From Radical Mastectomy to Partial Breast Irradiation: The Evolution of Breast Cancer Care

From Radical Mastectomy to Partial Breast Irradiation:

The Evolution of Breast Cancer Care

Johnny Ray Bernard, Jr., M.D.October 19, 2012

1852: Born in New York City Sept. 23 1870: Graduates from Phillips Academy

Andover 1874: Graduates Yale University

◦ Enrolls in Columbia University College of Physician and Surgeons in New York

1881: First emergency blood transfusion, performed on sister ◦ Performs one of first operations for

gallstones in U.S., performed on mother 1882: Development of Halsted radical

mastectomy 1884: Begins cocaine research, developing the

nerve block and other local anesthesia techniques.

1889: Invention of surgical gloves

William Stewart Halsted

1889: Publishes inguinal hernia repair method at the same time as Edoardo Bassini.

1890: Appointed first Chief of Surgery at Johns Hopkins Hospital

1892: Performs first successful subclavian artery ligation

1893: Started the first formal surgical residency training program in the United States

1898: American Surgical Association establishes Halsted's mastectomy and inguinal hernia repair as gold standards

1922: Dies in Baltimore from post-op complications of bile duct surgery September 7

William Stewart Halsted

Halsted Radical Mastectomy Developed and first

performed by William Stewart Halsted in 1882.

En bloc removal of the breast, muscles of the chest wall, and contents of the axilla

Osborne, MP. Lancet Oncol. 2007 Mar;8(3):256-65.

Halsted Radical Mastectomy

The “established and standardized operation for cancer of the breast in all stages, early or late”

From 1895 to the mid-1970s, about 90% of the women being treated for breast cancer in the US underwent the radical mastectomy.

Halsted Radical Mastectomy

Bloodgood JC. Problems of cancer. J Kansas Med Soc 1930;31:311-6

Patient dissatisfaction with results, anecdotal information regarding other procedures, some surgeons advocating more extensive surgery, some surgeons advocating more limited operations led to controversy regarding the procedure by the mid 1960’s

Also new information about tumor spread suggested that less radical surgery might be just as effective as the more extensive operations that were being performed.

What Changed?

To help resolve the controversy, the NSABP initiated the B-04 clinical trial in 1971

Aim: To determine whether patients with either clinically negative or clinically positive axillary nodes who received local or regional treatments other than radical mastectomy would have outcomes similar to those achieved with radical mastectomy.

National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04

Fisher B, et al. N Engl J Med. 2002 Aug 22;347(8):567-75.

1765 women (1665 in this report) with operable breast cancer were randomized between July 1971 and September 1974. No women received adjuvant chemotherapy. 87% followed for at least 25 years or were known to have died before that time.

Clinically Negative Axilla, N=1079

Halsted Radical Mastectomy,

N=362

Total Mastectomy, no AD, +XRT

N=352

Total (simple) Mastectomy Alone

N=365

Clinically PositiveAxilla, N=586


N=292

Total Mastectomy + XRTN=294

Supervoltage equipment Tangential fields Node negative: 50 Gy in 25 fractions,

2Gy/fraction Node positive:

◦ An additional boost of 10 to 20 Gy ◦ 45 Gy in 25 fractions, 1.8 Gy/fraction, was

delivered to both the internal mammary nodes and the supraclavicular nodes

Radiation


Local recurrence: recurrences in the chest wall, the surgical scar, or both

Regional recurrence: recurrences in the supraclavicular, subclavicular, or internal mammary nodes or in the ipsilateral axilla of patients treated with either radical mastectomy or total mastectomy and regional irradiation ◦ Women with negative nodes who had total

mastectomy alone and who subsequently had ipsilateral positive nodes that required axillary dissection were not considered to have had a recurrence unless the nodes could not be removed


Definitions

Calculated from the date of mastectomy Disease-free survival: The first local, regional,

or distant recurrence of tumor; contralateral breast cancer or a second primary tumor other than a tumor in the breast; and death of a woman who had no evidence of cancer

Relapse-free survival: The first local, regional, or distant recurrence or an event in the contralateral breast that was judged to be a recurrence

Distant-disease-free survival: Distant recurrences that occurred either as the first recurrence or after a local or regional recurrence, contralateral breast cancers, and other second primary cancers

Overall Survival: All deaths

End Points


25yr F/U: Results-DFS

Node Negative: No significant difference (P=0.65) ◦ 19% percent vs. 13%, RM vs. TM+XRT (P=0.49) ◦ 19% with TM alone (P=0.39, compared to RM) ◦ TM+XRT vs. TM alone (P=0.78)

Node Positive: No significant difference ◦ 11% vs. 10%, RM vs. TM+XRT (P=0.20)

Results-RFS

Node Negative: No significant difference (P=0.46) ◦ 53% percent vs. 52%, RM vs. TM+XRT (P=0.74) ◦ 50% with TM alone (P=0.27, compared to RM) ◦ TM+XRT vs. TM alone (P=0.15)

Node Positive: No significant difference ◦ 36% vs. 33%, RM vs. TM+XRT (P=0.40)

Results

Regardless of nodal status, most first events were related to distant recurrences of tumor and to deaths that were unrelated to breast cancer.

