# Radiation Oncology/Breast/Post mastectomy

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* NSABP trials
Postmastectomy Radiation Therapy

## Official guidelines

* Please see the Breast Guidelines page

## Patterns of failure

* With chemotherapy - LR for 4 or more positive LN: about 15-36%. LR for T3 tumor: about 20-30%. (multiple papers)
* Postmastectomy RT reduces LR recurrence in high-risk group to about 5-10%.

### Overall

* Florence, 2007 (1971-2003) PMID 17368813 -- "Loco-regional recurrence in 2064 patients with breast cancer treated with mastectomy without adjuvant radiotherapy." (Livi L, Eur J Surg Oncol. 2007 Mar 15)
** Retrospective. 2064 patients treated with mastectomy, without adjuvant RT
** Loco-regional failure: 18%; only prognostic factor tumor size, not number of LN+
** Conclusion: Number of LN+ not enough to justify adjuvant RT
* MDACC, 2005 - PMID 16169678 — "Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy." Strom EA et al. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1508-13.
** Retrospective. 1031 patients treated with mastectomy + ALND and doxorubicin-based chemo. No RT. On 5 clinical trials. Median axillary LN dissected 17, but no cN2 disease. Median F/U 9.7 years
** 10-year regional recurrence: axilla 3%, supraclav 8%
** Predictors for SCV failure: >=4 LN+, >20% LN+, gross LN ECE
** Conclusion: RT to axilla not necessary if ALND; RT to SCV if one of the risk factors
* NSABP pooled analysis, 2004 - PMID 15452182 — "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. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27.
** Included pts from B-15, B-16, B-18, B-22, and B-25. 90% had doxorubicin-based chemo.
** At 10 yrs, 12.2% had isolated LRF, 19.8% had LRF with or without DF, and 43.3% had DF alone as a first event.
** LRF (+/- DM) as a first event was 13% for 1-3 LN, 24.4% for 4-9 LN, and 31.9% for 10 or more LN. For tumor < 2 cm 14.9%, 2-5 cm 21.3%, and >5 cm 24.6%.
** Conclusion: recommend post-mastectomy XRT for large tumors and 4 or more LN.
* MDACC (1975-1994)
** Retrospective analysis of 1031 pts enrolled on prospective clinical trials. Pts treated with mastectomy, chemotherapy w/o tamoxifen, and without RT. Stage II-IIIA.
** 2001 PMID 11395242 -- "The influence of pathologic tumor characteristics on locoregional recurrence rates following mastectomy." (Katz A, Int J Radiat Oncol Biol Phys. 2001 Jul 1;50(3):735-42.)
*** Analysis of factors other than size and lymph node status that predict for increased risk of LRR. Multicentric disease defined as 2 or more separate areas of invasive carcinoma in more than one quadrant of the breast and separated by at least 4 cm. Multifocal disease defined as 2 or more areas within the same quadrant and/or separated by less than 4 cm.
*** Multicentric / Multifocal disease: pts with gross multicentric disease (clinically apparent, or seen on gross pathologic examination): LRR 37% vs 17% at 10 yrs. Pts with multifocal disease and those with microscopic multicentric disease did not have higher rates of LRR than those with unifocal disease.
*** LVSI: increased LRR 25% at 10 yrs.
*** Margins: positive or close (< 5 mm) margins, LRR 45%
*** Conclusion: Close or positive surgical margins, pectoral fascia involvement, clinical or gross multicentric disease, LVSI, and invasion of the skin or nipple predict for an increased risk of LRR in patients treated without RT.
** 2000 PMID 10920129 -- "Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation." (Katz A, J Clin Oncol. 2000 Aug;18(15):2817-27.)
*** 10-yr rate of isolated LRR 4% (0 LN), 10% (1-3 LN), 21% (4-9), and 22% (10 or more). T-stage, tumor size, and >= 2 mm extranodal extension predicted for LRR.
*** For pts with T1-T2 and 1-3 LN: pts with <10 nodes examined, LRR 24% vs 11%. Tumor size > 4cm or extranodal extension, LRR > 20%.
*** Conclusion: For pts with tumors >= 4 cm or >= 4 involved nodes, LRR is > 20% and pts should be offered RT. Additionally, pts with 1-3 LN and large tumors, extranodal extension, or inadequate axillary dissection may benefit from RT.
* ECOG
** 1999 (1978-87) PMID 10561205 -- "Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group." (Recht A, J Clin Oncol. 1999 Jun;17(6):1689-700.)
*** 2016 pts on 4 ECOG trials (E5177, E6177, E4181, E5181). Pts N+ and had mastectomy and chemo +/- hormones but without RT.
*** 10-yr risk of LRF (with or without DF) was 12.9% (1-3 LN) and 28.7% (4 or more). Tumor size, number of involved LNs, ER-, and decreasing number of nodes examined were significant for increased risk of LRF. Pt age and menopausal status were not significant.
*** Note: tables in paper give risk of isolated LRF, LRF, or DF only for each TNM category as well as by tumor size in cm and number of involved nodes.
*** Conclusion: LRF is a substantial problem for node-positive pts treated with mastectomy + chemohormonal therapy
** 1988 (1978-82): PMID 3292711 — "Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy." (Fowble B, J Clin Oncol. 1988 Jul;6(7):1107-17.)
*** 627 pts on ECOG trials (E5177, E6177). 225 pts had relapse at 3 yrs. In 31% of failures (11% of pts) the relapse was LR without DM. Pts with 4 or more positive LN or tumor size 5 cm or more are more likely to have a local failure.

### Node positive (1-3 LN+)

* BIG 02-98 Trial
** 2018 PMID 29534902 -- "Postmastectomy Radiation Therapy in Women with T1-T2 Tumors and 1 to 3 Positive Lymph Nodes: Analysis of the Breast International Group 02-98 Trial." (Zeidan YH, Int J Radiat Oncol Biol Phys. 2018 Jun 1; 101(2):316-324. doi: 10.1016/j.ijrobp.2018.01.105. Epub 2018 Feb 6.)
*** Retrospective analysis of chemotherapy trial (doxorubicin + docetaxel vs cyclophosphamide). PMRT given at discretion. 684 patients, T1-T2 and pN1, with axillary nodal dissection. PMRT in 49%
*** Outcome: 10-year LRR PMRT- 6.5% vs PMRT+ 2.5% (SS). Better LRR in non-taxane group (9.1% vs 3.4%, SS). No difference in BCSS (84%) or OS (~80%)
*** Conclusion: Excellent outcomes; PMRT improves LRR but events low compared to historical studies
* Taiwan, 2002 (1991-98) - PMID 11958892 — "Locoregional failure of postmastectomy patients with 1-3 positive axillary lymph nodes without adjuvant radiotherapy." Cheng JC et al. Int J Radiat Oncol Biol Phys. 2002 Mar 15;52(4):980-8.
* British Columbia, 2005 (1989-97) - PMID 15817335 — "Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy." Truong PT et al. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1337-47.
** 821 pts, pT1-2 with 1-3 LN positive, without RT. Systemic therapy in 94%.
** median f/u 7.7 yrs. 10-yr isolated LRR 12.7% and LRR with or without simultaneous distant recurrence 15.9%. Risk of >20% LRR for pts with 1-3 LN+ and one of the following: age < 45, ER negative, medial location, >25% nodes positive.

