1. Postmastectomy Radiation therapy (PMRT): Who needs it in 2008? Carol Marquez, M.D. Associate Professor, Department of Radiation Medicine Oregon Health and Sciences University

2. Goals of discussion Present evolution of thought and use of PMRT from the 1970’s to 1997. Present evolution of thought and use of PMRT from the 1970’s to 1997. Discuss result of recent randomized trials. Discuss result of recent randomized trials. Present recent retrospective analyses to determine patients at greatest risk of recurrence. Present recent retrospective analyses to determine patients at greatest risk of recurrence. Discuss techniques for PMRT. Discuss techniques for PMRT.

3. What we did prior to the 1970’s Many patients received PMRT after their surgery, RM or MRM. Many patients received PMRT after their surgery, RM or MRM. NSABP B-02 randomized pts after RM to receive regional radiation. No difference in overall survival but decrease in regional recurrence. NSABP B-02 randomized pts after RM to receive regional radiation. No difference in overall survival but decrease in regional recurrence. Initiated in 1971, NSABP B-04 randomized pts after RM, TM, or TM + XRT if clinically node neg and if node + to RM or TM +XRT. Initiated in 1971, NSABP B-04 randomized pts after RM, TM, or TM + XRT if clinically node neg and if node + to RM or TM +XRT. Ten year results showed no difference in disease free or overall survival among the groups. Radiation arms did show decrease in local recurrences. Ten year results showed no difference in disease free or overall survival among the groups. Radiation arms did show decrease in local recurrences.

4. What happened in the 80’s? By the mid-80’s, the safety of regional nodal irradiation was questioned with an excess of cardiac mortality seen in patients followed for 10 years. By the mid-80’s, the safety of regional nodal irradiation was questioned with an excess of cardiac mortality seen in patients followed for 10 years. Meta-analysis of 7 randomized trials of PMRT initiated before 1975 showed an increase in cardiac-related deaths in those receiving RT that was almost balanced by a reduction in the deaths due to breast cancer. Meta-analysis of 7 randomized trials of PMRT initiated before 1975 showed an increase in cardiac-related deaths in those receiving RT that was almost balanced by a reduction in the deaths due to breast cancer. The excess cardiac mortality was largely due to the increase in cardiac dose from radiation to the internal mammary nodes. The excess cardiac mortality was largely due to the increase in cardiac dose from radiation to the internal mammary nodes.

5. Paradigm shift to Alternate hypothesis Breast cancer is both a local and systemic problem at presentation. Breast cancer is both a local and systemic problem at presentation. More extensive local treatment will not improve survival. More extensive local treatment will not improve survival. Supported the trials examining less extensive surgery. Supported the trials examining less extensive surgery.

6. Who did we treat in the 1990’s? Because of the concern of late toxicity, the indications for PMRT were greatly limited to include only those patients with more advanced disease: T3/4, more than 4 positive nodes. Because of the concern of late toxicity, the indications for PMRT were greatly limited to include only those patients with more advanced disease: T3/4, more than 4 positive nodes. The rationale for choosing these patients is that their risk for local recurrence was at least 30% which radiation could reduce by at least half. The goal of treatment was only to reduce local and regional recurrence and not to improve overall survival. The rationale for choosing these patients is that their risk for local recurrence was at least 30% which radiation could reduce by at least half. The goal of treatment was only to reduce local and regional recurrence and not to improve overall survival. The treatment volume typically included the chest wall, supraclavicular nodes, and axillary nodes and much less often, the internal mammary nodes. The treatment volume typically included the chest wall, supraclavicular nodes, and axillary nodes and much less often, the internal mammary nodes.

7. What did we learn in 1997? Two articles published in the NEJM 10/97 showed improvement in survival with PMRT in premenopausal women, all of whom also received chemotherapy (CMF). Two articles published in the NEJM 10/97 showed improvement in survival with PMRT in premenopausal women, all of whom also received chemotherapy (CMF). Patients enrolled in these trials included were (generally) node + with the majority having only 1- 3 positive nodes and the majority having tumors < 5 cm in size. Patients enrolled in these trials included were (generally) node + with the majority having only 1- 3 positive nodes and the majority having tumors < 5 cm in size. Fields treated included chest wall and all regional nodes (including internal mammary). Fields treated included chest wall and all regional nodes (including internal mammary). Similar results seen in postmenopausal stage II/III women treated with tamoxifen and XRT, improvement in DFS and overall survival. Similar results seen in postmenopausal stage II/III women treated with tamoxifen and XRT, improvement in DFS and overall survival.

