Study of Failure pattern Among High-Risk Breast cancer Patients with or without Postmastectomy Radiotherapy: Long –term results from the Danish Breast cancer Cooperative Group DBCG DBCG82 82 82b and c Randomized Studies b Presented by Kanograt Tangsriwong Journal of clinical oncology; May 2006 P. 2268 2268-75 Hanne M. Nielsen,Marie Overgaard, Cai Grau Grau, Anni R. Jensen, and Jens Overgaard Post mastectomy radiotherapy in high-risk breast cancer patients can reduce locoregional recurrence and improve disease free survival IntroductionHalstedian 1894: Tumor spread Direct permeation LN Hypothesis Fischer 1980: Tumor size & no CMT Distant metastasis Hypothesis Hellmann 1994: LN +ve Malignant biology persistent disease Hypothesis Distant metastasisTo examine the overall disease recurrence pattern among patients randomly assigned to receive treatment with or without RT ObjectivePopulation -3,083 high-risk breast cancer patients after total mastectomy and partial axillary dissection -Department of Experimental clinical oncology, Patient & method Aarhus University , Aarhus DenmarkHigh risk of recurrence: Tumor size larger than 5 cm and/or positive axillary nodes and/or invasion of the skin or pectoral fascia Adjuvant systemic therapy: -Combination of cyclophosphamide 600mg/m2 , methotrexate 40mg /m2 , and fluorouracil 600mg/m2 -Given intravenously every 4 weeks to a total of 8 cycles for RT and 9 cycles for no RT Chemotherapy and RT were delivered using a sandwich technique: RT interpolated after 1st cycle of CMF Postmenopausal women received tamoxifen 30mg daily for 1 yearRT 1,538 patients Megavoltage RT 1,341 patients Orthovoltage RT 120 patients No RT 1545 patients Incomplete RT 77 patientsRT 1,538 patients Megavoltage RT 1,341 patients (50 Gy in 25F, 5F /week or 48 Gy in 22F, 4F /week) Orthovoltage RT 120 patients (36 Gy in 20F, 5F /week)Follow up Up to 10 years or until first recurrence, death, or occurrence of a new primary cancer, or distant metastasis ,contralateral breast cancers A short questionnaire to consider recurrence status • LRR : locoregional recurrence An ipsilateral chest wall failure (local) or ipsilateral axillary or supra/infraclavicular failure (regional) • Metastes to internal mammary lymph nodes were not recorded as a regional failureLRR alone: LRR with no sign of subsequent distant metastasis within 1 month• Simultanoeus failure LRR followed by distant metastasis within the same month •Distant metastasis -Any failure outside the ipsilateral mammary region and the regional lymph nodes -Histopathologic was not performed routinely and often the diagnosis of distant metastasis was based on clinical or radiologic findingsStatistical analysis -Kaplan-Meier method: estimate probability -Relative risk: describe any differences in failure sites in the two treatment groups -X2 test: comparison of qualitative dataResults No RT RT No recurrence 19 % LRR alone 30% Sim LRR-DM 8% DM 28% 30 % 5% 5% Results: overall failure pattern Contralateral breast CA 4% Dead 11% 41% 5% 13%No RT RT Time to 1st site failure 3.9 yr Prob. of 1st site failure 73 % All LRR 49 % 7.9 yr 59% 14% Results: first site of failure Chest wall failure 55 % Axillary failure 43 % 70% 24%No RT RT DM subsequent to LRR 35% Any DM 64% Time to DM 6.5 yr 6% 53% 12.3 yr Results: Distant metastasis Bone metastases 40% 32%Hazard ratio increased among patient with no RT Hazard ratio decreased with time after mastectomy in both groups Bone metastases were most often part of first distant metastases Results: Distant metastasis Lung, CNS, skin metastases outside ipsilateral chest wall were significantly lower in RT group Orthovoltage Megavoltage LRR 20% Any DM 55% 12% 52% Results: ORTHO VS MEGA VOLTAGE Invasion of deep fascia and LRR are more frequent significantly among the orthovoltage-irradiated groups Results: ORTHO VS MEGA VOLTAGEFactors influenced the high LRR risk in Danish trials -No RT -Suboptimal axillary surgery Discussion -T-stagePremenopausal women -CMF chemotherapy : not effective in locoregional control when suboptimal surgery more effective regimens Post menopausal women Discussion -ER –ve : chemotherapy -ER +ve : 5-yr tamoxifen therapy (instead of 1-yr) or long-term aromatase inhibitors Stockholm trials Node +ve less than 1/3 -> less DM (45% in No RT and 37% in RT groups ) Danish trials Node +ve nearly all of patients -> more DM Discussion (64% in No RT and 53% in RT groups )Chemotherapy before RT in post lumpectomy patients had a lower DM rate than RT before CMT groups ; recent data shows DM rate was independent of the sequencing of RT and CMT The sequence depends on margin status and Discussion effectiveness of systemic therapiesPost mastectomy RT is indicated in high-risk patients with >=4 positive nodes and /or T3 and T4 tumors Role of postmastectomy RT in 1-3 positive nodes is Discussion unclear Locoregional RT will be beneficial in patients with primary tumor not yet metastatized Discussion Postmastectomy RT could reduce 1st site LRR and overall distant metastasis Conclusion Clinical investigation: Regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy Presented by Kanograt Tangsriwong International journal radiation oncology Vol.63 No.5 2005: P .1508-13 Eric