### Node negative

* Data from EBCTCG (PMID 16360786) shows 5-year LR rate of 6% after mastectomy and axillary clearance (systemic therapy unspecified)
* Similarly, data from NSABP (PMID 16921044) shows 10-year LR rate of 7% after mastectomy and axillary clearance (systemic therapy in 75%)
* Data from the Danish trials (PMID 9395428, PMID 10335782) showed LRF rate of 17% and 23% respectively in patients not receiving PMRT. Because this figure is much higher than the EBCTCG and NSABP data, and because the LN axillary dissection is considered suboptimal, it is possible that some of these T3N0 patients were occult N+ (PMID 16921044)
* Based on EBCTCG results, RT decreases the 6% LR rate to 2%, for an absolute 4% gain in local control. There is no impact on 15-year BCA mortality, but there is an overall survival decrement associated with RT.
* Patients with T3N0 disease have historically (PMID 15667954) been treated with PMRT, but data now suggests that large tumors as a sole criterion probably do not require PMRT. LVI+ status however is an independent prognostic factor for LRF
* Conversely, patients with T1-2N0 disease have not historically been treated with PMRT, but combination of some factors (young age, LVI+, tumors >2cm, and close margins) may increase LRF risk to 20-40%
* A meta-analysis from UK suggests that patients with two or more risk factors (LVI, Grade 3, T2+, close SM, or age <50/premenopausal) should be treated with PMRT, since their LRR risk is >= 15%
Any T N0
* NHS Trust, UK; 2009 PMID 18996609 -- "Radiotherapy to the chest wall following mastectomy for node-negative breast cancer: A systematic review." (Rowell NP, Radiother Oncol. 2009 Apr;91(1):23-32. Epub 2008 Nov 7.)
** Meta-analysis.
** Predictive factors for LRR: LVI, Grade 3, T2+, close SM, age <50/premenopausal
** Local recurrence rate: no risk factors 5%, one risk factor ~10%, 2+ risk factors >=15%
** Conclusion: Use of PMRT in N0 women requires re-evaluation; RT should be considered for those with 2+ factors
T1-2N0
* Ankara, 2007 (Turkey) PMID 17398017 -- "Can a subgroup of node-negative breast carcinoma patients with T1-2 tumor who may benefit from postmastectomy radiotherapy be identified?" (Yildirim E, Int J Radiat Oncol Biol Phys. 2007 Mar 28; [Epub ahead of print])
** Retrospective. 502 patients. T1-2 tumors, N0. Median F/U 6.4 years
** Recurrence: local 3%, distant 11%
** Local recurrence predictors: if <=40 years - LVI+ HR 9.0, tumor size (>2cm) HR 5.4; if >40 - LVI+ HR 18.0, tumor size (>3cm) HR 8.6, grade HR 7.0
** Distant recurrence predictors: tumor size, grade, ER status, her2 status
** Conclusion: Consider RT for N0 patients if <40 and large tumors or LVI+, or if >40 and large tumors or high grade
* Mass General, 2005 (1980-2000) PMID 15990006 - Jagsi R et al. "Locoregional recurrence rates and prognostic factors for failure in node-negative patients treated with mastectomy: Implications for postmastectomy radiation." Int J Radiat Oncol Biol Phys. 2005 Jul 15;62(4):1035-9.
** Retrospective. 877 patients. Node negative, mastectomy, no RT. Median F/U 8.3 years
** Locoregional recurrence: 6% as first event; chest wall 80%
** Independent risk factors: Size > 2 cm, margin less than 2 mm, premenopausal status, and lymphovascular invasion (LVI)
** Recurrence stratified: no RFs 1%, 1 RF 10%, 2 RFs 18%, 3 RFs 41%
** Conclusion: treating chest wall in patients with multiple RFs reasonable
** 2011 Update (1980-2004) PMID 21420245 - Abi-Raad R et al. "Patterns and risk factors of locoregional recurrence in T1-T2 node negative breast cancer patients treated with mastectomy: implications for postmastectomy radiotherapy." Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):e151-7.
*** 1136 pts. Median F/U 9 years. Risk factors: size, close margins, age < 50, LVSI, no systemic therapy. 10-yr LRR with 3 or more risk factors: 19.7%.
* British Columbia, 2005 (1989-99) PMID 15850919 -- "Patient subsets with T1-T2, node-negative breast cancer at high locoregional recurrence risk after mastectomy." (Truong PT, Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):175-82.)
** 1505 pts with pT1-T2 N0 breast cancer, negative margins, s/p mastectomy without RT.
** Median f/u 7.0 yrs. 10-yr total LRR 7.8%. LRR risk of approximately 20% in pts with grade 3 disease and +LVI or with grade 3, T2 tumor, with no systemic therapy.
** Conclusion: "Women with pT1-T2N0 breast cancer experienced a LRR risk of approximately 20% in the presence of Grade 3 disease with LVI or Grade 3 disease, T2 tumors, and no systemic therapy. These subsets of node-negative patients warrant consideration of for postmastectomy radiotherapy."
* British Columbia & Mass General, 2014; Biologic subtype (1998-9) PMID 24161421 -- "Is Biological Subtype Prognostic of Locoregional Recurrence Risk in Women With pT1-2N0 Breast Cancer Treated With Mastectomy?" (Truong PT, Int J Radiat Oncol Biol Phys. 2014 Jan 1;88(1):57-64.)
** 1994 pts (1582 from BC and 412 from MGH) treated with MRM without RT. All had subtyping based on ER/PR/Her2 and grade. 5 subtypes defined as: 1) luminal A (ER or PR+, HER2-, grade 1-2), luminal B (ER/PR+, HER-, gr 3), luminal HER 2 (ER/PR+, HER2+), HER2 (ER/PR-, HER2+), triple negative TNBC (ER-, PR-, HER2-).
** 60.3% were luminal A, 14.7% luminal B, 11.1% LumHER2, 5.3% HER2, 8.6% TNBC. Median f/u 4.3 yr. 5-yr LRR: no significant difference by subtype -- 1.8% lumA, 3.1% lumB, 1.7% lumHER2, 1.9% HER2, and 1.9% TNBC. 5-yr DR highest in TNBC 9.6%; 5% lumB, 2.4% lumHER2, 1.8% lmA, 1.1% HER2. On MVA, factors predictive of higher LRR: tumors > 2cm, lobular histology, close/positive margins.
** Conclusion: The 5-year risk of LRR in our pT1-2N0 cohort treated with mastectomy was generally low, with no significant differences observed between approximated subtypes.
T3N0
* Emory University, 2017 (2003-2011) PMID 28387923 -- "The role of postmastectomy radiotherapy in women with pathologic T3N0M0 breast cancer." (Cassidy RJ, Cancer. 2017 Aug 1;123(15):2829-2839. doi: 10.1002/cncr.30675. Epub 2017 Apr 7.)
** Retrospective NCDB data. 3437 patients, PMRT in 48% (chest wall alone 67%, chest wall and regional lymph nodes 33%). PMRT more likely if age <40, tumor >=7 cm, and chemotherapy or endocrine therapy
** Outcome: 5-year OS PMRT+ 86% vs PMRT- 66% (SS). No benefit to regional lymph node radiation on OS
** Conclusion: PMRT is associated with improved overall survival, regardless of SM status, tumor size, or systemic therapy
* University of Utah; 2017 (2004-2012) PMID 28193571 -- "Outcomes and utilization of postmastectomy radiotherapy for T3N0 breast cancers." (Francis SR, Breast. 2017 Apr;32:156-161. doi: 10.1016/j.breast.2017.02.001. Epub 2017 Feb 10.)
** Retrospective NCDB analysis. 4291 patients, no neoadjuvant chemotherapy. PMRT given in 47%
** Outcome: Improved overall survival if PMRT given (HR 0.7, SS), if chemotherapy given (HR 0.51, SS), and if endocrine therapy given (HR 0.63, SS). Propensity matched cohort of 2800 patients analyzed. 5-year OS PMRT+ 84% vs PMRT- 80% (SS); 10-year OS 67% vs 59%
** Conclusion: PMRT was associated with improved survival in pT3N0 breast cancer
* NSABP, 2006 PMID 16921044 -- "Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials." (Taghian AG, J Clin Oncol. 2006 Aug 20;24(24):3927-32.)
** Retrospective. 313 patients with tumors >=5cm. NSABP B13, B14, B19, B20, B23 treated with MRM, no RT, no systemic therapy 25%. Median F/U 15 years
** 10-year outcome: isolated LRF 7%, LRF+DM 3%, DM 24%. Majority on chest wall 86%. If 1-5 LN removed, isolated LRF 17%
** By systemic treatment: none 13% vs. chemo alone 6% vs. TAM alone 5% vs. chemo+TAM 5% (NS).
** No multivariate predictors for LRF
** Conclusion: If LN- and T3 tumors at MRM, LRF as first event remains low and PMRT should not be routinely used for these patients
* MGH/MDACC/Yale, 2006 (1981-2002) PMID 16887288 -- "Low local recurrence rate without postmastectomy radiation in node-negative breast cancer patients with tumors 5 cm and larger." (Floyd SR, Int J Radiat Oncol Biol Phys. 2006 Oct 1;66(2):358-64.)
** Retrospective. 70 patients with tumor size >=5cm and N0, treated with mastectomy + systemic chemo, but no RT. Three institutions. Median F/U 7 years
** 5-year LRF: 8%; 4/5 in chest wall. DFS 83%, OS 86%
** LVI+ significantly associated with LRF (21% vs. 4%), DFS, and OS
** Conclusion: Large tumors alone may not need RT after mastectomy/chemo. But, LVI+ highly correlated with poor outcome

### HER2+

* HERA HER2+ Trial; 2020 PMID 31654782 -- "Post-Mastectomy Radiation Therapy in Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer Patients: Analysis of the HERA Trial" (Jaoude JA, Int J Radiat Oncol Biol Phys. 2020 Mar 1;106(3):503-510. doi: 10.1016/j.ijrobp.2019.10.022. Epub 2019 Oct 22.)
** Post-hoc analysis. 1633 patients. Enrolled in HERA trial, mastectomy, adjuvant chemotherapy, adjuvant maintenance trastuzumab. PRMT (58%) vs no PMRT (42%). PMRT 50 Gy in 25 fractions, volumes and boosts at discretion. Median F/U 11 years
** Outcome: For N0 patients (PMRT n=98 vs no PMRT n=390): LRR ~95% both arms (NS). For N1 patients: LRR PMRT 97% vs no PMRT 90% (p=0.004). For ER+ 97% vs 89% (SS), for ER- 97% vs 91% (NS). OS 87% vs 82% (p=0.06)
** Conclusion: PMRT decreases LRR for HER2+ with pN1 disease, though benefit smaller than historically.

