT did not receive treatment (3 Refused, 1 Insurance denial, 2 other illness) • 3 patients in SDC received HDCT off protocol elsewhere • Median follow-up 53 months

  32. Randomized Controlled TrialsM.D. Anderson Trial by Hortobagyi et. al

  33. Randomized Controlled TrialsM.D. Anderson Trial by Hortobagyi et. al • Results • No significant EFS or OS between groups • 4 Treatment Related Deaths in HDCT vs. None in SDCT • Author concluded small trial but that HDCT is “unlikely to produce major improvements over SDCT”

  34. Randomized Controlled TrialsNetherlands Trial by Rodenhuis et. al

  35. Randomized Controlled TrialsNetherlands Trial by Rodenhuis et. al • Eligibility Criteria • Age < 60 • “Extensive Axillary Involvement” • Operable tumor • No distant Metastasis

  36. Randomized Controlled TrialsNetherlands Trial by Rodenhuis et. al • Patients Matched • Mastectomy • Breast Conserving surgery • Estrogen Receptor Status • Progesterone Receptor Status • T and N Stage • P53 status • Neu status

  37. Randomized Controlled TrialsNetherlands Trial by Rodenhuis et. al • 81 Patients Randomized (40 HDCT, 41 SDCT) • Median Follow-up 49 months • All patients received therapy

  38. Randomized Controlled TrialsNetherlands Trial by Rodenhuis et. al • Results: • Overall Survival: 75% • Event-Free Survival: 54% • No significant differences between two groups • No treatment related mortality • Study limited by small size

  39. Randomized Controlled TrialsSouth African Study by Bezwoda et. al • Randomized Controlled Trial Evaluating HDCT vs. SDCT • First Trial to demonstrate significant benefit of HDCT • Onsite review of study showed “much disparity” between reviewed records and presented data • Concluded: Bezwoda study should not be used to determine efficacy in HDCT

  40. Randomized Controlled TrialsCALGB Study by Peters et. al

  41. Randomized Controlled TrialsCALGB Study by Peters et. al • Eligibility Criteria • Stage II or IIIA Breast Cancer • >10 Lymph nodes • No Evidence of Metastatic Disease • Determined by CT Scan and Bone Marrow Biopsies

  42. Randomized Controlled TrialsCALGB Study by Peters et. al • 874 Patients admitted to trial • 91 not randomized (22 Recurrent disease, 2 death from CAF toxicity, 26 insurance denial, 20 withdrew, 21 ineligible) • 783 Patients randomized (394 HDCT, 389 IDCT) • Median Follow Up: 37 months

  43. Randomized Controlled TrialsCALGB Study by Peters et. al

  44. Randomized Controlled TrialsCALGB Study by Peters et. al • Results: • No significant difference between HDCT and IDCT • Fewer relapses in HDCT and IDCT (22% vs. 32%) Not significant. • 29 Therapy Related deaths vs. None in IDCT Group • Author notes data is preliminary

  45. Randomized Controlled TrialsDose-Response Relationship • Wood et. al examined CAF at different doses • 1572 women with Stage II breast cancer randomized to receive high, intermediate, or low dose therapy • Low and intermediate groups received 6 while high dose received 4 cycles q 28 days • Median Follow up 3 years

  46. Randomized Controlled TrialsDose Response Relationship

  47. Randomized Controlled TrialsDose-Response Relationship • Results • Significant differences between low dose and either high/intermediate doses • No significant difference between the intermediate and high dose groups • Appears to be a plateau at which the chemotherapy does not provide clinical benefits

  48. Randomized Controlled TrialsDose-Response Relationship • Fisher et. al examined cyclophosphamide at standard and increased dose intensity in Stage II Breast Cancer • 2305 randomized to receive 4 cycles standard dose (600 mg/m2), 2 cycles of increase dose (1200 mg/ m2) or 4 cycles of increased dose therapy. • All patients also received Doxorubicin • Follow up: 5 years

  49. Randomized Controlled TrialsDose-Response Relationship

  50. Randomized Controlled TrialsDose-Response Relationship • Results • No significant difference between any groups • Appears that 600 mg/m2 is appropriate dose for cyclophosphamide • CALGB 9344 studied Doxorubicin at 60/75/90 mg/m2. • 18 month follow up: No differences

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