INVASIVE BREAST CANCER CURRENT ISSUES IN RADIATION

Transcription

1 INVASIVE BREAST CANCER CURRENT ISSUES IN RADIATION Bruce G. Haffty, MD Professor and Chairman Dept Radiation Oncology UMDNJ-RWJMS Cancer Institute of New Jersey

2 Mastectomy vs BCS +RT BCS Without Radiation Elderly patients Controversies and Special Circumstances Collagen Vascular Disease Risk Factors for IBTR: Margins,Age, Interactions BRCA1/2 and Breast Conserving Therapy Histological Subtypes, LCIS, Triple Negative Technical and Management Issues Sequencing Chemo-RT and Tamoxifen Fractionation Options Boost Regional Nodal RT IMRT Prone Breast

3 Randomized Trials: Mastectomy vs Breast Conserving Therapy Equivalent long term survival and DFS is evident from numerous randomized trials from the U.S.And Europe NSABP, NCI, Milan, Danish, Dutch, UK, others Outcome is similar for both node positive and node negative patients for tumor sizes up to 4-5 cm. Follow-up over 20 years in US, Milan trials

4 No. of patients Comparing CS+RT With Mastectomy For Early-Stage Breast Cancer (Prospective Randomized Trials) Institut Gustave -Roussy ( ) Milan ( ) NSABP B-06 ( ) NCI ( ) EORTC ( ) Danish ( ) Follow-up (yr) Overall survival CS+RT (%) Mastecto my (%) Local recurrence CS+RT (%) Mastecto my (%)

5 Local-Regional Relapse: MASTvs BCS Jatoi, Am J Clin Oncol, 2005

6 Is there a group where RT might not be needed?

7 Breast Conserving Surgery?with or without radiation Multiple randomized trials 3-fold reduction in local (inbreast)relapse Small but significant differences in disease free survival?small difference in survival

8 BCS with/without RT-Local Control Randomized Trials Author n Follow-up RT No RT Fisher B Years 12.4% 40.9% Liljegren Years 2.3% 18.4% Veronesi Years 5.8% 23.5% Clark Years 5.5% 25.7% Fisher B years 2.8% 16.5% Winzer years 3.2% 27.8%

9 BCS with/without RT Local Control Meta-analysis Vinh-Hung, JNCI 96:2004

10 BCS With/Without RT Survival Meta-Analysis Vinh-Hung, JNCI 96:2004)

11 EBCTCG-Meta-analysis-BCS+/- RT (EBCTCG, Lancet 366:17,2005) Local Relapse Node Negative Survival Node Negative Local Relapse Node Positive Survival Node Positive

12 EBCTCG-Meta-analysis

13 EBCTCG-Meta-analysis (EBCTCG, Lancet 366:17,2005) women in 78 Randomized Trials- RT vs No RT Comparisons involving <10% difference in LR had little impact on mortality Comparisons involving >10% difference in LR had substantial impact-5% absolute difference in mortality Over 15 years-avoidance of one breast cancer death for every 4 local relapse CHILE 2007

14 BCS without RT- Is it acceptable in Selected Cases?-Prospective data (Lim et al: Int J Rad Onc. 65:2006) Prospective Trial Patients with favorable histology 1 cm margins, No EIC, No LVI Pre-selected stopping boundry crossed 23% Local Relapse (19 patients) Conclude that even in this favorable subset, RT is indicated

15 Lumpectomy without RT in Older Patients Canadian study Local relapse 7.7% vs 0.6%, p =.001 Axillary relapse 2.5% vs 0.5%, p =.049 No difference in distant metastasis or survival Fyles AW, NEJM, 351:10, CALGB study Local relapse 4% vs 1% No difference in mastectomy rates, mets, survival Cosmesis poorer with RT Hughes K, NEJM, 351:10, 2004

16 CALGB/RTOG Update Hughes, Proc. San Antonio Meeting, 2006 Now with median F/U = 7.9 years LRR-3(1%) TamRT vs 23(7%) Tam, p<.001 Subsequent mastectomy 3 vs 9, p =.07 Breast Cancer Mortality 2% vs 2%, p =.92 All Cause Mortality 26% vs 27%, p =.84 CHILE 2007

