Postmastectomy Postmastectomy Radiation therapy Radiation therapy (PMRT): Who needs it (PMRT): Who needs it in 2008?in 2008?

Carol Marquez, M.D.Carol Marquez, M.D.Associate Professor, Associate Professor, Department of Radiation MedicineDepartment of Radiation MedicineOregon Health and Sciences Oregon Health and Sciences UniversityUniversity

Goals of discussionGoals of discussion

Present evolution of thought and Present evolution of thought and use of PMRT from the 1970’s to use of PMRT from the 1970’s to 1997.1997.

Discuss result of recent Discuss result of recent randomized trials.randomized trials.

Present recent retrospective Present recent retrospective analyses to determine patients at analyses to determine patients at greatest risk of recurrence.greatest risk of recurrence.

Discuss techniques for PMRT.Discuss techniques for PMRT.

What we did prior to What we did prior to the 1970’sthe 1970’s Many patients received PMRT after their Many patients received PMRT after their

surgery, RM or MRM.surgery, RM or MRM. NSABP B-02 randomized pts after RM to receive NSABP B-02 randomized pts after RM to receive

regional radiation. No difference in overall regional radiation. No difference in overall survival but decrease in regional recurrence. survival but decrease in regional recurrence.

Initiated in 1971, NSABP B-04 randomized pts Initiated in 1971, NSABP B-04 randomized pts after RM, TM, or TM + XRT if clinically node neg after RM, TM, or TM + XRT if clinically node neg and if node + to RM or TM +XRT.and if node + to RM or TM +XRT.

Ten year results showed no difference in Ten year results showed no difference in disease free or overall survival among the disease free or overall survival among the groups. Radiation arms did show decrease in groups. Radiation arms did show decrease in local recurrences. local recurrences.

What happened in the What happened in the 80’s?80’s? By the mid-80’s, the safety of regional nodal By the mid-80’s, the safety of regional nodal

irradiation was questioned with an excess of irradiation was questioned with an excess of cardiac mortality seen in patients followed cardiac mortality seen in patients followed for 10 years. for 10 years.

Meta-analysis of 7 randomized trials of PMRT Meta-analysis of 7 randomized trials of PMRT initiated before 1975 showed an increase in initiated before 1975 showed an increase in cardiac-related deaths in those receiving RT cardiac-related deaths in those receiving RT that was almost balanced by a reduction in that was almost balanced by a reduction in the deaths due to breast cancer. the deaths due to breast cancer.

The excess cardiac mortality was largely due The excess cardiac mortality was largely due to the increase in cardiac dose from radiation to the increase in cardiac dose from radiation to the internal mammary nodes.to the internal mammary nodes.

Paradigm shift to Paradigm shift to Alternate hypothesisAlternate hypothesis

Breast cancer is Breast cancer is both a local and both a local and systemic problem systemic problem at presentation.at presentation.

More extensive More extensive local treatment will local treatment will not improve not improve survival.survival.

Supported the trials Supported the trials examining less examining less extensive surgery.extensive surgery.

Who did we treat in Who did we treat in the 1990’s?the 1990’s? Because of the concern of late toxicity, the Because of the concern of late toxicity, the

indications for PMRT were greatly limited to indications for PMRT were greatly limited to include only those patients with more advanced include only those patients with more advanced disease: T3/4, more than 4 positive nodes.disease: T3/4, more than 4 positive nodes.

The rationale for choosing these patients is that The rationale for choosing these patients is that their risk for local recurrence was at least 30% their risk for local recurrence was at least 30% which radiation could reduce by at least half. which radiation could reduce by at least half. The goal of treatment was only to reduce local The goal of treatment was only to reduce local and regional recurrence and not to improve and regional recurrence and not to improve overall survival.overall survival.

The treatment volume typically included the The treatment volume typically included the chest wall, supraclavicular nodes, and axillary chest wall, supraclavicular nodes, and axillary nodes and much less often, the internal nodes and much less often, the internal mammary nodes. mammary nodes.

What did we learn in What did we learn in 1997?1997? Two articles published in the NEJM 10/97 Two articles published in the NEJM 10/97

showed improvement in survival with PMRT in showed improvement in survival with PMRT in premenopausal women, all of whom also premenopausal women, all of whom also received chemotherapy (CMF).received chemotherapy (CMF).

Patients enrolled in these trials included were Patients enrolled in these trials included were (generally) node + with the majority having (generally) node + with the majority having only 1-3 positive nodes and the majority only 1-3 positive nodes and the majority having tumors having tumors < < 5 cm in size.5 cm in size.

Fields treated included chest wall and Fields treated included chest wall and allall regional nodes (including internal mammary). regional nodes (including internal mammary).

Similar results seen in postmenopausal stage Similar results seen in postmenopausal stage II/III women treated with tamoxifen and XRT, II/III women treated with tamoxifen and XRT, improvement in DFS and overall survival.improvement in DFS and overall survival.

