1. Systemic chemotherapy of breast cancer: adjuvant and neoadjuvant Systemic chemotherapy of breast cancer: adjuvant and neoadjuvant Alexandru Eniu, MD, PhD Medical Oncologist Department of Breast Tumors Cancer Institute Ion Chiricuţă Cluj-Napoca, Romania

2. Cancer treatment Localised disease CURABLE Metastatic disease INCURABLE Therapy Surgery Radiation therapy Systemic therapy Endocrine therapy Chemotherapy Biologic therapy Natural history

3. Bernard Fisher- surgeon l “Breast cancer is a systemic disease involving a complex spectrum of host- tumor interactions […] variations in effective locoregional treatment are unlikely to affect survival substantially.”

4. First studies of adjuvant chemotherapy l First trial(1958) initiated by the NSABP with thiotepa- positive results (1968) l 1973: Bonadonna study using CMF

5. Evolution of Systemic Adjuvant Chemotherapy for Early-Stage Breast Cancer Mastectomy alone Adjuvant CMF Adjuvant CAF, CEF Adjuvant AC, EC, FEC Adjuvant AC +T Dose-dense AC + T Addition of tamoxifen, aromatase inhibitors Progressive improvement in disease- free and overall survival TAC Bonadonna G et al. N Engl J Med. 1995;332:901-906; Citron ML et al. J Clin Oncol. 2003;21: 1431-1439; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;351:1451-1467; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;352:930-942; Henderson IC et al. J Clin Oncol. 2003;6:976-983; Nabholtz JM et al. ASCO 2002; Orlando, Fla. Presentation.

6. Effect of chemotherapy: average 15 years results ( n=14 250) EBCTCG overview, Lancet 2005 May;365(9472):1687-717

7. Chemotherapy Basic Principles l Greatest efficacy against cycling cells l  growth fraction =  chemosensitivity –neoplastic cells –gastrointestinal mucosa –bone marrow l  growth fraction =  chemosensitivity –plateau phase of growth –cells in G 0

8. Chemotherapy Basic Principles Pharmacologic principles l therapeutic index –ratio of toxic dose to effective antitumor dose –optimal dose balances tumor vs. host toxicity –body surface area vs. body weight dosing

9. Chemotherapy Safety Drug Reconstitution

10. ACUTE TOXICITY CONSILIERE BONE MARROW ALOPECIA ORAL MUCOSA DIGESTIVE TUBE

11. TOXICITYTOXICITY l ACUTE ( common for most drugs) –Hematologic (except: Bleomicin, Vincristin) –Digestive l Nausea/Vomiting (CTX, ADR, DDP…) l Diarheea (5-FU, irinotecan…) –Alopecia l Chronic- drug related –Cardiac ( anthracyclines > Total dose, 5-FU) –Renal (CDDP, HD MTX) –Pulmonary (Bleo) l Long term: –sterility, second cancer, cognitive function

12. Common Toxicity Criteria CTCAE v3.0 2006 l standardised classification of side effects used in assessing drugs for cancer therapy l range of grades from 0-5 l general guideline is: –1 - Mild, –2 - Moderate –3 – Severe –4 - Life threatening –5 - Death

14. When to use chemotherapy? l Adjuvant chemotherapy: –after complete removal of all tumor –for patients at risk for distant metastases –goal: eradication of micrometastases l Neoadjuvant chemotherapy: –before local treatment, to facilitate surgery –goal: treatment of primary tu and micromets –excellent research opportunities- in vivo test l Palliative chemotherapy: –for metastatic or inoperable tumors –goal: palliate, improve QoL, prolong survival

15. Contraindications of chemotherapy 1. Previous extensive squelletal radiotherapy 2. Unrecovered myelosupression (N< 1500/mm3) 3. Diffuse bone & liver metastases 4. Renal failure 5. Anemia <8g%, hypoproteinemia, Plt <100000/mm3 6. Vomiting, uncontrolled diarrhea, HE & AB imbalance 7. Cachexia 8. Depression or patient’s refusal 9. Performance status 3-4

