1. Johnny Ray Bernard, Jr., M.D.
From Radical Mastectomy to Partial Breast Irradiation: The Evolution of Breast Cancer Care
Johnny Ray Bernard, Jr., M.D.
October 19, 2012

2. William Stewart Halsted
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

3. 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

4. Halsted Radical Mastectomy
Developed and first performed by William Stewart Halsted in
En bloc removal of the breast, muscles of the chest wall, and contents of the axilla

5. Halsted Radical Mastectomy
Osborne, MP. Lancet Oncol Mar;8(3):

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

8. What Changed?
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.

9. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04
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.
Fisher B, et al. N Engl J Med Aug 22;347(8):

10. 1765 women (1665 in this report) with operable breast cancer were randomized between July 1971 and September 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 Positive
Axilla, N=586
Halsted Radical
Mastectomy, N=292
Total Mastectomy + XRT
N=294

11. Radiation 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
Fisher B, et al. N Engl J Med Aug 22;347(8):

12. Definitions
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
Fisher B, et al. N Engl J Med Aug 22;347(8):

13. End Points 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
Fisher B, et al. N Engl J Med Aug 22;347(8):

14. 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)

15. 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)

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

17. Results
Fisher B, et al. N Engl J Med Aug 22;347(8):

18. No Axillary Treatment
Clinically Negative
Axilla, N=1079
no XRT, N=362
Mastectomy,
Halsted Radical
Total Mastectomy,
no AD, +XRT
N=352
Mastectomy Alone
Total (simple)
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 years in 1/68 (1%) woman
Median time from mastectomy to the identification of positive axillary nodes was months (range, 3.0 to ).

19. 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

20. Results-DDFS & OS
Also, no difference in distant-disease-free survival or overall survival
Fisher B, et al. N Engl J Med Aug 22;347(8):

21. 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.
Fisher B, et al. N Engl J Med Aug 22;347(8):

22. Conclusions
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.

23. So now we know that we don’t have to perform such extensive surgery, what about not removing the whole breast at all?

24. Surgical Pathology
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):

25. NSABP B-06
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 Oct 17;347(16):

26. 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 Axillary nodes were removed regardless of the treatment assignment.
Stage I/II Breast
Cancer <4cm
N=1851
Total Mastectomy
N=589
Mastectomy)+XRT
(Segmental
Lumpectomy
N=628
N=634
Alone

27. Treatment
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
Fisher B, et al. N Engl J Med Oct 17;347(16):

28. Definitions
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.
Fisher B, et al. N Engl J Med Oct 17;347(16):

29. Endpoints 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
Fisher B, et al. N Engl J Med Oct 17;347(16):

30. 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%
Fisher B, et al. N Engl J Med Oct 17;347(16):

31. Results
As in B-04, the most frequent first events were distant recurrences
Fisher B, et al. N Engl J Med Oct 17;347(16):

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

33. 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

34. 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.

35. Recurrence & Contralateral Cancer
Fisher B, et al. N Engl J Med.
2002 Oct 17;347(16):

36. 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.
Fisher B, et al. N Engl J Med Oct 17;347(16):

37. Conclusions
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.

38. Pathologic Findings from the NSABP B-06
110 local breast recurrences were observed in 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 May 1;57(9):

39. 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?

40. Leading the Way to PBI 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)

41. 3D CRT

42. Evolution of Brachytherapy Techniques
Interstitial
Balloon
Strut Applicator
Multi-catheter
Single catheter
Multi-catheter
Let’s take a moment to recall the evolution of brachytherapy techniques. Interstitial breast brachytherapy was developed in the mid-1990’s initially in response to making post-lumpectomy radiation more time convenient for women. But we quickly began thinking about the clinical advantages of delivering a more conformal dose of radiation over a shorter period of time. For instance we could reduce the amount of radiation being delivered to healthy tissue and we could minimize some of the unfavorable cosmetic effects caused by radiating the entire breast.
MammoSite’s single-channel balloon design was instrumental in making breast brachytherapy available to more women. The complexity of the implant was dramatically reduced – but with this simplicity also came a few disadvantages.
SAVI was developed to help physicians regain the sophisticated, conformal treatment offered by the interstitial technique, without sacrificing the easier implants offered by MammoSite.

43. What Can Happen After a Balloon?
The image on the left is mammogram of patient at 26 months post MammoSite treatment. The image on the upper right is of an ultrasound showing a well defined seroma with an irregular contour where the arrow indicates which prompted a biopsy. Finally, the image in the lower right is an excised persistent seroma. Notice the fibrous capsule.

44. Persistent Seroma Balloon applicators Potential causes
Symptomatic: 3%-46%
Potential causes
Contiguous V200
Tissue compression
Both?
Persistent seroma is a seroma cavity that exists after 6 months. Persistent seroma in itself is not as troubling as symptomatic persistent seroma. These symptomatic seroma are painful to the patient, may require draining, biopsy and re-excision. Patients are concerned when they feel a lump in their breast. In addition, mammography interpretation is often more difficult and another modality may be required to follow the patient.
The cause of persistent seroma has been postulated in several papers. There are two contributing factors - the dose distribution of a balloon catheter has a radial geometry causing a contiguous high dose of radiation (V200); and, balloons compress tissue. As you know, hypoxic tissue is more resistant to radiation.

45. Strut Based Applicator
Greater flexibility
Treats the widest array of cavity & breast sizes
Enhanced performance
Eliminates skin spacing restrictions
Better outcomes
Lowers toxicity & risk of persistent seroma
Exceptional precision
Sculpt dose with selective radiation
Added convenience
Simple, secure placement and removal
Essentially, SAVI combines many of the benefits of both interstitial and balloon brachytherapy. It is the only single-entry device that enables physicians to sculpt the dose to patient-specific anatomy. The result is better outcomes for your patients, and the flexibility that enables you to offer APBI to more women.

47. Cosmesis Good/Excellent (%)
APBI Data Review
Institution
# of Cases
Median F/U (months)
Local Recurrence (%)
Cosmesis Good/Excellent (%)
ASBS MammoSite Registry
1440
60.5
1.8 90
Virginia Commonwealth University
483 24
1.2 91
National 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 92
Ochsner Clinic
164 65 3 75
RTOG 95-17 99 51 4
Not Reported
Mass General Hospital 48 84 2 68
National Institute of Oncology, Hungary Phase I/II Trial 45 80
6.7
MammoSite FDA Trial 43 83
Tufts/Brown 33
6.1 88
Total
2681
3.1 APBI
2.8 WBI
Not only does brachytherapy allow for a dramatic change in the treatment schedule from several weeks to just five days, it also is associated with fewer radiation-related toxicities and an improved cosmetic outcome.
* 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.

48. Strut Based Applicator Data Review

49. Strut Based Applicator Data Review

50. Strut Based Applicator Data Review

51. Strut Based Applicator Data Review

53. From Old School to New School

54. Thank you!
Johnny Ray Bernard, Jr., M.D., DABR Southern Ohio Medical Center Senior Medical Director Radiation Oncology (O)