17 BCS vs BCS+RT in Elderly Smith et al. JNCI: 98:2006 8,724 patients From the SEER- MEDICARE Database CALGB 9343 eligible Complete SEER-Medicare records Compared those who received CS alone to those who received CS+RT CHILE 2007

18 SEER-Medicare/ T1/N0/ Events by RT

19 Number NeededTreat( # pts w/rt to prevent 1 LR) Age with low comorbidity NNT Similar NNT (21) of antihypertensive medication (X-10 years) to prevent 1 coronary event Similar NNT for biphosphonates X 3 years to prevent 1 bone fracture Age 85 and older w/comorbidity NNT-125 CHILE 2007

20 Special circumstances: Contraindications to BCS+RT? BRCA1/BRCA2 carriers-no Collagen Vascular Disease-No Focally Involved margin-no Special Histology (Lobular, Medullary, rare subtypes)-no Advanced Disease-No-Neo-adjuvant Multiple Lesions-Selected cases OK? Prior Radiation-Selected cases OK?

21 Collagen Vascular Disease and Breast RT Initial anecdotal reports of poor cosmesis and complications were of concern Several case-control analysis, however failed to confirm these concerns with some minor exceptions Sceroderma subset of CVD patients, however, appear to have more problems

22 Study CVD Findings De Naeyer et al. Fleck et al. Robertson et al. Total No. No. with breast cancer Design 3 1 Case report 9 4 Case report 2 2 Case report Necrosis and progressive fibrosis Necrosis, brachial plexopathy, and severe moist desquamation Severe breast fibrosis, erythema, and pain Chen et al Case control Morris et al Retrospec tive Ross et al. 61? Case control Phan et al. 38? Case control Rakfal et al. 6 4 Case report Late complication rates higher only in scleroderma Increased radiation late effects appear in nonrheumatoid arthritis cases No differences in acute/chronic complications No difference was observed in the incidence of acute or late complications between the two groups. No severe acute or late radiation complications

23 Effect of Margins On Local Relapse Study # Pts Jobsen et al. Smitt et al. Vicini et al. Freedman et al. Neuschatz et al. Obedian and Haffty Peterson et al. F/U (Yrs) LR- Neg LR Close LR Pos % 12.2% % 16% 9% % 18-24% 30% % 14% 12% % 9% 17% % 2% 17% % 17% 11%

24 Margin Status Age and IBTR Jobsen, Int. J. Rad Onc. 57:2003

25 Local relapse in Conservatively Managed Breast Cancer-Margins, Systemic Therapy and Age Complex interactions of clinical, pathological and likely molecular variables Margins are a significant contributing factor Use of systemic therapy likely modifies the effect of margins (?Delays effect vs decreases effect) Evidence suggests that margins may be more critical in younger women

26 Margins and the conservative management of breast cancer Although wide margins are desirable, focally involved margins are not an absolute contraindication to breast conserving therapy Uncertainties in the available data necessitate the use of sound clinical judgment and common sense Review the pathology Talk to the surgeon

27 Young Age and IBTR Study Patient Age Younger Older P- # Cutoff IBTR IBTR Value Tenon % 10%.001 Curie % 15%.0001 JCRT % 10%.002 PENN % 12%.001 Beaumont % 7%.004 Yale % 12%.001

28 Young Age and Local relapse (BCT) These and other studies clearly demonstrate a strong correlation between young age and IBTR. Young age was also a significant predictor of IBTR in the EORTC boost vs no boost trial. The use of a boost was most beneficial in the younger patients.

29 BCT and BRCA1/2 Selected Studies Study #Pts. +DEL F/U IBTR Sporadic IBTR Genetic Rotterdam year 16% 30% MSKCC/ Montreal year 7% 13% MSKCC year 6.9% 22% Yale year 21% 46% Collaborative Group yrs 17% 24% Reduced by BSO

30 BCT and BRCA1/2 Ipsilateral Breast Events

31 Local (in breast) relapses in BRCA1/2 The majority of in-breast relapses in BRCA1/2 patients are new second tumors (not true relapses This observation is based on changes in histology and location of the second in breast event Examples: Medullary tumor recurring after 21 years in a different location from an infiltrating ductal primary DCIS occurring after 8 years from an infiltrating tubular primary