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

 

British Columbia British Columbia Randomized trial: 20 Randomized trial: 20 year resultsyear results

1. Breast Cancer Specific Survival

2. Overall Survival

1. 2.

Where did we go in Where did we go in 2000?2000? Many people began recommending Many people began recommending

treatment for any node positive patient treatment for any node positive patient following mastectomy.following mastectomy.

Intergroup study attempted to address Intergroup study attempted to address role of postmastectomy XRT in women role of postmastectomy XRT in women with 1-3 positive nodes but closed in with 1-3 positive nodes but closed in June 2003 secondary to lack of accrual. June 2003 secondary to lack of accrual.

Many discussions regarding the value of Many discussions regarding the value of treating clinically uninvolved nodes and treating clinically uninvolved nodes and how that may impact overall survival. how that may impact overall survival.

What is the downside What is the downside of PMRT?of PMRT? Greater risk for lymphedema of breast Greater risk for lymphedema of breast

and armand arm Increased amount of lung that is Increased amount of lung that is

fibrosed by radiation, primarily from fibrosed by radiation, primarily from treatment of either the supraclavicular treatment of either the supraclavicular nodes or internal mammary nodes.nodes or internal mammary nodes.

May expose contralateral breast to May expose contralateral breast to radiation.radiation.

Decrease in the quality of the cosmetic Decrease in the quality of the cosmetic outcome following reconstruction, outcome following reconstruction, especially with implants.especially with implants.

Who needs PMRT in Who needs PMRT in 2008?2008? All women with > 3 positive nodes.All women with > 3 positive nodes. All women with any positive node All women with any positive node

and a tumor larger than 5 cm.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 ? Women with 1-3 positive nodes

and T1/T2.and T1/T2.

When positive margins When positive margins are the only risk factorare the only risk factor Hard to demonstrate the value of Hard to demonstrate the value of

PMRT in patients where positive PMRT in patients where positive margins is the margins is the onlyonly risk factor for local risk factor for local recurrence; retrospective reviews have recurrence; retrospective reviews have found LRF rates of <15% without XRT.found LRF rates of <15% without XRT.

Retrospective multivariate analysis of Retrospective multivariate analysis of large group in Canada found a LRF large group in Canada found a LRF rate of >20% in those pts with positive rate of >20% in those pts with positive margins who also had T2 tumor, <51 margins who also had T2 tumor, <51 years old, grade 3, or LVSI.years old, grade 3, or LVSI.

Canadian retrospective Canadian retrospective review of + marginsreview of + margins Included T1-2, N0 Included T1-2, N0

patients with + patients with + margins; n=98.margins; n=98.

Admitted bias Admitted bias inherent in inherent in retrospective retrospective review.review.

Found longer time Found longer time to local relapse in to local relapse in those receiving XRT those receiving XRT (3 vs. 4 years). (3 vs. 4 years).

T3N0, Do they really T3N0, Do they really need it?need it? Retrospective review of 5 NSABP Retrospective review of 5 NSABP

studies found that in pts treated with studies found that in pts treated with or without systemic therapy and or without systemic therapy and without PMRT, those with T3N0 had a without PMRT, those with T3N0 had a LRF rate of 7% at 10 years (not LRF rate of 7% at 10 years (not significantly decreased by systemic significantly decreased by systemic therapy).therapy).

Similar review from combined data Similar review from combined data base of MGH, Yale, and MDACC base of MGH, Yale, and MDACC showed a similar LRF rate of 7% (at 5 showed a similar LRF rate of 7% (at 5 years) but showed that presence of years) but showed that presence of LVSI significantly increased risk of LRF. LVSI significantly increased risk of LRF.

Review of 5 NSABP Review of 5 NSABP Trials: T3N0 do not Trials: T3N0 do not need PMRTneed PMRT

JCO 24: 3927-32, 2006

The common group: 1-The common group: 1-3 positive nodes3 positive nodes

Randomized data: Randomized data: Canadian Trial, Just the Canadian Trial, Just the 1-3 + node group1-3 + node group

Still see benefit in Still see benefit in this group both in this group both in breast cancer breast cancer specific and specific and overall survival. overall survival.

Magnitude of Magnitude of benefit is slightly benefit is slightly less than in the 4 less than in the 4 or more node + or more node + group.group.

Retrospective reviewsRetrospective reviews

Review of 5 NSABP trials found a 19% Review of 5 NSABP trials found a 19% LRF in pts <50 yrs with T2 tumor with 1-LRF in pts <50 yrs with T2 tumor with 1-3 positive nodes; those >50 with 1-3 3 positive nodes; those >50 with 1-3 nodes had LRF rates of 3-12%.nodes had LRF rates of 3-12%.

