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BALKAN MCO 2011 - E. Vrdoljak - Locoregional therapy in LABC
 

BALKAN MCO 2011 - E. Vrdoljak - Locoregional therapy in LABC

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    BALKAN MCO 2011 - E. Vrdoljak - Locoregional therapy in LABC BALKAN MCO 2011 - E. Vrdoljak - Locoregional therapy in LABC Presentation Transcript

      • Locoregional therapy in locally advanced breast cancer
      • Prof.dr.sc.Eduard Vrdoljak
      • Center of Oncology
      • Clinical Hospital Split, Croatia
    • Justification for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer
      • Postmastectomy radiotherapy reduces locoregional recurrence from 30% to 10% at 15 year follow-up
      • R eduction in the risks of distant relapse and death (5% OS at 15 yrs)
      EBCTCG. Lancet 2005.
    • Effects of RT on breast cancer mortality and all cause mortality after breast conserving / mastectomy and axillary clearance EBCTCG. Lancet 2005.
      • Patients with stage III breast cancer have clinically relevant risk of locoregional recurrence after mastectomy and thus would benefit from adjuvant radiotherapy
      • There is not an accepted standard of care concerning post mastectomy radi otherapy for stage II breast patients
      P ostmastectomy radiotherapy (PMRT) for patients with invasive breast cancer
      • The Danish 82b
      • The Danish 82c
      • British Columbia trial
        • Among women with breast cancer at high risk of locoregional recurrence
          • Systemic therapy reduces distant micrometastasis
          • Allows the effects of PMRT in reducing locoregional tumour burden to enhance disease control and survival
      Phase III randomized trials
    • Danish 82b Trial
      • PMRT (thoracic wall and regional lymphatics) and 8 cycles CMF vs. 9 cycles CMF alone in premenopausal patients ( n= 1706)
      • stage II or III breast cancer
      • median of 7 lymph nodes were removed
      • 8% of patients were node negative
      • Overgaard et al. NEMJ 1997.
    •  
    • Results
      • r eduction in locoregional failure (9% v s . 32%,
      • p < 0.001)
      • 10-year disease-free survival (48% v s . 34%, p < 0.001)
      • 10-year o verall survival (54% v s . 45%, p < 0.001) with PMRT
      • Results-subgroup analysis
      • locoregional failure at 10-year in chemotherapy only group:
      • 40% for 0-3 LN dissected
      • 32% for 4-9 LN dissected
      • 27% for 10 or more LN
      • locoregional rates were very similar in irradiated patients,
      • regardless of the number of LN
      • a ll three subgroups had improved DFS and OS when PMRT was used
      • PMRT  10% increase in 10 yr OS for 0-3/4-9 LN dissected
      • 4% increase in 10 yr OS for 10 or more LN
      • Overgaard et al. NEMJ 1997.
      • Results-subgroup analysis
      • prem enopausal patients
      • n o diff erence in locoregional failure or DF S for
      • age < 40 years, 40 – 4 9, 50 or more years
      • f irst two had similar improv ement in 10-y ea r DF S and OS rates resulting from PMRT
      • Overgaard et al. NEMJ 1997.
      • Conclusion
      • Statistically significant differences in
      • LRF, RFS, and OS rates favoring the irradiated patient arm for patients with negative, one to three positive, and four or more positive nodes in the Danish 82b trial
      Overgaard et al. NEMJ 1997.
    • Danish 82c Trial
      • PMRT and 1 year of tamoxifen vs. tamoxifen alone in postmenopausal patients ( n= 1374)
      • Stage II and III breast cancer
      • Overgaard et al. Lancet 1999.
    • Results
      • r eductions in locoregional failure (8% v s . 35%, p < 0.001)
      • 10-year di sease-free survival (36% v s . 24%, p < 0.001)
      • 10-year o verall survival (45% v s . 36%, p = 0.03) with PMRT
      Overgaard et al. Lancet 1999.
      • Results-subgroup analysis
      • In the 82c trial, there were substantial differences in LRF, RFS, and OS rates favoring the irradiated patient arm for patients with negative, one to three positive, and four or more positive nodes, but the statistical significance of these differences was not reported
      Overgaard et al. Lancet 1999.
    • Danish 82b and 82c trials
      • Locoregional recurrence rate at 18 year , 14% vs. 49% (p<0.0001)
      • Rates of distant metastasis at 18 year, 53% vs. 64% (p<0.0001)
      • Overall survival rates not provided
      • Nielsen et al. JCO 2006.