32 Ipsilateral and contralateral events in BRCA1 and BRCA2 Carriers None of our BRCA carriers were on adjuvant tamoxifen None of our BRCA carriers had prophylactic oophorectomy Both of these interventions have been shown in recent studies to lower the rate of second breast cancers

33 Reduction in 2nd primary breast tumors from Tamoxifen Data from Narod demonstrated a significant reduction in second breast tumors in BRCA carriers with Tamoxifen Odds ration of 0.38 for BRCA1 Odds ratio of 0.63 for BRCA2

34 Reductions in Breast Cancer Risk from Prophylactic Oophorectomy in BRCA Carriers Kauff :significant reduction in 2nd primary breast tumors by prophylactic oophorectomy 3 of 98 in prophylactic group compared to 8 of 72 in surveillance group Rebbeck demonstrated similar reductions in breast cancer risk with prophylactic oophorectomy Risk of breast cancer developing in prophylactic group was 21% compared to 42% in control group (hazard ratio of 0.47)

35 Risk of IBTR in BRCA Carriers-Effect of Prophylactic BSO and Tamoxifen Pierce et al. JCO, 24: BRCA1/2 (GC) compared to 445 sporadic controls (SC) Overall no significant difference in 15 year risk of IBTR (GC-24% vs SC-17%) GC who did not undergo BSO compared to SC: IBTR HR was 1.9, p =.03 GC who did undergo BSO risk of IBTR was similar to SC Tamoxifen was associated with a nonsignificant reduction in IBTR CHILE 2007

36 BRCA1/2 in CS+RT Late local relapses result in high local relapse rates if left unchecked Hormonal manipulation and/or oophorectomy appear to decrease this risk If CS+RT is chosen, prophylactic oophorectomy and hormonal therapy seems prudent No evidence of compromised normal tissue reactions with radiation CHILE 2007

37 Histological Subtypes: Lobular Invasive Lobular Similar overall prognosis as IDC Usually ER+ More commonly mammographically occult Despite presumed multifocality Not a contraindication to BCS Similar relapse rates as IDC, but some conflicting reports (Hussein, The Breast, 12:2002. Peiro, Br Can Res Trt, 59:2000.)

38 Lobular: Outcomes with BCS+RT MD Anderson Experience (Vo et al. Am J Surg,192:2006) 84 ILC compared to 1126 IDC No Difference in any endpoint Local Failure 3.5% ILC vs 8.3% IDC Overall failure 20% ILC vs 21% IDC Survival 81% ILC vs 85% IDC Contralateral events 11.9% ILC vs 11.3% IDC

39 Component of LCIS Local Relapse Rates Study # # IBTR IBTR P Ctrl LCIS Ctrl LCIS Yale % 7% Ns Harvard % 13% ns Michigan % 0% ns Beaumont % 14%.04 FoxChase % 15%.001

40 LCIS Alone Histological Subtypes LCIS Can be observed or treated with mastectomy Not treated with RT-However 25 Women with LCIS tx with BCS+RT Only 1 IBTR 17.6% Contralateral Breast Authors propose CS+RT as an alternative Cutuli, Eu J Can 41:2005

41 Histologic Subtypes Triple Negative-ER,PR,Her2/neu (Basal Type Cancers) Aggressive cancers-not responsive to hormonal agents or herceptin Mounting evidence that these tumors may be better treated with alternative chemotherapy agents (cis-platin, mitomycin, PARP inhibitors Common histology of patients with BRCA1 mutations Theoretically should be radiation sensitive CHILE 2007

42 Distant metastasis and local control Triple neg (n=117) vs Others (n=375) Haffty et al. J Clin Oncol, 24: CHILE 2007

43 Integrating systemic therapy and radiation in breast cancer In conservatively managed patients systemic therapy alone (without radiation) does not significantly improve local control NSABP-06 Lumpectomy Arm Results Local relapse 40% with Lumpectomy (Without RT) and CTX However, systemic therapy used in combination with RT following BCS, clearly impacts on local control

44 Systemic Tx-Effect on Local Control Selected Series of BCS+RT Study #pt F/U SysTx With Local Relapse SysTx Without SysTx NSABP CTX 2.6% 13%.001 P NSABP Tam 3.4% 10.3%.001 Buchholz CTX TAM Haffty CTX Van der Leest 758 (<40 yrs) TAM 4.4% 14.8%.004 6% 12% CTX 10% 22% <.001