### Positive Margins

* Harvard, 2012 (1998-2005) PMID 22543200 -- "Surgical margins and the risk of local-regional recurrence after mastectomy without radiation therapy." (Childs SK, Int J Radiat Oncol Biol Phys. 2012 Dec 1;84(5):1133-8.)
** Retrospective. 397 pts treated with MRM and no RT.
*** superficial margin: positive in 41 pts (10%) and close margin (<2 mm) in 56 (14%).
*** deep margin: positive in 23 (6%) and close in 34 (9%).
** Median f/u 6.7 yr.
** Margin status associated with time to isolated LRR. Positive margins: 5-yr LRR of 6.2%. Close margins: 1.5%. Negative margins: 1.9%.
** Conclusion: "Patients with positive mastectomy margins had a significantly higher rate of LRR than those with a close or negative margin. However, the absolute risk of LRR in patients with a positive surgical margin in this series was low, and therefore the benefit of postmastectomy radiation in this population with otherwise favorable features is likely to be small."
* Fox Chase, 1998 (1984-93) PMID 9635708 -- "A close or positive margin after mastectomy is not an indication for chest wall irradiation except in women aged fifty or younger." (Freedman GM, Int J Radiat Oncol Biol Phys. 1998 Jun 1;41(3):599-605.)
** Retrospective. 34 pts treated with MRM, tumor < 5 cm, 0-3 LN, margins < 1 cm, and no postoperative RT.
** 5 chest wall recurrences (1 isolated, 1 with axillary recurrence, 3 with distant mets). Chest wall recurrence rate 9% 5-yr and 18% 8-yr. For patient age ≤50, 28% vs 0% for age > 50.
** The subgroup of patients age 50 or younger with T1-T2 tumor size and 0-3 positive nodes with a close (<5mm) or positive margin are at high risk (28%) for chest wall recurrence and should receive chest wall irradiation.

### Dermal Lymphatic Invasion

* Fox Chase; 2009 PMID 19194121 -- "Dermal lymphatic invasion and inflammatory breast cancer are independent predictors of outcome after postmastectomy radiation." (Abramowitz MC, Am J Clin Oncol. 2009 Feb;32(1):30-3.)
** Retrospective. 70 patients, either inflammatory breast cancer alone (n=31), or dermal lymphatic invasion alone (n=21), or both dermal lymphatic invasion and inflammatory breast cancer (n=18). All treated with postmastectomy radiation.
** Outcome: LRR for DLI 10%, IBC 8%. DM 45%, 44%. Dead of disease 50%, 48%. DLI only independent predictor for LRR (HR 4.8, SS). IBC, >=4 involved lymph nodes predicted for DM and OS
** Conclusion: Dermal lymphatic involvement and inflammatory breast cancer independent predictors of poor outcome. DLI associated with increased LRR, IBC with DM and OS

## Predictive models

* Taiwan, 2006 - PMID 16472935, 2006 — "Prognostic index score and clinical prediction model of local regional recurrence after mastectomy in breast cancer patients." Cheng SH et al. Int J Radiat Oncol Biol Phys. 2006 Apr 1;64(5):1401-1409.
** Divided pts into low, intermediate, and high-risk groups based on nodal status, ER status, LVI, and age.
** Score: 1 pt for age (<=40), ER (negative), and LVI (prominent vs absent or focal). For nodes, score 1 pt for 1-3 LN+, 2 pt for 4-9, and 3 pt for 10 or more.
*** Low risk = score 0-1. Intermediate risk = 2-3. High risk = 4-6.
** In low risk group, no influence of PMRT on LRR or survival. For intermediate risk, PMRT involves LRC but not metastasis-free or overall survival. For high risk, PMRT improves LRC, DFS, and OS.
* IBCSG, 2003 PMID 12663706 -- "Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII." (Wallgren A, J Clin Oncol. 2003 Apr 1;21(7):1205-13.)
** Retrospective. 5352 women treated with MRM without RT on seven protocols (1275 N0, 4077 N+). Median F/U 12-15.5
** N0 risk factors: premenopausal: LVI+, >=T2; postmenopausal: LVI+
*** 10-year high risk recurrence rate: premenopausal 16%, postmenopausal 19%
** N+ risk factors: premenopausal: number of nodes, grade, LVI+; postmenopausal - number of nodes, grade, size
*** 10-year high risk recurrence rate: premenopausal 35%, postmenopausal 34%
** Conclusion: Locoregional failure significant problem, even for some N0 patients

## PMRT Target

* Traditionally includes chest wall, supraclavicular/axillary nodes, +/- IMN
* Information may be gleamed from:
** EORTC 22922/10925 (for intact breast) - randomizes RT to SCLV + IMN only
*** See details at: #Internal mammary irradiation
** SUPREMO - randomizes RT to chest wall only (no nodes)
*** See details at: #Mastectomy +/- RT

## Historical use of post-op RT

* Adair (1943) - No PMID — "The role of surgery and irradiation in cancer of the breast." Adair FE. JAMA. 1943;121:553.
** 3535 pts who received RT after mastectomy.
* Marshall and Hare (1947) - No PMID — "Carcinoma of the breast: results of combined treatment with surgery and roentgen rays." Marshall SF and Hare HF. Ann Surg. 1947;125:688.
* Guttmann (1958) - PMID 13487893 — "Effects of radiation on metastatic lymph nodes from various primary carcinomas." Guttmann RJ. Am J Roentgenol Radium Ther Nucl Med. 1958 Jan;79(1):79-82.
* Guttmann (1963) - PMID 13951487 — "Radiotherapy in the treatment of primary operable carcinoma of the breast with proved lymph node metastases: approach and results." Guttmann RJ. Am J Roentgenol Radium Ther Nucl Med. 1963 Jan;89:58-63
** These two studies by Guttmann showed that radiotherapy could effectively treat metastatic lymph nodes.