A. Storm, Wendy A. Woodward, Angela Katz. etc Survival benefit for postmastectomy radiotherapy has left several questions unanswered The optimal radiotherapy target remains unanswered Introduction Chest wall is the most common site of locoregional recurrence and should be treated in high-risk patients Regional nodal failures can be a source to seed Introduction distant metastasis and generally portend a poor prognosisAdjuvant treatment to the regional lymphatics increase the risk of treatment complications, including lymphadema and pneumonitis It is crucial to define the subgroups of patients Introduction with the greatest potential to benefit from regional nodal radiation to maximize the therapeutic ratio To describe regional nodal failure patterns in patients who had undergone mastectomy with axillary dissection to define subgroups of patients who might benefit from supplemental Objective regional nodal radiation to the axilla or supraclavicaulr fossa/axillary apexPopulation -1,805 breast cancer patients treated with doxorubicin-based adjuvant systemic therapy with or without tamoxifen after mastectomy -Department of radiation oncology, medical Patient & method oncology, surgical oncology and pathology, M.D. Anderson cancer center, Texas, USA Breast cancer patients with resectable stage II and IIIA disease Inclusion criteria Older than 75 yrs Evidence of distant dissemination Prior or concurrent malignancy Exclusion criteria Median age 48 yrs (42-56 yrs) Premenopausal 48% Postmenopausal 51% Patient & method: age & menopausal statusInvasive ductal or mixed invasive and lobular 1031 patients Other 4% Patient & method: pathology carcinoma 91% Invasive pure lobular carcinoma 5%Examined nodes > 10: 89% 5-9 : 9 % < 5 : 1 % Median number of examined nodes : 17 Patient & method: nodes Median number of involved nodes : 3 Radical mastectomy c level I and II axillary node 1,805 patients RT +/-surgery 774 Patient & method: treatment dissection 5 Modified radical mastectomy c axillary node dissection 1,026 Adjuvant CMT c no RT Tamoxifen 312Median follow-up time : 116 months 10-yr follow up: 370 patients 5-yr follow up: 766 patients Loss follow up <= 3yr: 13 patients Alive c no disease: 11 patients Alive c disease: 2 patients Patient & method: follow up • Low-mid axilla • Supraclavicaular fossa /axillary apex Classification of regional nodal failures According to radiation therapy fieldsAxillary lymph node levels in relation to the axillary vein and the muscles of the axilla (I = low axilla, II = midaxilla, III = apex of axilla)Results 10-year overall survival : 65 % 10-year disease-free survival: 55 % 10-year distant metastasis-free survival: 64 % Locoregional recurrence: 19 % (chest wall 67 %, regional nodal 53 %, low-mid axilla 12% and supraclavicular fossa/axillary apex 43% )Low-mid axilla recurrence: 21 /1,031 With presence of chest wall failure: 5 /21 No significant association with increasing number and Results: Failure in the low-mid axilla percentage of involved axillary LN, larger nodal size or gross extranodal extensionSupra/infraclavicualr recurrence: 77 /1,031 Without presence of chest wall failure: 49 /77 Significant association with >=4 involved axillary LN, Results: Failure in supraclavicular fossa/axillary apex greater than 20% involved node, LVSI +ve and gross extranodal extension (greater than 2mm)>=4 involved axillary LN greater than 20% involved node 15% 15% 10-yr actuarial rates, P < 0.0008 LVSI +ve gross extranodal extension 12% 19%Positive 1-3 nodes Positive > 4 nodes LVSI +ve 4-13 % 13-22% HR 1.89 Failure rates in the supraclavicular fossa/axillary apex Percentage of positive nodes HR 1.01T1/T2 disease and positive 1-3 nodes: -Recurring in supraclavicular or infraclavicular fossa is very low -Only number of positive nodes predicted for increased failure in the high axilla -3 nodes +ve : 10-yr recurrence free rate 10% -2 nodes +ve : 10-yr recurrence free rate 2%No statistical significant recurrence rate associates with greater than 20% involved nodes, the presence of gross extranodal extension, < 10 nodes removed, largest axillary node> 2cm or LVSI +ve T1/T2 disease and positive 1-3 nodes Increasing number of these factors had a higher failure rate 4 factors 40 % 3 factors 9 % 2 factors 6 % 1 factors 5 % No factors 2.5 % Discussion Axillar recurrence in this trial: 14% of LRR Axillar recurrence in Danish trial: 45% of LRR Chest wall was the most common site, followed by the supraclavicular fossa/axillary apex Discussion None of the factors were predictive of recurrence in the low-mid axilla 4-7% risk of axillary failure after Sx and adjuvant Rx for patients with extranodal extension Supplemental radiation to the low-mid axilla is not indicated Discussion >=4 positive or > 20% involved axillary nodes and gross extranodal extension were predictive of recurrence in the supraclavicular fossa/axillary apex 15-20% risk of supraclavicular fossa/axillary apex failure after Sx and adjuvant Rx for patients with those factors Supplemental radiation to the supraclavicular fossa/axillary apex is recommendedDiscussion Supplemental radiation to the dissected axilla is not routinely used for patients with operable breast cancer End of Presentation Thank You