    • Danish 82b and 82c trials
      • Analysis of 1152 patients with 8 or more dissected lymph nodes
      • RT reduced the 15-year loco-regional failure rate from 51% to 10% (p < 0.001) in 4+ positive node patients
      • and from 27% to 4% (p < 0.001) in patients with 1–3 positive nodes
      • the 15-year survival benefit after RT was improved in both patients with 1–3 positive nodes (57% vs 48%,
      • p = 0.03) and in patients with 4+ positive nodes (21% vs 12%, p = 0.03).
      • Overgaard et al. Radioth Oncol 2007.
    • PMRT 1-3 L N+ with 8 or more nodes dissected- DBCG 82 b and 82 c trial Overgaard et al. Radioth Oncol 2007. RT No RT p value LRR 4% 27% <0.001 Overall survival 57% 48% 0.03
    • British Columbia Trial
      • PMRT (37.5 Gy/16 fr) and CMF vs. CMF alone in premenopausal women with node-positive breast cancer ( n=318 )
      • median of 11 lymph nodes dissected
      • locoregional recurrence rate at 20 years, 13% vs. 39% ( p < 0.00 01 )
      • rates of distant metastasis, 52% vs. 69%, ( p = 0.0 04 )
      • survival rates at 20 years , 47% vs. 37%, ( p = 0.0 3 )
      • Ragaz et al. NEJM 1997.
      • Ragaz et al. JNCI 2005.
    • . Pierce L J JCO 2005 . British Columbia Trial - OS
    • Limitations of Evidence
      • The rate of LRF was higher in all 3 trials than any other trial
      • Limited axillary dissection performed (median number of axillary nodes removed was 7 in the Danish trials and 11 in the British Columbia trial)
      • Danish 82c trial, 1 year of tamoxifen therapy
      • Danish 82b trial and the British Columbia trial, CMF was used as opposed to anthracycline
    • Cofactors associated with higher LRR in 1-3 lymph nodes positive and without radiotherapy
      • Cheng et al. (age < 40 years,tm = or > 3 cm, ER neg., LVI positive)
      • Wallgren et al. (premenopausal, grade 2 or 3, LVI +; or postmenopausal grade 3, or postmenopausal grade 2, T2)
      • Taghian et al. (age<50, T2)
      • Katz et al. (tm> 4 cm, extracapsular exstension >2 mm, <10 lymph nodes removed, 20% lymph nodes involved, invasion of skin/nipple, invasion of pectoral fascia, close or positive margins)
      • Truong et al. (age< 45, 25% lymph nodes involved, ER neg., grade 3, medial tm location)
    • Randomized trials comparing systemic therapy with systemic therapy plus PMRT -meta analysis
      • 18 randomized trials, 6300 patients
      • PMRT substantially reduced the risk of LRF (by roughly 2/3 – 3/4)
      • The chance that a benefit in relapse-free and overall survival rates was shown seems related to trial size
      • Only the DBCG trials 82b and 82c and the British Columbia trial showed statistically significant improvements in the overall survival rate for the combined-modality arm.
      • Whelan et al. JCO 2000.
      • Therefore, in 1998, the Health Services Research Committee of the American Society of Clinical Oncology (ASCO) commissioned a panel to evaluate the evidence with regard to the value of PMRT in patients treated with systemic therapy
    • Summary of ASCO guidelines
      • Patients With Four or More Positive LN
      • PMRT is recommended
      • Patients With 1-3 + LN
      • There is insufficient evidence to make recommendations or suggestions for the routine use of PMRT in patients with T1 - 2 tumors with one to three positive nodes
      • 3. PMRT is suggested for patients with T3 tumors with positive axillary nodes and patients with operable stage III tumors
      • Patients Undergoing Preoperative Systemic Therapy
      • There is insufficient evidence to make recommendations or suggestions on whether all patients initially treated with preoperative systemic therapy should be given PMRT.
      • There is insufficient evidence to make recommendations or suggestions regarding the routine use of PMRT based on other tumor- related, patient-related, or treatment-related factors.
      • 6. Chest Wall Irradiation
      • In patients given PMRT, we suggest that adequately treating the chest wall is mandatory
      • 7 . There is insufficient evidence for the Panel to recommend or suggest such aspects of chest wall irradiation as total dose, fraction size, the use of bolus, and the use of scar boosts.
      • 8 . Axillary Nodal Irradiation
      • We suggest that full axillary radiotherapy not be given routinely to patients undergoing complete or level I/II axillary dissection
      • 9 . Clinical supraclavicular failure is sufficiently great in patients with four or more positive LN that we suggest a supraclavicular field should be irradiated in all such patients
      • 10 . Nodal Irradiation for Patients With 1-3 positive LN There is insufficient evidence to state whether a supraclavicular field should or should not be used
      • 1 1 . There is insufficient evidence to make suggestions or recommendations on whether deliberate internal mammary nodal irradiation should or should not be used in any patient subgroup.