## Mastectomy +/- RT
### Overall

see also: EBCTCG in #Meta-analysis section
* NSABP B-02, 1970 (1961-68)
** 1103 pts. All pts received radical mastectomy (Halsted). Until 1967, premenopausal pts randomized to 1 of 3 arms: post-op RT, triethylenethiophosphoramide (TSPA), or placebo. Institutions either randomized all postmenopausal women to 3 arms (as in premenopausal women) or they used a different scheme where only LN+ pts were randomized to 3 arms and LN- pts were randomized 1:1 between TSPA and 5-FU. After May 1967, placebo arm was dropped.
*** RT technique: used OLD radiation therapy equipment. Many were orthovoltage. Required at least 200 kV. Dose was 3500 Roentgens in 3 weeks up to 4500 R in 5 weeks. RT was to IMN, apex of axilla, and supraclavicular fossa only. They did not irradiate the chest wall or the whole axilla.
** PMID 4989839 Full text, 1970 — "Postoperative radiotherapy in the treatment of breast cancer: results of the NSABP clinical trial." Fisher B et al. Ann Surg. 1970 Oct;172(4):711-32.
*** No benefit for RT.
* Danish trial 82b (1982-89)
** Importance: Previous trials of post-operative RT had not used chemotherapy.
** Randomized. 1708 pts. Premenopausal high-risk pts, who had one or more of: positive axillary LN, tumor > 5 cm, invasion of skin or pectoral fascia.
*** Randomized after surgery to: RT + CMF chemotherapy, CMF alone, or CMF + tamoxifen. (enrollment in the third group was stopped after 1986 due to higher mortality).
*** Surgery consisted of total mastectomy + axillary node dissection (level I and part of level II). Median # of LN removed was 7. RT was to chest wall, SCLV fossa, infraclavicular LN, axillary, and IMN in first 4 intercostal spaces. 50 Gy in 25 fx (or 48 Gy in 22 fx, 4days/wk). Recommended use of anterior electron field to treat CW and IMN. Chemotherapy: 8 cycles of CMF with RT, or 9 cycles if given alone. RT was sandwiched between first 2 cycles of chemo.
** PMID 9395428 Full text, 1997 — "Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial." Overgaard M et al. N Engl J Med. 1997 Oct 2;337(14):949-55.
*** Median f/u 114 months. LRR 9% (RT+CMF) vs 32% (CMF). 10-yr DFS 48% vs 34%. 10-yr OS 54% vs 45%. On MVA, RT improved DFS and OS irrespective of tumor size, number of positive LN, or grade, in these high risk pts. More than 50% of local recurrence were on the chest wall.
** Conclusion: improved survival with post-op RT
** Comment: influence of the number of positive LN is difficult to determine from this study because few nodes were removed (median: 7) and many pts had fewer than 4 nodes sampled.
* Danish trial 82c (1982-90)
** Randomized. 1375 pts. Postmenopausal high-risk pts. Randomized to: tamoxifen (for 1 yr), or to tam + RT.
** 1999 PMID 10335782 — "Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial." Overgaard M et al. Lancet. 1999 May 15;353(9165):1641-8.
*** Median f/u 123 months. LRR 8% (RT) vs 35% (No RT). DFS 36% vs 24%. 10-yr OS 45% vs 36%.
*** Conclusion: improved survival with post-op RT
* Combined Danish 82b and 82c
** RT techniques; 2005 - PMID 16150503 — "Audit of the radiotherapy in the DBCG 82 b&c trials--a validation study of the 1,538 patients randomised to postmastectomy radiotherapy." Nielsen HM et al. Radiother Oncol. 2005 Sep;76(3):285-92.
*** Description of RT technique
** Patterns of failure; 2006 - PMID 16618947 — "Study of Failure Patterns Among High-Risk Breast Cancer Patients With or Without Postmastectomy Radiotherapy in Addition to Adjuvant Systemic Therapy: Long-Term Results From the Danish Breast Cancer Cooperative Group 82 b and c Studies." Nielsen HM et al. J Clin Oncol. 2006 Apr 19. Page ?.
*** 18-yr rate of any breast cancer event was 73% (no RT) vs 59% (RT). LRR (with or without DM) was 49% vs 14%; DM subsequent to LRR 35% vs 6%; overall DM 64% vs 53%.
*** Conclusion: post-mastectomy RT changes the disease recurrence pattern. Fewer pts experience LRR and fewer pts overall have DM.
** Loco-regional recurrences; 2006 - PMID 16647152 — "Loco-regional recurrence after mastectomy in high-risk breast cancer-risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials." Nielsen HM et al. Radiother Oncol. 2006 Apr 25; (Epub)
*** 73% chance of DM after developing LRR. Initial randomization did not alter outcome after LRR. Combined treatment of LRR with surgery + RT improved LC over either modality alone.
** Cardiac toxicity - see at Heart toxicity
** Nodal status; 2007 - PMID 17306393 — "Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials." Overgaard M et al. Radiother Oncol. 2007 Mar;82(3):247-53.
*** Subgroup analysis. 1152 pts with positive nodes and >=8 nodes removed (i.e. above the median of 7). 552 pts with 1-3 positive nodes, 600 pts with 4+ positive nodes.
*** Median time after mastectomy was 18 yrs. At 15 yrs, LRR in 16% of pts; 15-yr LRR 6% (RT) vs 37% (no RT); RR=0.12. 15-yr OS 39% vs 29%, RR=0.63.
*** For subsets: LRR benefit for 1-3 +LN was 4% (RT) vs 27% (no RT); 4+ LN, 10% vs 51% (both were SS). OS, for 1-3 LN, 57% vs 48%; 4+ LN 27% vs 12% (both were SS).
*** Greater survival benefit for smaller tumors (<= 2cm) but greater LRR benefit for larger tumors
*** Conclusion: Similar and significant improvement in survival in irradiation pts in both groups (absolute survival of 9% at 15 yrs). Number needed to treat (NNTT) was the same in both groups. Pts with 1 or more positive nodes benefit from RT.
** Receptor status; 2008 PMID 18285604 -- "Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group." (Kyndi M, J Clin Oncol. 2008 Mar 20;26(9):1419-26.)
*** Subset analysis. 1000 patients analyzed with tissue microarray for ER and PR (Rec), and her-2. Constructed 4 groups: Rec+/her2- (63%), Rec+/her2+ (10%), Rec-/her2- (triple negative, 15%), and Rec-/her2+ (12%). Median F/U of alive patients 17 years
*** Outcome: Improved OS after PMRT only in patients Rec+/her2-. No OS benefit for patients that were Rec- or her2+.
*** LR control: Worse LRC for Rec- and Rec-/her2- (triple negative) compared with Rec+/her2-. However, all subgroups significant benefit (p=0.001 or better) to RT over observation
*** Conclusion: Hormonal receptor status is predictive of loco-regional control and overall survival
* British Columbia trial, 1997 (1979-86)
** 318 pts. Premenopausal, pN+, s/p MRM + ALND. Randomized to +/- RT. Received six months of CMF (q3w x 9 cycles). 128 pts with ER+ tumors underwent 2nd randomization to oophorectomy (using RT to the ovaries). RT technique: Chest wall, 37.5 Gy (16 fx; 2.34 Gy/fx) using tangents; supraclav/axillary field (with PAB), 35 Gy/16 fx; bilateral IM, 37.5 Gy/16fx. RT given between 4th and 5th chemo cycles. RT was cobalt-60.
** 15-year results, 1997 - PMID 9309100 Full text — "Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer." Ragaz J et al. N Engl J Med. 1997 Oct 2;337(14):956-62.
** 20-year results, 2005 - PMID 15657341 — "Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial." Ragaz J et al. J Natl Cancer Inst. 2005 Jan 19;97(2):116-26.
*** 191 of 318 pts had relapse; 190 of 318 pts died (170 from breast cancer, 20 from other causes). There were isolated locoregional relapses in 18% (27 of 154) vs 7% (12 of 164); locoregional relapse at any time before a systemic relapse in 28% (43) vs 10% (17)
*** Event free survival 25% vs 35% (RR=0.70;p=0.09), DFS 30% vs 48% (RR=0.63), survival free of isolated locoregional disease 74% vs 90% (RR=0.36), survival free of locoregional relapse before systemic 61% vs 87% (RR=0.32), systemic breast cancer free survival 31% vs 48% (RR=0.66), breast cancer specific survival 38% vs 53% (RR=0.67), overall survival 37% vs 47% (RR=0.73) (all SS except as otherwise stated). Similar interaction for 1-3 LN and >4 LN.
*** Of 39 pts with isolated locoregional recurrence, 37 developed systemic recurrence and died from breast cancer, despite salvage therapy.
*** Arm edema in 3.2% vs 9.1% (severe in 3.7% vs 0.6%)
** Conclusion: Improved overall survival. Control of locoregional disease leads to improved survival.
Failed studies:
* NCI Canada MA25 - 1-3 positive nodes
** Closed due to lack of accrual
* Intergroup / SWOG 9927 / RTOG 99-15 (Closed) - post-mastectomy RT for Stage II with 1-3 positive LN (T1-2N1)
** Protocol
** pT1-2 pN1 only. MRM with level I-II (or III) nodal dissection, negative margins. May not have clinically matted nodes, gross ECE (microscopic ECE allowed), gross residual disease in the axilla. RT within 2 months of surgery. RT to chest wall, SCLV, and IM (spaces 1-3). No PAB. Allows multiple RT techniques. 50 - 50.4 Gy with optional 10 Gy boost. Bolus qd or qod.
** Closed due to lack of accrual
Ongoing studies:
* SUPREMO Website - Selective Use of Postoperative Radiotherapy AftEr MastectOmy
** 1-3 positive nodes or T2N0 grade 3 or LVSI. Randomized to RT to the chest wall (no nodal RT) or observation.