45 Effect of CTX on Local Control Van der Leest, Cancer 109: 2007 CHILE 2007

46 Integrating systemic therapy and radiation in breast cancer These studies clearly indicate an impact of systemic therapy on local control in the conservative management of breast cancer However, how best to integrate systemic therapy and radiation remains controversial

47 Fig 2. Associations between delay in postoperative radiotherapy (RT) and local recurrence rates (LRRs) in studies of the sequencing of adjuvant RT and chemotherapy for breast cancer Huang, J. et al. J Clin Oncol; 21: Copyrigh t A m erican Society o f Clinical O ncolog y

48 Sequencing chemo-radiation in CS+RT These studies are in conflict with more recent evidence that shows no compromise in local control with chemo given first The randomized trial from Harvard sheds further light on this controversy, but questions remain regarding close or positive margins and the duration of chemotherapy

49 Sequencing chemo-rt in BCS 244 patients randomized to 12 weeks of CTX (CAMFP) before or after RT No overall differences in local control, distant metastasis or survival Interaction with margin status Negative marg-6% CTX first vs 13% RT first Close marg-32% CTX first vs 4% RT first Positive marg-23% CTX first vs 20% RT first Bellon et al, JCO 23:2005

50 Sequencing CTX-RT in CS+RT Data extracted from randomized trial of AC vs AC+T RT significantly delayed in AC+T arm by at least 84 days (4-21 day cycles of Taxol) No differences noted in toxicity No differences in local control Sartor, JCO 23:2005

51 Fig 2. Breast-conserving therapy with radiotherapy Sartor, C. I. et al. J Clin Oncol; 23: Copyrigh t A m erican Society o f Clinical O ncolog y

52 Sequencing CTX-RT In my view, the available evidence suggests no compromise in local control with reasonable delays in RT, provided CTX is given in an efficient, timely manner Questions remain regarding patients with close or positive margins Although concurrent chemo-rt has fallen out of favor, it might be considered for higher risk patients, preferably on prospective trials Challenge: Combining modern current agents with radiation and maintaining acceptable toxicity

53 Sequencing TAM and RT Theoretical compromise in local control if tamoxifen is given concurrently with radiation Cells put in resting state-less radiosensitive in laboratory settings Concurrent chemo and tamoxifen less effective than given sequentially No prospective or (until recently) retrospective data Trend has been to delay tamoxifen until after radiation has been administered

54 Sequencing Tamoxifen and RT J Clin Oncol: January 2005 Study # # IBTR IBTR Cosm/ Con Seq Con Seq Comp Yale % 7.5% NA Upenn % 4.8% No Diff SWOG % 14% No Diff

55 Sequencing TAM and RT Although retrospective, these 3 studies independently observed no difference in local control as a function of Tamoxifen Sequencing with RT A randomized trial, to investigate local control, cosmesis and complications has been suggested Worthy of investigation, but priority is in question

56 Post-Mastectomy RT Indicated Locally advanced regardless of nodal status (Even if CR or major response to Neoadjuvant chemo) Four or more nodes on dissection Possibly Indicated T1/T2 with 1-3 Nodes Strongly consider for +LVI, young age, close/positive margins, ECE, >20% nodes involved T3N0 Positive invasive margins Probably not Indicated T1/T2 Node Negative (or sentinel node with micrometastasis)

57 Co-Factors That Increase the LRR Risk for Patients with 1-3 +LN 10-yr LRR > 15% (1-3 +LN) LVSI younger age tumors >4 cm ECE over 2mm 3 +LN >20% +LN close margins Reference IBCSG NSABP MDACC MDACC NSABP MDACC MDACC CHILE 2007

58 Co-Factors That Increase the LRR Risk for Patients with 1-3 +LN 10-yr LRR > 15% (1-3 +LN) LVSI younger age tumors >4 cm ECE over 2mm 3 +LN >20% +LN close margins Reference IBCSG NSABP MDACC MDACC NSABP MDACC MDACC CHILE 2007