Results


No Axillary TreatmentClinically Negative

Axilla, N=1079


no XRT, N=362

Total Mastectomy, no AD, +XRT

N=352

Total (simple) Mastectomy Alone

N=365 68/365 women with negative nodes who underwent total mastectomy without radiation therapy (18.6%) subsequently had pathological confirmation of positive ipsilateral nodes. ◦ Identified within 2 years

after surgery in 51/68 (75%) women

◦ Between 2-5 years in 10/68 (15%) women

◦ Between 5-10 years in 6/68 (9%) women

◦ Between 10-25 years in 1/68 (1%) woman

Median time from mastectomy to the identification of positive axillary nodes was 14.8 months (range, 3.0 to 134.5).

Node negative: 68.3% of breast-cancer–related events occurred within the first 5 years of f/u -65.1% of these were distant recurrences, 10.3% contralateral breast cancer

Node positive: 81.7% of breast-cancer–related events occurred within the first 5 years of f/u -68.1% of these were distant recurrences

Results-DDFS & OS

Also, no difference in distant-disease-free survival or overall survival


Recurrence & Contralateral Cancer

The cumulative incidence of death after a recurrence or a diagnosis of contralateral breast cancer was 40% in women with negative nodes and 67% in women with positive nodes.


Similar outcomes for patients with either clinically negative or clinically positive axillary nodes who received local or regional treatments other than the gold standard Halsted radical mastectomy.

Thus, less extensive surgery can be safely performed. No benefit for radiation in clinically node negative patients in

terms of DFS, RFS, DDFS, OS vs. those with axillary node dissection ◦ Benefit in local control vs. those without axillary treatment.

Without any axillary treatment, ~20% risk of axillary disease, less with treatment, but still no change in DDFS or OS.

Most events occurred within 5 years but long term follow-up of patients is still needed as events still occurred after 5 years.

Treatment to improve distant recurrence needed.

Conclusions

So now we know that we don’t have to perform

such extensive surgery, what about not removing the whole breast at all?

Numerous surgical series of mastectomy specimens showed that breast cancer was multifocal and multicentric in nature.

Holland, et. al. noted that of 282 mastectomy specimens with invasive cancer, 177 (63%) specimens exhibited additional cancer aside from the index tumor, with 121 (43%) specimens having tumor more than 2cm away from the index tumor.

This suggested that women undergoing breast conservation would have a significant rate of local recurrence by removing only the primary tumor.

Holland R, et al. Cancer. 1985 Sep 1;56(5):979-90.

Surgical Pathology

To help resolve the controversy, the NSABP initiated the B-06 clinical trial in 1976.

Aim: To determine whether women with stage I or II breast tumors that were 4 cm or less in diameter who received breast-conserving surgery would have outcomes similar to those achieved with total (new standard) mastectomy.

Fisher B, et al. N Engl J Med. 2002 Oct 17;347(16):1233-41.

NSABP B-06

2163 women (1851 in this report) with invasive breast tumors that were <4 cm and with either negative or positive axillary lymph nodes (stage I or II breast cancer) were randomized between August 1976 and January 1984. Axillary nodes were removed regardless of the treatment assignment.

Stage I/II Breast Cancer <4cm

N=1851

Total Mastectomy N=589

Lumpectomy(Segmental

Mastectomy)+XRT N=628

Lumpectomy Alone N=634

Lumpectomy: Removal of sufficient normal breast tissue to ensure both negative margins (no tumor at inked margin) and a satisfactory cosmetic result◦ Only the lower two levels of the axillary nodes were

removed◦ +margins underwent total mastectomy but continued to

be followed for subsequent events Total Mastectomy:

◦ The axillary nodes were removed en bloc with the tumor Radiation:

◦ 2Gy/fraction to 50 Gy to the breast, but not the axilla Chemo: Any positive axillary nodes received adjuvant

systemic therapy with melphalan and fluorouracil

Treatment


Local recurrence: A first recurrence of a tumor in the chest wall or in the operative scar, but not in the ipsilateral breast, was classified as a local recurrence.◦ Ipsilateral breast recurrence after lumpectomy was

considered to be a cosmetic failure since women who underwent total mastectomy were not at risk for such an event.

Regional recurrence: Recurrences in the internal mammary, supraclavicular, or ipsilateral axillary nodes were classified as regional occurrences.