      • 1 2 . There is insufficient evidence to recommend the optimal sequencing of chemotherapy, tamoxifen, and PMRT. The Panel does suggest , based on the available evidence regarding toxicities, that doxorubicin not be administered concurrently with PMRT.
      • 1 3 . Integration of PMRT and r econstructive s urgery
      • There is insufficient evidence to make recommendations or suggestions
      • Recht. JCO 2001 .
      • 5,758 patients enrolled onto the B-15, B-16, B-18, B-22, and B-25 trials. Median follow-up time was 11.1 years.
      • Cumulative incidences for LRF as first event with or without DF for patients with one to three, four to nine, and ≥ 10 LN+ were 13.0%, 24.4%, and 31.9%, respectively ( P < .0001).
      • For patients with a tumor size of ≤ 2 cm, 2.1 to 5.0 cm, and more than 5.0 cm, these incidences were 14.9%, 21.3%, and 24.6%, respectively ( P < .0001).
      Patterns of Locoregional Failure in Patients With Operable Breast Cancer Treated by Mastectomy and Adjuvant Chemotherapy With or Without Tamoxifen and Without Radiotherapy: Results From Five National Surgical Adjuvant Breast and Bowel Project Randomized Clinical Trials Taghian A et al. JCO 2004
      • CONCLUSION: In patients with large tumors and four or more LN+, LRF as first event remains a significant problem. Although PMRT is currently recommended for patients with four or more LN+, it may also have value in selected patients with one to three LN+.
      • Supported all the ASCO recommendations and suggestions.
      Patterns of Locoregional Failure in Patients With Operable Breast Cancer Treated by Mastectomy and Adjuvant Chemotherapy With or Without Tamoxifen and Without Radiotherapy: Results From Five National Surgical Adjuvant Breast and Bowel Project Randomized Clinical Trials Taghian A et al. JCO 2004
    • Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival. An overview of the randomised trials Lancet 2005;366:2087-2106
    • Trials of post-mastectomy RT Effect on LR and breast cancer mortality in N- pts Mastect + AC Mastect + AC Mastect + AC + RT Mastect + AC + RT
    • Trials of post-mastectomy RT Effect on LR and breast cancer mortality in N+ pts Mastect + AC + RT Mastect + AC Mastect + AC + RT Mastect + AC
    • Main findings I
      • RT reduces the 5-y LR rate both in N+ and N- pts
      • The LR rate reduction give a comparable gain in
      • 15-y breast cancer mortality (5%).
      • For every 4 local recurrences avoided, about one
      • breast cancer death will be avoided over the next
      • 15 years.
    • Incidence of 2nd cancers and mortality from causes other than breast cancer
    • Breast cancer and overall mortality after RM/RT Mastect + AC Mastect + AC + RT Mastect + AC Mastect + AC + RT
    • Main findings II RT can increase mortality for heart disease and lung cancer and incidence of contr a lateral breast cance r which reduce its net beneficial effect on 15-y breast cancer mortality. Nevertheless, RT produced reductions not only in 15-y breast cancer mortality but also in 15-y overall mortality.
    • Conclusions
      • PMRT substantially reduces the risk of LRF in node positive patients
      • Not as uniformly, improves DF and OS rates
      • The magnitude of these improvements substantially outweigh the potential long-term risks of life-threatening complications from PMRT performed using modern radiotherapy techniques.
      • Treatment decisions individually tailored
    • Radiation t echnique
      • Chest wall-direct electron field or LL photons
      • Boost
        • 10 Gy for positive or close margins
      • 50 Gy in 25-28 fractions
    • Nodal i rradiation
      • N0 - no role for axillary RT
      • N+
        • 1-3 nodes, “adequate sampling” - no RT
        • > 4 nodes, RT to SCLV and axilla
    • RT c omplications
      • Lymphedema
        • After full axillary dissection + RT = 37%
        • Level I/II dissection + RT = 7%
      • Rib fracture = 1.8%
      • Pneumonitis = 1-5%
      • Cardiac toxicity - avoidable
      • Radiation-induced sarcoma
        • 0.78% at 30 yrs.
        • Pierce et al. JCO 2005.
    • Reducing Risk
      • Respiratory Gating
      • IMRT
    • 4D CT: sorting process Full respiratory cycle End-inspiration CT Image Sorting Program End-expiration 4 sec
    • Opto-electronic system IR flash IR flash Processing unit Motion analyzer Bunker Control room
    • Breath adapted radiotherapy D eep inspiration breath hold Free breathing Irradiated heart volume 8% Irradiated heart volume 1% AN Pedersen, Copenhagen
    •