### Triple negative

* China (multicenter); 2011 (2001-2006) -- Randomized.
** 681 women with triple negative Stage I-II breast cancer, s/p mastectomy. Randomized to 1) chemotherapy alone (315 pts), or 2) chemo and RT (366).
** Majority of pts were <= 50 yrs old, clinical Stage I, pT2, pN0.
** PMID 21852010 -- "Adjuvant chemotherapy and radiotherapy in triple-negative breast carcinoma: a prospective randomized controlled multi-center trial." (Wang J, Radiother Oncol. 2011 Aug;100(2):200-4.)
*** Median f/u 86 mos. 5-yr RFS 88.3% (RT) vs 74.6% (no RT)(SS). 5-yr OS 90.4% vs 78.7% (SS).
*** Conclusion: chemotherapy plus radiation therapy was more effective than chemotherapy alone in women with triple-negative early-stage breast cancer after mastectomy.

### Node negative

see also: EBCTCG in #Meta-analysis section .. for further details on PMRT in node negative pts.
T3N0
* US NCDB; 2017 (Emory)(NCDB 2003-2011) PMID 28387923 -- "The role of postmastectomy radiotherapy in women with pathologic T3N0M0 breast cancer." (Cassidy RJ, Cancer. 2017 Aug 1;123(15):2829-2839. doi: 10.1002/cncr.30675. Epub 2017 Apr 7.)
** Retrospective review of NCDB database, 3437 patients, pT3N0, mastectomy between 2003 and 2011. PMRT in 1644 (48%). PMRT given as chest wall 67% or chest wall +RNI (33%). PMRT associated with age <40, private insurance, location <10 miles, Charlson comorbidity 0, tumor >= 7 cm, and treatment with chemo/endocrine therapy
** Outcome: 5-year OS PMRT 86% vs no PMRT 66% (SS). This was independent of age, facility type, comorbidity, grade, size, margin status and systemic therapy. Regional nodal radiation did not impact OS (p=0.09)
** Conclusion: PMRT found to be associated with improved OS
* SEER; 2014 (Fox Chase) (SEER 2000-2010) PMID 24985911-- "Postmastectomy radiation therapy for T3N0: A SEER analysis." (Johnson ME, Cancer. 2014 Nov 15;120(22):3569-74)
** Retrospective SEER analysis. 2525 patients in SEER database, T3N0 breast cancer. PMRT rate 2000-2010 42.1%. Median FU 56 months.
** Outcome: CSS: PMRT 85% vs. no PMRT 82.4% (p<0.01). OS: 76.5% vs. 61.8% (p<0.01). PMRT associated with improved CSS and OS on MVA.
** Conclusion: In a modern cohort of patients, PMRT was associated with significant improvements in both CSS and OS in patients with T3N0M0 breast cancers treated with modified radical mastectomy from 2000-2010.
* British Columbia; 2011 PMID 20646860 -- "Outcomes of node-negative breast cancer 5 centimeters and larger treated with and without postmastectomy radiotherapy." (Goulart J, Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3):758-64.)
** 10-yr LRR 2.3% (+PMRT) vs 8.9% (-PMRT). All pts not undergoing PMRT who had LRR had grade 3 and did not receive hormonal therapy. On multivariate analysis, PMRT did not significantly improve the LRR or BCSS rates.
** Conclusion: Low LRR rate for node-negative breast cancer ≥ 5 cm. PMRT should be considered for grade 3 and for patients not undergoing hormonal therapy.
* Harvard; 2009 PMID 19201501 -- "Post-mastectomy radiation in large node-negative breast tumors: Does size really matter?" (Floyd SR, Radiother Oncol. 2009 Apr;91(1):33-7. Epub 2009 Feb 7.)
** Systematic literature review
* SEER; 2008 (Colorado) (SEER 1988-2002) PMID 18543316 -- "Impact of postmastectomy radiotherapy in T3N0 invasive carcinoma of the breast: a Surveillance, Epidemiology, and End Results database analysis." (McCammon R, Cancer. 2008 Aug 15;113(4):683-9.)
** Retrospective SEER analysis. 1865 patients in SEER database, T3N0 breast cancer. PMRT rate 1988-1997 22%, 1998-2002 41%.
** Outcome: 10-year CSS PMRT 82% vs. no PMRT 80% (NS); no subgroup benefit. 10-year OS 71% vs. 58% (SS), confined to women >50 years
** Conclusion: No improvement in cancer-specific survival with PMRT for T3N0 patients. Increased OS in absence of CSS likely reflects patient selection
* SEER; 2008 (Yale) (SEER 1988-2003) PMID 18442108 -- "Postmastectomy radiation therapy for lymph node-negative, locally advanced breast cancer after modified radical mastectomy: analysis of the NCI Surveillance, Epidemiology, and End Results database." (Yu JB, Cancer. 2008 Jul 1;113(1):38-47.)
** 1777 patients, T3N0 treated with MRM. 568 pts (32%) received PMRT. Median number of LNs examined: 14.
** No improvement in OS with the delivery of PMRT in this group. Local control was not analyzed.
** Conclusion: The use of PMRT for T3N0M0 breast carcinoma after MRM is not associated with an increase in overall survival.

### Node positive (1-3 LN+)

see also: EBCTCG in #Meta-analysis section .. for further details on PMRT in pts with 1-3+ LN.

## PMRT alone vs PMRT + Chemo vs Chemo Alone

* Scotland (1976-1982) -- PMRT alone vs PMRT + Chemo vs Chemo Alone
** Randomized, 3 arms. 322 women, age ≤ 70, operable breast cancer, pN+. Arm 1) PMRT vs Arm 2) PMRT followed by CMF vs Arm 3) CMF alone
** 2010 PMID 20673353 -- "Adjuvant radiotherapy and chemotherapy in breast cancer: 30 year follow-up of survival." (McArdle CS, BMC Cancer. 2010 Jul 30;10:398.) Median F/U 27 years (25-31 years)
*** Outcome: Deaths 81%, BCA deaths 63%. No difference in OS or CSS between the 3 arms (if RT+CMF baseline, HR for CSS for RT alone 1.24 (p=0.3) and HR for chemo alone 1.43 (p=0.08). CSS 10-years 41%, 20-years 34%, 30-years 33%.
*** Conclusion: No difference in long-terms survival between the different adjuvant regimens

## Internal mammary
### Internal mammary involvement

* Milan, 1983 (1965-80) - PMID 6639172 Full text — "Risk of internal mammary lymph node metastases and its relevance on prognosis of breast cancer patients." Veronesi U et al. Ann Surg. 1983 Dec;198(6):681-4.
** 1085 pts. Treated with radical mastectomy plus internal mammary dissection.
** IMN risk associated with younger age, larger size of primary tumor, and axillary node involvement. Worst prognosis for pts with both axillary and IM involvement.

### Internal mammary surgery

Randomized trials:
* Milan, 1999 (1964-1968) PMID 10658521 -- "The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial." (Veronesi U, Eur J Cancer. 1999 Sep;35(9):1320-5.)
** Randomized. 737 patients with T1-3N0-1. Treated with 1) Halsted mastectomy vs. 2) extended mastectomy + IMN dissection. No RT or chemo. 30 year F/U
** No difference in OS or DSS. 71% died from BCA
** Conclusion: Removal of IM nodes does not improve survival. Prognostic value however is high
* U. Chicago, 1989 (1973-82) - PMID 2642730 — "A controlled trial of extended radical versus radical mastectomy. Ten-year results." Meier P et al. Cancer. 1989 Jan 1;63(1):188-95.
** 123 pts (including 112 treated by one surgeon) randomized to radical vs extended mastectomy.
** For the pts treated by one surgeon, 10-yr OS was 60% (RM) vs 74% (EXT), p=0.13. For pts with central or medial tumors, 60% vs 86%, S.S. No benefit for lateral tumors.
* International Cooperative Trial, 1976 (1963-68) - PMID 1247957, 1976 — "Radical mastectomy versus radical mastectomy plus internal mammary dissection. Five-year results of an international cooperative study." Lacour J et al. Cancer. 1976 Jan;37(1):206-14.
** Randomized 1580 pts to radical mastectomy vs extended mastectomy (with IMN dissection).
** No difference in OS for the overall group. Benefit for extended mastectomy for the subgroup of N+ with inner or medial quadrant tumors. Highly signficant for T1-T2 tumors within this subgroup.