16. EVALUATION CRITERIA OF PERFORMANCE INDEX PIDisease signsDecreased effort capacity Weight loss FatigueWalkingPersonal hygiene Work 0123401234 < 5% 5 – 10% > 10% low medium severe low medium severe low medium severe low medium severe 0 = Able to carry on normal activities as before, no restrictions 1 = Restriction in difficult activities, but ambulatory and capable to carry on daily activities (e.g. office work, housekeeping) 2 = Ambulatory and capable of self care, but incapable to work. He spends less than 50% of day time in bed or armchair 3 = Capable of limited self care. The patient spends more than 50% day time in bed or armchair 4 = Bedridden, the patient can not take care of personal hygiene.

17. Therapy checklist: chemotherapy StrengthsWeaknessesRequired Resources Established role in the treatment of women with invasive breast cancer Costly in many instances Absolute benefits decrease with increasing age Requires a chemotherapy- experienced health care team Laboratory facilities  Monitor CBC and chemistry  Blood bank Pharmacy services  Compound the drugs  Antiemetics  Prophylactic and side effect management drugs Physical facilities to administer intravenous chemotherapeutic drugs Medical services to monitor and manage the toxicities of treatment  Microbiology and general laboratory facilities  Hydration facilities  Transfusion services for RBC, platelets  Broad-spectrum antibiotics  Growth factors  Pulmonary and cardiac monitoring Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008

18. Classical (oral) CMF Equivalent to regimens of anthracycline-based chemotherapy in certain situations An effective and less expensive adjuvant chemotherapy regimen 6 month treatment duration Multiple infusions Variable patient compliance Anthracycline -based chemotherapy (e.g., AC, EC, or FAC) Superior overall to CMF chemotherapy in unselected patients Generally a short course of therapy Doxorubicin generally less expensive than epirubicin Potential cardiac toxicity Costly 4-6 months treatment duration Taxanes Taxane chemotherapy may add benefit to anthracycline-based chemotherapy in some patients Expensive Additional toxicity (neurologic, bone marrow) RegimenStrengthsWeaknesses Therapy checklist: chemotherapy Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008

19. Treatment resource allocation Stage II breast cancer Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008

20. Chemotherapy regimens l CMF –Cyclophosphamide 100 mg po d1-14 –Methotrexate 40 mg/mp iv d 1+8 q28z –5-Fluorouracil 600/mp iv d 1+8 l EC –Farmorubicin 100mg/mp iv d 1 q21z –Cyclophosphamide 600 mg/mp iv d 1 l AC –Doxorubicin 60 mg/mp iv d 1 q21z –Cyclophosphamide 600 mg/mp d 1 l Docetaxel 100mg/mp iv z1 q 21 z l Paclitaxel 80mg/mp qw for 12 w

21. Dose is Important for Adjuvant Chemotherapy for Early-Stage Breast Cancer The Milan Study: Relapse-Free and Overall Survival With CMF 20-year follow-up (N = 386) Adapted from: Bonadonna G et al. N Engl J Med. 1995;332:901-906. Probability of Relapse-Free Survival (%) 5101520 0 40 60 80 100 Probability of Overall Survival (%) 5101520 0 40 60 80 100 Years After Mastectomy 0 0  85 (n = 42) 65-84 (n = 94)  65 (n = 71) Control (n = 179) Optimal Dose (%)

22. Primary chemotherapy for LABC What we know? l Initially used to shrink inoperable cancers l Not formally compared to local therapy alone… l Improvements in survival with combined modality established it as STANDARD OF CARE l Few studies conducted specifically in LABC l Heterogeneity (definition, regimens, endpoints) l Standard regimens are Anthracycline-based l Taxanes were evaluated in newer studies

23. The NSABP data OPERABLE breast cancer cCR pCR B-18 36% 13% 4 x AC n=1506 B-27 60% 26% 4 x AC + 4x Docetaxel n=2411 Wolmark, J Nat Cancer Inst Monogr. 2001, 30:96; Bear, J Clin Oncol 2006,24:2019