59 Fig 2. Unsupervised two-dimensional cluster analysis of 258 genes in 62 patients revealed two distinct groups of tumors; their locoregional recurrence rates were 41.4% (12 of 29) compared with 18.2% (six of 33) Cheng, S. H. et al. J Clin Oncol; 24: Copyrigh t A m erican Society o f Clinical O ncolog y

60 Genetic Profiling-PMRT Cheng SH et al. JCO 24:4594, 2006 Genomic profiling/258 and 34 gene profile 94 patients post-mastectomy (No RT) 67 without LRR 27 with LRR Predictive index <0.8 or > 0.8 Local-regional control 91% vs 40%

61 Genomic Predictors of LRR Category/ Genomic Score Node neg >0.8 < N >0.8 <0.8 >=4 + N >0.8 <0.8 Cheng SH et al. JCO 24:4594, 2006 # Patients/ # LRR 3 Year LRC Probability 24/1 96% 3/2 33% 34/1 100% 19/12 47% 4/1 75% 10/10 0%

62 Fig 3. Kaplan-Meier survival estimates for locoregional control in validation data set by (A) 258-gene and (B) 34-gene prediction tree models Cheng, S. H. et al. J Clin Oncol; 24: Copyrigh t A m erican Society o f Clinical O ncolog y

63 Technical Issues in RT Management Early Stage Breast Cancer Fractionation Schemes Boost Strategies Management of the Regional Lymphatics IMRT Prone Breast RT Partial Breast RT

64 Randomized Fractionation Trials Study Scheme # Patients Local Relapse Whelan 50 Gy/ % OCOG 42.5 Gy/ % Owen 50 Gy/ % ICR/UK 43 Gy/ % 39 Gy/ % Baillet 45 Gy/ Paris, Fr. 23 Gy/ UK START B 40 Gy/ Gy/25 UK FAST 30 Gy/ Gy/5 50 Gy/25

65 Fractionation in BCS+RT Although Gy/Day to Gy remains standard, randomized evidence supports other approaches Accelerated whole breast RT has been widely adopted in Canada and Europe Option for women with difficulty traveling or schedule conflicts Longer follow-up and additional data are awaited.

66 Randomized Boost Trials Study Scheme # Pts LR F/U (yrs) EORTC Bartelink UPDATE JCO 50 Gy/ Gy/ Lyon,Fr 50 Gy/ Romestaing + 10Gy/ Nice, Fr 50 Gy/ Teissier +10 Gy/ Budapest Polgar 50 Gy/ /

67 EORTC-Boost vs No Boost Bartelink, NEJM 345:19:2001

68 EORTC-Boost Trial Age Dependent Benefit of Boost Update 2007 Benefit to Boost in All Age groups <= % vs 13.5% % vs 8.7% % vs 4.9% >= % vs 3.8% Bartelink JCO: 25: 2007 CHILE 2007

69 Use of a Boost in CS+RT Benefit has been clearly demonstrated in randomized trials, but the absolute benefit is small in some patients I routinely boost the vast majority of patients, but acknowledge a relatively small benefit (but small risk) in older women with clear margins I also routinely boost DCIS

70 Standard Tangents w/heart Block Consider in Left-Sided, Tx w/adria/herceptin other cardiotoxic regimens CHILE 2007

71 Regional Nodal Irradiation in BCS+RT No clear consensus Potential Benefits Improved regional control Improved DFS or OS, extrapolating from post-mastectomy studies Potential Risks Added toxicity Added complexity and costs

72 Regional Nodal RT in BCS EORTC Ongoing Trials Node positive or any medial/central Randomized to Breast Only vs Breast +Upper IM, Medial Supraclav NCIC MA.20 Node positive and high risk node negative Randomized to Breast only vs Breast plus supraclav, high axilla and upper IM

73 Regional Nodal RT-My Practice Node negative by dissection (>6 Nodes), or Sentinel Node Negative Breast only Node positive by dissection Breast + SC +/- IM Node positive by Sentinel Node Breast + SC if dissected Breast + SC + Axilla if no dissection +/- IM Selected cases consider high tangents Node unknown-no dissection Breast + SC + Axilla +/- IM Selected cases consider high tangents