### Internal mammary irradiation

    See also: Internal mammary irradiation after lumpectomy
Unknown benefit. Low risk of relapse in IM chain. Likely covered by tangent fields.
Randomized:
* EORTC 22922/10925 (ongoing), 1996-ongoing
** Purpose: to evaluate the effects of internal mammary node irradiation on loco-regional control and survival.
*** Randomized to treat the breast or chest wall only or to include the internal mammary lymph nodes and medial supraclavicular nodes (IM-MS).
*** Technique: Mixed beam. Fields: Recommended standard fields, but treatment centers may use their own variations. SCLV field: superior border - 3 cm above head of clavicle, lateral border - middle of clavicle, medial - 1 cm across midline. Block to shield larynx. IMN field: inferior border - lower border of 4th rib. Dose: 50 Gy in 25 fx (26 Gy delivered with photons, 24 Gy with electrons). Photons prescribed at 3 cm depth.
** Irradiation techniques: PMID 11514005 — "A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer." Lievens Y et al. Radiother Oncol. 2001 Sep;60(3):257-65.
* French 2013 (1991-97) - Post-mastectomy RT + SCF +/- IMN RT
** See details at Internal mammary RT
* There was a completed randomized trial for +/- IMN RT in the intact breast setting. See Internal mammary irradiation after lumpectomy.
Non-randomized:
* Israel (1994-98)
** Prospective, non-randomized. 100 pts, high-risk Stage II-IIIA. Treated on protocol with induction chemotherapy followed by high-dose chemotherapy with autologous stem-cell support and regional radiotherapy + tamoxifen. Surgery was mastectomy or lumpectomy. First 32 pts (1994-95) treated with RT including internal mammary nodes (with anterior electron beam). For the next 33 pts (1996-7), IMN irradiation was omitted but treatment was otherwise identical. Last 35 pts (1997-on) were treated similarly to the first group.
** PMID 12860949 Full text, 2003 — "The role of irradiation of the internal mammary lymph nodes in high-risk stage II to IIIA breast cancer patients after high-dose chemotherapy: a prospective sequential nonrandomized study." Stemmer SM et al. J Clin Oncol. 2003 Jul 15;21(14):2713-8.
*** Median f/u 77 months. DFS 73% (IM) vs 52% (no IM), S.S. OS 78% vs 64%, p=0.08. No difference in locoregional recurrence.
** Conclusion: improved DFS and OS for pts treated with IM RT. Caveat, non-randomized.