8. Overall survival results Figure 1A. Overall survival in the Danish Breast Cancer Cooperative Group Trial. (5) Figure 1B. Overall survival in the British Columbia Trial. (6)

9. British Columbia Randomized trial: 20 year results 1.Breast Cancer Specific Survival 2.Overall Survival 1. 2.

10. Where did we go in 2000? Many people began recommending treatment for any node positive patient following mastectomy. Many people began recommending treatment for any node positive patient following mastectomy. Intergroup study attempted to address role of postmastectomy XRT in women with 1-3 positive nodes but closed in June 2003 secondary to lack of accrual. Intergroup study attempted to address role of postmastectomy XRT in women with 1-3 positive nodes but closed in June 2003 secondary to lack of accrual. Many discussions regarding the value of treating clinically uninvolved nodes and how that may impact overall survival. Many discussions regarding the value of treating clinically uninvolved nodes and how that may impact overall survival.

11. What is the downside of PMRT? Greater risk for lymphedema of breast and arm Greater risk for lymphedema of breast and arm Increased amount of lung that is fibrosed by radiation, primarily from treatment of either the supraclavicular nodes or internal mammary nodes. Increased amount of lung that is fibrosed by radiation, primarily from treatment of either the supraclavicular nodes or internal mammary nodes. May expose contralateral breast to radiation. May expose contralateral breast to radiation. Decrease in the quality of the cosmetic outcome following reconstruction, especially with implants. Decrease in the quality of the cosmetic outcome following reconstruction, especially with implants.

12. Who needs PMRT in 2008? All women with > 3 positive nodes. All women with > 3 positive nodes. All women with any positive node and a tumor larger than 5 cm. All women with any positive node and a tumor larger than 5 cm. ? Women with positive margins ? Women with positive margins ? Women with T3N0 ? Women with T3N0 ? Women with 1-3 positive nodes and T1/T2. ? Women with 1-3 positive nodes and T1/T2.

13. When positive margins are the only risk factor Hard to demonstrate the value of PMRT in patients where positive margins is the only risk factor for local recurrence; retrospective reviews have found LRF rates of <15% without XRT. Hard to demonstrate the value of PMRT in patients where positive margins is the only risk factor for local recurrence; retrospective reviews have found LRF rates of <15% without XRT. Retrospective multivariate analysis of large group in Canada found a LRF rate of >20% in those pts with positive margins who also had T2 tumor, 20% in those pts with positive margins who also had T2 tumor, <51 years old, grade 3, or LVSI.

14. Canadian retrospective review of + margins Included T1-2, N0 patients with + margins; n=98. Included T1-2, N0 patients with + margins; n=98. Admitted bias inherent in retrospective review. Admitted bias inherent in retrospective review. Found longer time to local relapse in those receiving XRT (3 vs. 4 years). Found longer time to local relapse in those receiving XRT (3 vs. 4 years).

15. T3N0, Do they really need it? Retrospective review of 5 NSABP studies found that in pts treated with or without systemic therapy and without PMRT, those with T3N0 had a LRF rate of 7% at 10 years (not significantly decreased by systemic therapy). Retrospective review of 5 NSABP studies found that in pts treated with or without systemic therapy and without PMRT, those with T3N0 had a LRF rate of 7% at 10 years (not significantly decreased by systemic therapy). Similar review from combined data base of MGH, Yale, and MDACC showed a similar LRF rate of 7% (at 5 years) but showed that presence of LVSI significantly increased risk of LRF. Similar review from combined data base of MGH, Yale, and MDACC showed a similar LRF rate of 7% (at 5 years) but showed that presence of LVSI significantly increased risk of LRF.

16. Review of 5 NSABP Trials: T3N0 do not need PMRT JCO 24: 3927-32, 2006

17. The common group: 1-3 positive nodes

18. Randomized data: Canadian Trial, Just the 1-3 + node group Still see benefit in this group both in breast cancer specific and overall survival. Magnitude of benefit is slightly less than in the 4 or more node + group.

19. Retrospective reviews Review of 5 NSABP trials found a 19% LRF in pts 50 with 1-3 nodes had LRF rates of 3-12%. Review of 5 NSABP trials found a 19% LRF in pts 50 with 1-3 nodes had LRF rates of 3-12%. Analysis of large Canadian database examining pts with T1/2 tumors and 1-3 nodes showed 25% of nodes positive associated with increased risk of LRF. Analysis of large Canadian database examining pts with T1/2 tumors and 1-3 nodes showed 25% of nodes positive associated with increased risk of LRF.