74 Mono-isocentric 3 Field Breast Technique

75 CHILE 2007

76 High Tangents Schlembach, Int J Rad Onc: 51:2001 Cranial Edge 2cm below humeral head Deep edge 2cm lung from chestwall interface Covers 80% of Level I/II Nodes

77 Axillary Treatment with CS High tangents may provide more adequate coverage For those without dissection at high risk my own bias is to use a third field treating the SC and Axilla, with CT planning to document coverage Numerous studies demonstrate adequate axillary control rates with XRT without Surgery

78 Axillary Dissection vs Radiation Louis-Sylvestre J Clin Oncol 22: 2004 Randomized Trial-658 Clinically Node Negative Randomized to AXD vs AXRT No Difference in DFS or OS Axillary Control at 15 years favored AXD (1% vs 3%, p =.04) CHILE 2007

79 Regional Nodal Irradiation Sentinel Node Postive-MDACC 196 Patients SLN+ NO Dissection 60% Received RT No Axillary Relapses Hwang et al. Cancer 110:2007 Authors suggest that RT to may be alternative to completion AXD CHILE 2007

80 Axillary radiation in lieu of surgery for SN Positive Patients Sentinel Node Positive-Current standard is to proceed with nodal dissection Available data suggests axillary radiation may be adequate in this setting Retrospective data is evolving Studies to address this are under way- EORTC-AMAROS Trial AMAROS TRIAL Sentinel Node Positive Patients Randomized to AXD vs AXRT

81 Internal Mammary Treatment Remains Controversial Study IM Survival Survival P Note Tx W/IM WO/IM Meier Surg Randomized Lacour Surg 56% 53%.40 Randomized Fowble RT 80% 81%.87 Retrospective All BCS +RT Obedian RT 72% 84%.63 Retrospective All BCS +RT Stemmer RT 78% 64%.08 RT not given NO IM group: Technical Problems

82 IMRT for Early Breast Role of IMRT in early breast cancer and the associated technology is rapidly evolving Numerous techniques have been reported Can be performed in standard time slots Improved dose homogeneity is evident Potential advantage in large breasts and other selected patients Clinical outcomes data, cost/benefit, optimal technique and patient selection await further studies

83 Dose Homogeneity with IMRT Uncompensated IMRT Vicini, Int J Rad Onc, 54: 5, 2002

84 Dose Homogeneity Open vs Wedge vs Electronic Compensator OPEN FIELD WEDGED E-COMP HOT SPOT HOT SPOT CHILE 2007

85 IMRT for Breast Is it beneficial in all settings? What is the Cost vs Benefit? What is considered IMRT? Is inverse planning required? Are standard tangents with electronic compensation/field within field IMRT? Is there a minimum number of fields required? What are the issues regarding gating/breath holding techniques? What is the threshold/criteria for an IMRT charge ($$$) code?

86 IMRT-ASTRO Plenary Session Randomized Trial: IMRT vs Standard Wedges-358 Patients IMRT improved homogeneity (p <.0001) Decrease in Moist Desquamation w/ IMRT (31% vs 48%, p=.0019) Pignot et al. ASTRO, 2006 CHILE 2007

87 Prone Breast RT Clinical Data and Techniques are evolving Check out Current ASTRO Presentations May be advantageous for large pendulous breasts receiving whole breast RT Role in Partial Breast External Beam promising (Formenti et al, Int J Rad Onc, 60: ,2004)

88 Prone Breast RT

89 Prone Breast RT Goodman, Int J Rad Onc: 60: 2004

90 Prone Breast RT-MSKCC 245 Pts, Median F/U = 4.9 years Local Relapse 6.1% Stegman IJROBP, 68: 2007 Treatment breaks-2% Grade III dermatitis 2% Grade III fibrosis 2.4% Preferred treatment for breast only at MSKCC CHILE 2007

91 Early Breast Questions for the future APBI Fractionation Subsets for withholding RT Role of regional nodal irradiation Axillary RT vs AXD Concurrent chemoradiation Risk factors and contraindications Randomized Trials UK Start/Others CALGB/Canadian/ ECOG DCIS Others EORTC/NCIC and other studies EORTC-AMAROS Novel prospective trials Pathologic profiling genetic/molecular

92 Thank You Congreso de la Sociedad Chilena de Mastologia Bruce G. Haffty, MD CHILE 2007