## Indications for radiotherapy following neoadjuvant chemotherapy

* Based on MD Anderson retrospective data (all patients treated with mastectomy + ALND)
** If no PMRT was given: 5-year LRR is 23%, with 15% being isolated first failure. In patients with pCR, LRR is 19% . Predictive factors were clinical Stage IIIB+ or pathological LN+ >=4, or lack of tamoxifen use. Clinical T1-2 had LRR 4% vs. cT3-4 LRR 46% (SS). Clinical N0 had LRR 23% vs. N+ 27% (NS)
** When neoadjuvant patients without PMRT were compared to mastectomy only patients without PMRT by pathologic stage, neoadjuvant patients had significantly higher risk of LRR. When compared by initial clinical stage, the LRR was comparable
** PMRT was typically given for higher stage patients. Overall 10-LRR without PMRT was 22%, with PMRT (despite higher clinical stage) 11% (SS). Subsets of patients that gained significant benefit were clinical T3, clinical Stage III-IV, and pathological >=4 LN+
** For patients who achieve pCR after neoadjuvant chemo, there is no benefit for PMRT in clinical Stage I-II, but dramatic benefit in clinical Stage III-IV for LRR (7% vs. 33%), DMFS, DSS, and OS with the addition of PMRT
* Two two major Phase III US neoadjuvant chemo trials (NSABP B-18 and NSABP B-27) which enrolled patients with cT-3N1 patients (no fixed LNs) did not allow post-mastectomy RT
* A large National Cancer Database Analysis demonstrated improved OS with PMRT for all women with positive lymph nodes at diagnosis (cN1) regardless of pathologic nodal response to neoadjuvant chemotherapy (PMID 26861597)
* The 2016 NCCN guidelines recommend PMRT decisions based on the pre-chemotherapy staging and risk factors.
* An ongoing randomized trial (NSABP B-51/RTOG 1304: NCT01872975) is evaluating PMRT and regional nodal RT for for women with cN1 disease who convert to ypN0 after neoadjuvant chemotherapy
Recurrence after neoadjuvant chemotherapy without PMRT
* NSABP
** 3088 pts. Combined analysis of NSABP B-18 and B-27. Neoadjuvant chemotherapy was either AC alone or AC + Taxane. Pts treated with mastectomy did not receive PMRT. Lumpectomy pts received adjuvant RT.
** 2012: PMID 23032615 Full text -- "Predictors of Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From Combined Analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27." (Mamounas EP, J Clin Oncol -- online before print, Oct 1, 2012.)
*** 335 LRR events after 10 yrs f/u. In mastectomy pts (treated w/o RT), 10-yr cumulative LRR 12.3%. In lumpectomy pts (+RT), LRR 10.3%.
*** Predictors of LRR. In lumpectomy pts -- age, clinical N-stage (before neoadj chemo), pathologic nodal status / breast tumor response. In mastectomy pts -- clinical tumor size (before neoadj chemo), clinical N-stage (before chemo), and pathologic nodal status / breast tumor response.
*** Defined groups at low, intermediate, and high risk of LRR after neoadjuvant chemotherapy.
LRR risk in patients treated with mastectomy :
| Initial stage | Response | CW recurr. (%) | Nodal recurr. (%) |
| T ≤ 5 cm, N0 | pCR | 2.2 | 4.3 |
| T ≤ 5 cm, N0 | ypN- / ypT+ in breast | 4 | 2.3 |
| T ≤ 5 cm, N0 | ypN+ | 7.8 | 3.4 |
| T ≤ 5 cm, N+ | pCR | 0 | 0 |
| T ≤ 5 cm, N+ | ypN- / ypT+ in breast | 2.7 | 8.1 |
| T ≤ 5 cm, N+ | ypN+ | 10.6 | 6.4 |
| T > 5 cm, N0 | pCR | 0 | 6.2 |
| T > 5 cm, N0 | ypN- / ypT+ in breast | 8.6 | 3.2 |
| T > 5 cm, N0 | ypN+ | 12.3 | 2.3 |
| T > 5 cm, N+ | pCR | 0 | 0 |
| T > 5 cm, N+ | ypN- / ypT+ in breast | 9.2 | 0 |
| T > 5 cm, N+ | ypN+ | 17.6 | 4.8 |
*** Conclusion: "In patients treated with NC, age, clinical tumor characteristics before NC, and pathologic nodal status/breast tumor response after NC can be used to predict risk for LRR and to optimize the use of adjuvant radiotherapy."
* MD Anderson (1974-98)
** Retrospective review of multiple institutional prospective trials. 150 patients treated with mastectomy after neoadjuvant chemo who did not receive post-mastectomy RT. Inflammatory BCA excluded. cT3-T4 stage 59%, cLN+ 70%. Stage III or IV (SCLV involvement) 56%. Median number LN at surgery 15. Additional adjuvant chemo after surgery 92%.
** 2002 PMID 11773149, 2002 — "Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation." (Buchholz TA, J Clin Oncol. 2002 Jan 1;20(1):17-23.). Median F/U 4.1 years
*** Outcome: 10% pCR, pN0 41%. Overall recurrence 47%; LRR 23% (15% isolated first failure) and DM 42%. OS at 5-yr 57% and 10-yr 40%.
*** 5-year LRR rates:
**** Clinical stage: cT-stage: cT1 0%, cT2 12%, cT3 25%, cT4 51%. cN-stage: cN0 23%, cN+ 27% (NS). However, higher LRR for advanced N-stage (N2-3 vs. N0-1).
**** Pathologic stage: pT-stage: ypT1 18%, ypT2 36%, ypT3-4 46%. pN-stage: (0 LN, 12%; 1-3, 18%; 4-9, 57%; >10 no 5-year survivors). pCR: 19% vs. pPR 28% (NS, but small numbers). Use of tamoxifen: 7% vs 36%.
**** Nodal status: cN0 and pN0 3%, cN+ and pN0 14%, cN0 and pN+ 63%, cN+ and pN+ 32% (wide confidence intervals)
*** 3 factors associated with LRR: 1) clinical stage IIIB+ (cT4 or cN3=SCV/IM LN+) (HR 4.5), 2) >=4 positive LN (HR 2.7), and 3) lack of tamoxifen use (HR 3.9). No clear relationship between disease response to chemo and LRR. LRR 46% for cT3-4 vs 4% for cT1-T2.
*** Conclusion: Both clinical (pre-neoadjuvant chemo) and pathologic factors impact risk for LRR
** 2002 PMID 12095553, 2002 — "Pathologic tumor size and lymph node status predict for different rates of locoregional recurrence after mastectomy for breast cancer patients treated with neoadjuvant versus adjuvant chemotherapy." Buchholz TA et al. Int J Radiat Oncol Biol Phys. 2002 Jul 15;53(4):880-8.
*** Retrospective. 150 patients treated with neoadjuvant chemo + mastectomy (NEO) vs. 1031 treated with mastecomy + adjuvant chemo (ADJ). Neither group received PMRT. NEO group significantly higher clinical disease
*** Outcome: pathologic stage for NEO group significantly lower than for ADJ group. However, 5-year LRR NEO 27% vs. ADJ 15% (SS); true for all pathologic size, and for >= 4 LN+. If matched for clinical stage, no difference in LRR. Subset ypT2 and 1-3 LN+ worse outcome (32% vs. 8%)
*** Conclusion: RT should be offered for tumor >5 cm, clinical Stage IIIA, or >= 4 LN+ regardless of neoadjuvant/post-op chemo
Outcomes after neoadjuvant chemo with PMRT
* Paris/Ruijin Hospital China; 2018 (2005 - 2012) PMID 29306555 -- "Outcome of postmastectomy radiotherapy after primary systemic treatment in patients with clinical T1-2N1 breast cancer." (Cao L, Cancer Radiother. 2018 Feb;22(1):38-44. doi: 10.1016/j.canrad.2017.07.051. Epub 2018 Jan 3.)
** Retrospective. Two institutions. Clinical T1-2N1 breast cancer, status post neoadjuvant systemic therapy, and mastectomy, +/- regional nodal radiation. At surgery 53/88 patients had ypN0. Median F/U 5 years
** Outcome. 5-year locoregional control PMRT(+) 97% vs PMRT(-) 78% (SS). If ypN0, locoregional control PMRT(+) 95% vs PMRT(-) 73%, DMFS 93% vs 75%, and DFS 93% vs 63%.
** Conclusion: PMRT could significantly improve locoregional control, including in patients with good response to initial chemotherapy
* National Cancer Database, 2016 (Rusthoven CG et al, Ann Oncol 2016) (PMID 26861597)
** >15,000 women (2003-2011) with cN1 breast cancer receiving neoadjuvant chemotherapy, surgery, and varying RT approaches.
** On propensity score-matched and multivariate analyses, PMRT associated with improved OS for cN1 patients regardless of pathological nodal status, including ypN0, ypN1, and ypN2-3.
** Post-chemotherapy pathologic nodal status was not predictive of the relative survival benefit obtained from PMRT.
* MD Anderson
** Overall; 2004 (1974-2000) PMID 15570071 — "Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy." (Huang EH et al. J Clin Oncol. 2004 Dec 1;22(23):4691-9.)
*** Retrospective. 542 patients treated on 6 prospective trials with neoadjuvant chemo, mastectomy, and PMRT compared to 134 patients on same trials treated without PMRT. Adjuvant chemo 95%. Median number of LN recovered 15. PMRT patients significantly higher clinical stage. RT CW+lymphatics 50 Gy + 10 Gy CW boost. Median F/U 5.7 years
*** Outcome: 10-year LRR PMRT 11% vs. no PMRT 22% (SS); rate of isolated LRR 8% vs. 20% (SS)
**** Clinical stage LRR: I-IIA no benefit for PMRT. Stage IIB+ PMRT 11% vs. no PMRT 26% (SS), cT3-T4 8% vs. 22% (SS), cN2-3 12% vs. 40%.
**** Pathologic stage LRR: ypT2+ PMRT 14% vs. no PMRT 59% (SS). Stage II with 1-3 LN+ no benefit for PMRT (but small n). pN0 4% vs. 11% (SS), >=4 LN+ 16% vs. 59% (SS)
**** Survival benefit: CSS cStage IIIB+ PMRT 44% vs. no PMRT 22% (SS), cT4 45% vs. 24% (SS), cN2-3 49% vs. 27% (SS), >=4 LN+ 44% vs. 18%
*** Predictors for LRR: no PMRT, >20% LN+, no tamoxifen, cStage IIIB+, no response to neoadjuvant chemo
*** Conclusion: PMRT should be considered for clinical T3, clinical Stage III-IV and patients with >=4 LN+ at surgery, regardless of response to chemotherapy
** Recurrences; 2005 PMID 15890574 -- "Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiotherapy." (Huang EH, Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):351-7.)
*** Retrospective. 542 patients (same as Huang, 2004). Median F/U 5.8 years
*** Outcome: LRR 5-years 9%, 10-years 11%.
*** Univariate predictors: Clinical: cStage IV (21%), cT4 (14%), pT3+ (23-47%), clinical response to neoadjuvant, and hormonal therapy. Pathological: multifocal/multicentric disease (13-30%), skin/nipple involvement (19%), LVI+ (15%), <10 LN sampled (19%), positive >=4 LN+ (16%), ER-
*** Multivariate predictors: skin/nipple involvement (19%), SCV LN+ (21%), ECE+ (15%), ER- and no hormonal treatment. 10-year LRR 0-1 factors 4%, 2 factors 8%, 3+ factors 28%
*** Conclusion: Predictors for recurrence after neoadjuvant chemo, mastectomy, and PMRT identified.
** pCR; 2007 (1982-2002) PMID 17418973 -- "Postmastectomy radiation improves the outcome of patients with locally advanced breast cancer who achieve a pathologic complete response to neoadjuvant chemotherapy." (McGuire SE, Int J Radiat Oncol Biol Phys. 2007 Jul 15;68(4):1004-9. Epub 2007 Apr 6.)
*** Retrospective. 106 patients, no inflammatory BCA, neoadjuvant chemotherapy and pCR at surgery. Clinical Stage I 2%, II 31%, IIIA 30%, IIIB 25%, IIIC 11%. Antracycline in 92%, taxane in 38%. PMRT in 72, no PMRT in 34. Median F/U of survivors 5 years
*** Outcome: 10-year LRR Stage I-II 0% regardless of PMRT. Stage III PMRT 7% vs. no PMRT 33% (SS). 10-year DMFS 88% vs. 41% (SS), DSS 87% vs. 40% (SS), OS 77% vs. 33% (SS)
*** Conclusion: PMRT improves significantly LRR and OS for patients with clinical Stage III and achieve pCR
* GEPAR Analysis
** DOI: 10.1200/jco.2015.33.15_suppl.1008 Journal of Clinical Oncology 33, no. 15_suppl (May 20, 2015) 1008-1008.
*** Post hoc analysis of 3 prospective German trials. 3481 patients treated with neoadjuvant chemotherapy 209 patients did not receive adjuvant radiation (extent of RT not indicated). Median FUP 56 months.
**** 5 yr LRFS 90% with RT, 82% without (p < 0.001)
**** 5 yr DFS 75% with RT, 67% without (p < 0.001)
**** With cN+ prior to chemotherapy 5 yr LRFS and DFS improved with PMRT (HR 2.32, 95% CI 1.54-3.50; p < 0.001; HR 1.97, 95% CI 1.48-2.62; p < 0.001)
**** Patients with pCR
***** 5-yr LRFS was 95.7%% with RT vs 86.6% without RT (HR 3.32, 95% CI 1.00-11.08; p = 0.051)
***** 5-yr DFS was 86.9% and 56.1% (HR 3.52, 95% CI 1.82-6.83; p < 0.001)
**** Patients without pCR
***** 5-yr LRFS was 88.6% with RT vs 80.7% without RT (HR 1.86, 95% CI 1.29-2.67; p < 0.001)
***** 5-yr DFS was 72.6% vs 65.7%; HR 1.39, 95% CI 1.07-1.81; p = 0.014)
T3 N0 subset:
* MD Anderson
** 2011 PMID 21885207 -- "Local-regional recurrence with and without radiation therapy after neoadjuvant chemotherapy and mastectomy for clinically staged T3N0 breast cancer." (Nagar H, Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):782-7.)
*** 162 pts clinical T3N0 treated with neoadj chemo and mastectomy. 119 pts received PMRT and 43 did not.
*** 5-yr LRR 4% (+PMRT) vs 24% (-PMRT). For -PMRT pts: pN+ predicted LRR (53% LRR for N+ vs 14% for N0).
*** Conclusion: "Breast cancer patients with clinical T3N0 disease treated with NAC and mastectomy but without PMRT had a significant risk of LRR, even when there was no pathologic evidence of LN involvement present after NAC. PMRT was effective in reducing the LRR rate. We suggest PMRT should be considered for patients with clinical T3N0 disease."