24. The MD Anderson experience- LABC pCR Predictive Kuerer 12% ER-, G3 4 x FAC n=372 Green (n=258) 4x q3wP + 15,7% ER-, PR- 4 x FAC 12 x wP + 28,2% 4 x FAC Kuerer, J Clin Oncol,1999; Green, J Clin Oncol 2005; Hennessy, J Clin Oncol 2005

25. Treatment resource allocation Locally advanced breast cancer Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008

26. Evaluation prior to primary systemic therapy for LABC l Clinical examination (schematic represent): –Clinical size of tumor ( measure it!) –Skin changes: erythema, edema, ulceration, and dimpling –Lymph node status ( measure!) l Photo documentation (inflammatory, T4’s…) l Elicitation of symptoms suggestive for distant metastasis l Natural history of the disease (rapid growing versus neglected tumor…)

27. Evaluation prior to primary systemic therapy for LABC (2) l Pathology: CORE BIOPSY /FNA –(grade, invasion, RE, RP and Her2 (?)) l Adequate breast imaging: extent of disease –Mammography –Ultrasound for T and N l Staging: X-ray, blood tests (CBC, liver, AP) –optional: bone scan, abdominal CT

28. Response assessment l Clinical exam at each cycle (T, N)-> to identify progression l Post therapy: 2 weeks after last cycle of chemo –Clinical exam: notoriously inaccurate! –Mammography / ultrasound ( Chagpar, Ann Surg, 2006) Clinical utility?

29. Surgery after primary chemotherapy l Surgery: 3-6 w after chemo –WBC nadir : 1,5-2 weeks –N>1500, Plt >50 000 l Type of surgery –MRM for all LABC ?! Cancer Treat Res 1997) l Criteria for breast conservation ( Singletary, Cancer Treat Res 1997) –Resolution of skin edema –Residual tumor size <5 cm –Absence of extensive breast lymphatic invasion –Absence of extensive suspicious microcalcifications ->MRM –No evidence of multicentricity-> MRM

30. Systemic treatment after surgery l Hormone receptor positive -> hormone therapy l (Her2 positive -> adjuvant trastuzumab ) l Further chemotherapy ? l Many (all?) patients had anthra+alkylator and taxanes l No data to suggest further benefit from chemo l In the absence of trial data, further chemotherapy should not be administered if anthra and taxanes have been already used Would more chemotherapy be better? Yes, tumor is really sensitive to chemo No, prognosis is already very good Would more chemotherapy be better? Yes, high risk imposes further treatment No, tumor does not respond to chemo

31. Conclusions -Neoadjuvant chemotherapy l Standard primary chemotherapy for LABC should include an anthracycline (FEC, AC, EC…) l Optimal duration is unknown –4 -8 cycles l Dose-intense anthracycline regimen does not improve outcome (metronomic schedule may) l Addition of taxanes improved outcomes but not DFS or S ( sequential, not concurrent ?) l 4 cycles of Anthra plus 4 cycles of docetaxel or 12 w of weekly paclitaxel, before surgery

32. Treatment resource allocation Metastatic breast cancer Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008

33. ASSESMENT OF TREATMENT RESPONSE WHO, bidimensional measurements - Complete remission (disappearance of all symptoms & signs for at least 1 month) -Partial remission (reduction >50%) -Stable disease (reduction <50%, growth <25%) -Progressive disease (growth >25% or new lesions) RECIST criteria principles One-dimensional measurements Measurable, non-measurable disease Target and non-target lesions Time interval 4-6 weeks

34. l CR (complete response) = disappearance of all target lesions l PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions l PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions l SD (stable disease) = small changes that do not meet above criteria RECISTRECIST

35. Response evaluation Patient A BaselineWeek 12

36. Social Well Being Family Distress Roles and Relationships Affection/Sexual Function Appearance Enjoyment Isolation Finances Work Psychological Well Being Control Anxiety Depression Enjoyment/Leisure Fear of Recurrence Cognition/Attention Distress of Diagnosis and Control of Treatment Physical Well Being and Symptoms Functional Activities Strength/Fatigue Sleep and Rest Overall Physical Health Fertility Pain Spiritual Well Being Meaning of Illness Religiosity Transcendence Hope Uncertainty Inner Strength QoL Quality of Life Ferrell, BR and Grant, M. City of Hope Beckman Research Institute(2004)