Definitions


Calculated from the date of surgery Disease-free survival: The first recurrence of

disease at a local, regional, or distant site; the diagnosis of a second cancer; and death without evidence of cancer

Distant-disease–free survival: Distant metastases as first recurrences, distant metastases after a local or regional recurrence, and all second cancers, including tumors in the contralateral breast

Overall survival: All deaths

Endpoints


20yr F/U: Results IBTR 14.3 % L+XRT vs. 39.2% L

alone (P<0.001) Benefit of XRT independent

of nodal status◦ Node Neg: 17% vs. 32%

(P<0.001) ◦ Node Pos: 44% vs. 9%

(P<0.001) L+XRT Time to Recurrence

◦ <5yrs: 40%◦ 5-10yrs: 29%◦ >10yrs: 31%

L alone Time to Recurrence◦ <5yrs: 73%◦ 5-10yrs: 18%◦ >10yrs: 9%


Results

As in B-04, the most frequent first events were distant recurrences


Results-DFS

No significant difference (P=0.26)36% vs. 35% vs. 35%, TM vs. L+XRT vs. L alone

Results-DDFS & OS

DDFS: No significant difference (P=0.34)49% vs. 46% vs. 45%, TM vs. L+XRT vs. L alone

OS: No significant difference (P=0.57)47% vs. 46% vs. 46%, TM vs. L+XRT vs. L alone

69% of first recurrences were detected <5yrs of surgery, 20% between 5-10yrs, and 11% after 10 years

9% of local recurrences, 7% of regional recurrences, and 13% of distant recurrences were detected after 10 years

Contralateral breast: 38% detected <5yrs of surgery, 30% 5-10yrs, and 32% after 10 years.




The cumulative incidence of death after a recurrence or a diagnosis of contralateral breast cancer was 40% in women with negative nodes and 67% in women with positive nodes.


Women with early stage breast cancer who have breast conserving surgery have outcomes similar to those achieved with total mastectomy.

Radiation therapy is a critical component of breast conservation.

Breast conservation should be offered to women with early stage breast cancer.

Most events occurred within 5 years but long term follow-up of patients is still needed as events still occurred after 5 years

Treatment to improve distant recurrence needed.

Conclusions

110 local breast recurrences were observed in 1108 pathologically evaluable patients

All 110 recurrences were noted to be in or close to the quadrant of the initial or index cancer.

The most common presentation of breast recurrence appeared to be a localized mass within or close to the quadrant of the index cancer (86%).

In 14% the recurrence not only involved the same quadrant, but was more diffuse within the breast.

Fisher ER, et al. Cancer. 1986 May 1;57(9):1717-24.

Pathologic Findings from the NSABP B-06

So now we know that BCT is feasible and most

recurrences occur close to the original tumor site, what about not radiating

the whole breast?

Other pathologic studies confirming findings Patients not desiring weeks of radiation

treatment Phase I/II studies of accelerated WBI in 4-5

days using multi-catheter interstitial brachy Radiation to just the tumor bed

◦ Multi-catheter interstitial brachytherapy◦ Balloon catheters and 3DCRT◦ Strut based catheter (SAVI)

Leading the Way to PBI

3D CRT

Evolution of Brachytherapy Techniques

Interstitial Balloon Strut Applicator

Multi-catheterSingle catheterMulti-catheter

What Can Happen After a Balloon?

Persistent Seroma Balloon applicators

Symptomatic: 3%-46%

Potential causes Contiguous V200 Tissue compression Both?

Greater flexibilityTreats the widest array of cavity & breast

sizes

Enhanced performanceEliminates skin spacing restrictions

Better outcomesLowers toxicity & risk of persistent

seroma

Exceptional precisionSculpt dose with selective radiation

Added convenienceSimple, secure placement and removal

Strut Based Applicator

APBI Data ReviewInstitution # of Cases Median F/U (months) Local Recurrence (%) Cosmesis Good/Excellent

(%)ASBS MammoSite Registry 1440 60.5 1.8 90Virginia Commonwealth University 483 24 1.2 91National Institute of Oncology, Hungary Phase III Trial* 127 APBI

131 WBI 66 4.7 APBI 3.4 WBI

81 APBI 62 WBI

William Beaumont Hospital 199 71 1.6 92Ochsner Clinic 164 65 3 75RTOG 95-17 99 51 4 Not ReportedMass General Hospital 48 84 2 68National Institute of Oncology, Hungary Phase I/II Trial 45 80 6.7 84

MammoSite FDA Trial 43 66 0 83Tufts/Brown 33 84 6.1 88Total

2681 65 3.1 APBI 2.8 WBI 84

* Conclusion - Partial breast irradiation using interstitial HDR implants or EB to deliver radiation to the tumor bed alone for a selected group of early-stage breast cancer patients produces 5-year results similar to those achieved with conventional WBI. Significantly better cosmetic outcome can be achieved with carefully designed HDR multi-catheter implants compared with the outcome after WBI.

There have been no differences in survival with APBI compared to WBI.

Strut Based Applicator Data Review




From Old School to New School

Johnny Ray Bernard, Jr., M.D., DABRSouthern Ohio Medical Center

Senior Medical DirectorRadiation Oncology(O) 740-356-7490

[email protected]

Thank you!

mailto:[email protected]

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From Radical Mastectomy to Partial Breast Irradiation: The Evolution of Breast Cancer Care