Analysis of large Canadian database Analysis of large Canadian database examining pts with T1/2 tumors and 1-3 examining pts with T1/2 tumors and 1-3 nodes showed <45 years, ER-, medial nodes showed <45 years, ER-, medial tumor location, and >25% of nodes tumor location, and >25% of nodes positive associated with increased risk of positive associated with increased risk of LRF. LRF.

Review of NSABP trials: Review of NSABP trials: T1-3, N+ treated with T1-3, N+ treated with chemochemo

Concluded that the routine use of PMRT in this group is not warranted. JCO 22: 4247-4254, 2004

Canadian retrospective Canadian retrospective review of 1-3+ nodes: review of 1-3+ nodes: Risk classification Risk classification

IJROBP 61:1337-1347, 2005

Who needs PMRT in Who needs PMRT in 2007?2007? All women with > 3 positive nodes.All women with > 3 positive nodes. All women with any positive node and All women with any positive node and

a tumor larger than 5 cm.a tumor larger than 5 cm. ? Women with positive margins: ? Women with positive margins: Only Only

with other risk factors like size, age, or with other risk factors like size, age, or gradegrade..

? Women with T3N0: ? Women with T3N0: Probably not, Probably not, especially in older womenespecially in older women..

? Women with 1-3 positive nodes and ? Women with 1-3 positive nodes and T1/T2: T1/T2: Definitely worth a discussion in Definitely worth a discussion in young women (<50).young women (<50).

Why has our thinking Why has our thinking changed?changed? Systemic therapy has improved; Systemic therapy has improved;

with this, improvements in local with this, improvements in local control may be more meaningful.control may be more meaningful.

The “paradigm” for breast cancer The “paradigm” for breast cancer is again shifting to somewhere is again shifting to somewhere between Halsted and Fisher.between Halsted and Fisher.

Impact of local control Impact of local control on systemic on systemic recurrencerecurrence Long term follow of Long term follow of

Canadian trial shows Canadian trial shows that there is a that there is a decrease in systemic decrease in systemic recurrence in those recurrence in those patients receiving patients receiving XRT.XRT.

““Alternate Alternate hypothesis” may hypothesis” may need to be modified need to be modified where the impact of where the impact of local control is local control is emphasized.emphasized.

Techniques for PMRTTechniques for PMRT

Toxicity of PMRT increases with inclusion Toxicity of PMRT increases with inclusion of internal mammary nodes.of internal mammary nodes.

Comparison of various methods (standard Comparison of various methods (standard tangents, reverse hockey stick, tangents, reverse hockey stick, photon/electron mix, and partial wide photon/electron mix, and partial wide tangents) for CW and IMN coverage tangents) for CW and IMN coverage showed no single best technique.showed no single best technique.

Partial wide tangents gave the best Partial wide tangents gave the best balance between target coverage and balance between target coverage and normal tissue sparing. (IJROBP 52:1220-normal tissue sparing. (IJROBP 52:1220-30, 2002) 30, 2002)

Importance of 3D Importance of 3D treatment planningtreatment planning 3D planning is 3D planning is

critical in the critical in the sparing of normal sparing of normal tissues.tissues.

Use of IMRT Use of IMRT techniques are techniques are increasing; increasing; problems remain problems remain motion and dose to motion and dose to contralateral breast contralateral breast and lung.and lung.

Toxicity of PMRTToxicity of PMRT

Lung: With addition Lung: With addition of nodal fields, Vof nodal fields, V20Gy20Gy can increase to can increase to 30%.30%.

Arm: Incidence of Arm: Incidence of lymphedema may lymphedema may increase to 20-30% increase to 20-30% with axillary field; with axillary field; risk increases with risk increases with increased BMI.increased BMI.

Heart: Some dose to Heart: Some dose to the heart but clinical the heart but clinical impact is small.impact is small.

Use of PMRT with Use of PMRT with reconstructionreconstruction Any pt irradiated with implant Any pt irradiated with implant

reconstruction will not look as good as reconstruction will not look as good as a pt who does not receive XRT.a pt who does not receive XRT.

Autologous reconstruction appear to Autologous reconstruction appear to “tolerate” XRT better, with better “tolerate” XRT better, with better cosmesis.cosmesis.

Less long term data on cosmetic Less long term data on cosmetic results with newer methods of results with newer methods of reconstruction, eg. DIEP flap. reconstruction, eg. DIEP flap.

PMRT with implant PMRT with implant reconstructionreconstruction MSKCC recently published their algorithm MSKCC recently published their algorithm

for PMRT with implant reconstruction. for PMRT with implant reconstruction. They recommend placement of They recommend placement of permanent implant after expansion permanent implant after expansion during chemotherapy and before start of during chemotherapy and before start of XRT. XRT.

Report that interval between end of Report that interval between end of chemo and start of XRT did not chemo and start of XRT did not deleteriously impact outcomes. deleteriously impact outcomes.

Dosimetry studies around metallic ports Dosimetry studies around metallic ports of expander have shown no significant of expander have shown no significant impact on dose or complications.impact on dose or complications.