20. Review of NSABP trials: T1- 3, N+ treated with chemo Concluded that the routine use of PMRT in this group is not warranted. JCO 22: 4247-4254, 2004

21. Canadian retrospective review of 1-3+ nodes: Risk classification IJROBP 61:1337-1347, 2005

22. Who needs PMRT in 2007? All women with > 3 positive nodes. All women with > 3 positive nodes. All women with any positive node and a tumor larger than 5 cm. All women with any positive node and a tumor larger than 5 cm. ? Women with positive margins: Only with other risk factors like size, age, or grade. ? Women with positive margins: Only with other risk factors like size, age, or grade. ? Women with T3N0: Probably not, especially in older women. ? Women with T3N0: Probably not, especially in older women. ? Women with 1-3 positive nodes and T1/T2: Definitely worth a discussion in young women (<50). ? Women with 1-3 positive nodes and T1/T2: Definitely worth a discussion in young women (<50).

23. Why has our thinking changed? Systemic therapy has improved; with this, improvements in local control may be more meaningful. Systemic therapy has improved; with this, improvements in local control may be more meaningful. The “paradigm” for breast cancer is again shifting to somewhere between Halsted and Fisher. The “paradigm” for breast cancer is again shifting to somewhere between Halsted and Fisher.

24. Impact of local control on systemic recurrence Long term follow of Canadian trial shows that there is a decrease in systemic recurrence in those patients receiving XRT. Long term follow of Canadian trial shows that there is a decrease in systemic recurrence in those patients receiving XRT. “Alternate hypothesis” may need to be modified where the impact of local control is emphasized. “Alternate hypothesis” may need to be modified where the impact of local control is emphasized.

25. Techniques for PMRT Toxicity of PMRT increases with inclusion of internal mammary nodes. Toxicity of PMRT increases with inclusion of internal mammary nodes. Comparison of various methods (standard tangents, reverse hockey stick, photon/electron mix, and partial wide tangents) for CW and IMN coverage showed no single best technique. Comparison of various methods (standard tangents, reverse hockey stick, photon/electron mix, and partial wide tangents) for CW and IMN coverage showed no single best technique. Partial wide tangents gave the best balance between target coverage and normal tissue sparing. (IJROBP 52:1220-30, 2002) Partial wide tangents gave the best balance between target coverage and normal tissue sparing. (IJROBP 52:1220-30, 2002)

26. Importance of 3D treatment planning 3D planning is critical in the sparing of normal tissues. 3D planning is critical in the sparing of normal tissues. Use of IMRT techniques are increasing; problems remain motion and dose to contralateral breast and lung. Use of IMRT techniques are increasing; problems remain motion and dose to contralateral breast and lung.

27. Toxicity of PMRT Lung: With addition of nodal fields, V 20Gy can increase to 30%. Lung: With addition of nodal fields, V 20Gy can increase to 30%. Arm: Incidence of lymphedema may increase to 20-30% with axillary field; risk increases with increased BMI. Arm: Incidence of lymphedema may increase to 20-30% with axillary field; risk increases with increased BMI. Heart: Some dose to the heart but clinical impact is small. Heart: Some dose to the heart but clinical impact is small.

28. Use of PMRT with reconstruction Any pt irradiated with implant reconstruction will not look as good as a pt who does not receive XRT. Any pt irradiated with implant reconstruction will not look as good as a pt who does not receive XRT. Autologous reconstruction appear to “tolerate” XRT better, with better cosmesis. Autologous reconstruction appear to “tolerate” XRT better, with better cosmesis. Less long term data on cosmetic results with newer methods of reconstruction, eg. DIEP flap. Less long term data on cosmetic results with newer methods of reconstruction, eg. DIEP flap.

29. PMRT with implant reconstruction MSKCC recently published their algorithm for PMRT with implant reconstruction. They recommend placement of permanent implant after expansion during chemotherapy and before start of XRT. MSKCC recently published their algorithm for PMRT with implant reconstruction. They recommend placement of permanent implant after expansion during chemotherapy and before start of XRT. Report that interval between end of chemo and start of XRT did not deleteriously impact outcomes. Report that interval between end of chemo and start of XRT did not deleteriously impact outcomes. Dosimetry studies around metallic ports of expander have shown no significant impact on dose or complications. Dosimetry studies around metallic ports of expander have shown no significant impact on dose or complications.