37. Major Therapeutic Approaches in Hormone-Dependent Breast Cancer E E production ER Block Estrogen -TAMOXIFEN (Pre or Post) - SERMs Reduce Estrogen -Ovarian Function Suppression (Pre) -Aromatase Inhibitors (Post )

38. Menopausal status l Women over 60 years of age l Bilateral ooforectomy l Women over 45 years with spontaneous cessation of menses for more than 12 months l Women over 45 years with cessation of menses after chemotherapy AND FSH and estradiol values in the menopausal range l For patient under 45 years of age, postchemotherapy amenorheea is a contraindication for AI*! * * Smith et al. J Clin Oncol. 24:2444-2447. © 2006

39. Effect of TAMOXIFEN: average 15 years results ( n=46975) EBCTCG overview, Lancet 2005 May;365(9472):1687-717

40. Effect of ovarian ablation: average 15 years results ( n=8 000) EBCTCG overview, Lancet 2005 May;365(9472):1687-717

41. Adjuvant endocrine therapy in women with ER+ and/or PR+ or - unknown receptors substantially reduces the risks of disease recurrence and death Limited toxicity Easily administered by general practitioner or surgeon Absolute benefits in adjuvant setting increase with increasing risk of recurrence Optimally requires availability of ER and PR determination Benefits are limited in low-risk breast cancer Compliance varies Need ability to manage rare but potentially serious side effects Pathology* Tumor steroid hormone receptor content Tumor histologic grade Stage of disease (biochemistry and radiological investigation) Resources for diagnosis and management of toxicities Pharmacy/drug distribution StrengthsWeaknessesRequired Resources Therapy checklist: endocrine therapy Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008

42. Ovarian ablation (medical, surgical, radiother apy) Effective for pre-menopausal women with ER+ and/or PR+ or -unknown receptors: Combined medical oophorectomy (LHRH + tamoxifen) is equivalent to CMF chemotherapy Oophorectomy (surgery or radiation) plus tamoxifen may be considered an appropriate adjuvant endocrine therapy Surgical and radiation induced ovarian ablation is likely to be cost-effective compared with chemotherapy alone Long-term adverse effects of estrogen deprivation in young women High cost of LH- RH agonists RegimenStrengthsWeaknesses Therapy checklist: ovarian ablation Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008

43. TamoxifenImproves disease-free and overall survival in all age groups and nodal subsets and with or without chemotherapy in ER+ and/or PR+ or – unknown receptors disease Reduces risk of second, contralateral breast ca Maintains bone mineral density in postmenopausal women Inexpensive Known long-term toxicity profile Toxicity Hot flashes Thromboembolic disease Endometrial carcinoma Rare ocular toxicities Aromatase inhibitors (AIs) In postmenopausal women with ER+ and/or PR+ or -unknown resected breast cancer:  Adjuvant AIs are superior to tamoxifen  Sequential AI following 2–3 years of tamoxifen is superior to tamoxifen alone  Extended AI therapy following 5 years of tamoxifen is superior to 5 years of tamoxifen  No increase in thromboembolic events or endometrial cancer Absolute difference between AIs and tamoxifen alone in terms of disease- free survival is small No clear impact on survival Substantially higher cost compared with tamoxifen Toxicity: increased risk of bone fracture, arthralgias Therapy checklist: tamoxifen and AI RegimenStrengthsWeaknesses Anderson, BO et al, Cancer 113:S8, 2221-2243, 2008

44. Fear of symptoms Toxicity data Impact on QoL TUMOR BIOLOGY Factors driving treatment decisions Risk of death Risk of progressive disease Personal issues Chance of response to therapy Patients preference

45. ConclusionsConclusions l Important advances have been achieved in the management of breast cancer l Mortality has decreased in developed countries l Resource constraints impose alterations of the multidisciplinary pattern of care l Build a strategy for improving care l Incremental, step-by-step allocation l Optimal care to all is the ultimate goal