## Meta-analysis

* Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (1964-86)
** 2014 PMID 24656685 -- "Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials." (EBCTCG, Lancet. 2014 Mar 19. [Epub ahead of print])
*** 8135 pts; 22 trials of +/- RT to chest wall and regional lymph ndoes.
*** For pN0(n=700), RT had no effect on LRR, overall recurrence, or BCSM.
*** For pN+(any), OS difference 5% at 10-years in favor of RT.
*** For pN+(1-3 nodes)(n=1314), RT reduced LRR (3.8% vs 20.3%), overall recurrence (34.2% vs 45.7%, RR 0.68), and BCSM (42.3% vs 50.2%, RR 0.80).
*** For pN+(1 LN)(n=318), RT reduced LRR (2.3% vs 17.8%), overall recurrence (24.1% vs 36.4%, RR 0.60), and BCSM (31.7% vs 38.2%, RR 0.79).
*** For pN+(4+ nodes)(n=1772), RT reduced LRR (13.0% vs 32.1%), overall recurrence (66.3% vs 75.1%, RR 0.79), and BCSM (70.7% vs 80.0%, RR 0.87).
*** Conclusion: "After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given. For today's women, who in many countries are at lower risk of recurrence, absolute gains might be smaller but proportional gains might be larger because of more effective radiotherapy."
* Whelan (Ontario), 2000 - PMID 10715291 — "Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis." Whelan et al. J Clin Oncol. 2000 Mar;18(6):1220-9.
** Meta-analysis. 18 trials, 6,367 pts. 1967-1999. Most were N+ treated with mastectomy. Radiation reduced any recurrence, LR, and mortality (17% reduction).
* Cuzick et al. (United Kingdom)
** First report (1987): PMID 2856861 — "Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer." Cuzick J et al. Cancer Treat Rep. 1987 Jan;71(1):15-29.
*** Meta-analysis. 7941 pts. Randomized to RT vs no RT after simple or radical mastectomy.
*** No difference in survival before 10 years. After 10 years, there was an increase in the number of deaths in pts who received RT.
** Update (1994): PMID 8120544 — "Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy." Cuzick J et al. J Clin Oncol. 1994 Mar;12(3):447-53.
*** Trials started before 1975.
*** Previous increase in mortality after 10 years is no longer significant. Benefit in overall survival associated with RT. Excess of cardiac deaths with RT offset by reduced deaths due to breast cancer.
** Radical mastectomy vs simple mastectomy + RT (1987): PMID 3539330 — "Overview of randomized trials comparing radical mastectomy without radiotherapy against simple mastectomy with radiotherapy in breast cancer." Cuzick J et al. Cancer Treat Rep. 1987 Jan;71(1):7-14.
*** No difference in survival, but a trend for pts who received RT to do worse after 15 yrs.

## Hypofractionation

* Rangsit University, Thailand; 2011 (2004-2006) PMID 21717886 -- "A retrospective study comparing hypofractionated radiotherapy and conventional radiotherapy in postmastectomy breast cancer." (Pinitpatcharalert A, J Med Assoc Thai. 2011 Mar;94 Suppl 2:S94-102.)
** Retrospective. 215 patients, 31% treated with conventional RT (1.8-2.0 Gy in 25 fxs) and 69% with hypofractionated RT (2.65 Gy in 16-18 fxs). Median F/U 3.2 years
** Outcome: 5-year LRC CRT 87% vs HFRT 86% (NS), 5-year OS 63% vs 70% (SS)
** Toxicity: No difference in CW appearance, skin fibrosis, braxial plexopathy, arm edema, pulmonary fibrosis, rib fractures or carciovascular events
** Conclusion: Hypofractionated radiation as effective as conventional in postmastectomy breast cancer
* INMOL, Pakistan -- PMRT 27/5 vs 35/10 vs 40/15
** Randomized. 300 patients, BCA Stage T2-4N+. Arm 1) 27/5 in one week vs Arm 2) 35/10 in 2 weeks vs Arm 3) 40/15 in 3 weeks. Delivered using Co-60 with 4 fields
** 2009 PMID 19438129 -- "Post mastectomy adjuvant radiotherapy in breast cancer: a comparision of three hypofractionated protocols." (Shahid A, J Pak Med Assoc. 2009 May;59(5):282-7.)
*** Outcome: LRR 27/5 was 11%, 35/10 was 12%, and 40/15 was 10% (NS); OS 83% vs 82% vs 80% (NS).
*** Toxicity: Grade 3-5 skin 37% vs. 28% vs. 14% (SS); cardiac toxicity 5% vs 6% vs 5%; pulmonary toxicity 4% vs 5% vs 5% (NS). No rib fractions
*** Conclusion: All 3 protocols equally effective, with similar toxicity, and were helpful in reducing work load
* Beijing, 2003 (1987-1993) PMID 12839697 -- "[Post-mastectomy radiotherapy with different fractionated dose schemes in early breast cancer] - [Article in Chinese]" (Wu JX, Zhonghua Zhong Liu Za Zhi. 2003 May;25(3):285-8.)
** Retrospective. 367 patients with early BCA, treated with 50/25/5 weeks (149 patients) vs. 45/15/5 weeks (177 patients) vs. 23/4/3 weeks (41 patients). 257 chemotherapy
** 5-year DFS: 91% vs. 86% vs. 85% (NS)
** 5-year LR: 2.7% vs. 2.8% vs. 2.4% (NS)
* St. Thomas Hospital (UK)
** Randomized. 411 patients s/p mastectomy. Treated with BIW (12 fx in 28 days) vs. TIW (6 fx in 18 days) regimens. Max dose 36 Gy. CW treated with 70kV RT, axilla with Co-60
** 1975 5 year results. PMID 1201630 -- "A prospective clinical trial of post-operative radiotherapy delivered in three fractions per week versus two fractions per week in breast carcinoma." (Bates TD, Clin Radiol. 1975 Jul;26(3):297-304.)
*** 5-year outcomes: early and late radiation effects comparable and acceptable
** 1988 10 year results. PMID 3044476 -- "The 10-year results of a prospective trial of post-operative radiotherapy delivered in 3 fractions per week versus 2 fractions per week in breast carcinoma. (Bates TD, Br J Radiol. 1988 Jul;61(727):625-30.)
*** 10-year outcomes: 6 fx technique better than 12 fx technique (equally effective, fewer late sequelae)

## DCIS

See Radiation_Oncology/Breast/DCIS#Mastectomy

## Breast Reconstruction

See also: for RT combined with breast reconstruction, see Irradiation after breast reconstruction
* Memorial Sloan Kettering; 2008 PMID 18843123 -- "Breast reconstruction after surgery for breast cancer." (Cordeiro PG, N Engl J Med. 2008 Oct 9;359(15):1590-601.)
** Review

## Reviews

* European Perspective; 2009 PMID 19164209 -- "Postmastectomy Radiotherapy: Will the Selective Use of Post Mastectomy Radiotherapy Study End the Debate?" (Russells NS, J Clin Oncol. 2009 Jan 21. [Epub ahead of print])
* Duke; 2008 PMID 18445836 -- "One to three versus four or more positive nodes and postmastectomy radiotherapy: time to end the debate." (Marks LB, J Clin Oncol. 2008 May 1;26(13):2075-7.)
* MD Anderson; 2002 PMID 12490741, 2002 — "Controversies regarding the use of radiation after mastectomy in breast cancer." Buchholz TA et al. Oncologist. 2002;7(6):539-46.

## Local recurrence after mastectomy

* MD Anderson/British Columbia; 2010 PMID 20306128 -- "Among women who experience a recurrence after postmastectomy radiation therapy irradiation is not associated with more aggressive local recurrence or reduced survival." (Woodward WA, Breast Cancer Res Treat. 2010 Mar 20. [Epub ahead of print])
** Retrospective. 229 LRR/1500 MDACC patients and 66 LRR/318 BCCA patients. Evaluated outcomes depending on whether PMRT was given or not
** Outcome: If LRR, 10-year OS PMRT- 34% vs PMRT+ 19% (SS); however, PMRT+ patients developed more mets prior to LRR (34% vs 63%), and had higher TN stages. However, if isolated LRR, no difference in DM and OS
** Conclusion: Irradiation does not promote biologically aggressive local recurrence