3 Pathologic Anatomy of Early-Stage Breast Cancer and its Relevance to Accelerated Partial Breast Irradiation: Defining the Target

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Chapter

3.1 Determining the Extent of Disease Beyond the Lumpectomy Cavity

While several recent studies have demonstrated excellent 5-year results using acceler- ated partial breast irradiation (APBI), the optimal clinical target volume (CTV) to be used in these patients has not been clearly defined (Vicini et al. 2003; Wallner et al.

2004). The CTV, which refers to the volume of breast tissue around the lumpectomy cavity requiring radiotherapy (RT), is crucial in determining the efficacy of adjuvant PBI in comparison to whole-breast RT. It is important to consider whether PBI treats the ap- propriate volume of breast tissue at risk of harboring residual disease.

There are three bodies of data that can be used to help define the optimal CTV for APBI. These data include (1) mastectomy studies in which the distribution of cancer in the breast is correlated with the site of the initial tumor, (2) re-excision studies in which the presence, amount, and distance of residual disease is correlated with the initial tu- mor, and (3) published results with APBI in which the actual CTV used is correlated with the local recurrence rates.

Pathologic Anatomy of Early-Stage Breast Cancer and its Relevance to Accelerated Partial Breast Irradiation:

Defining the Target

Shruti Jolly, Larry L. Kestin,

Neal S. Goldstein and Frank A. Vicini

3

Contents

3.1 Determining the Extent of Disease Beyond the Lumpectomy Cavity . . . 31

3.1.1 Mastectomy Studies . . . 32

3.1.2 Re-Excision Pathologic Studies . . . 34

3.1.2.1 Concerns Regarding Re-Excision Analysis . . . 35

3.1.3 Recurrence Patterns in PBI . . . 35

3.1.4 Composite Disease Extension . . . 36

3.2 Impact of Radiation on Elsewhere Failures . . . 36

3.3 Conclusions . . . 37

References . . . 38

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Shruti Jolly, Larry L. Kestin, Neal S. Goldstein and Frank A. Vicini



3.1.1 Mastectomy Studies

The classic pathologic evaluation of mastectomy specimens performed by Holland et al.

suggested that microscopic disease was present in a multicentric pattern with relatively high frequency. Breast cancer multifocality was studied in mastectomy specimens by correlated specimen radiography and histologic techniques. It was found that up to 40%

of patients undergoing breast conservation therapy (BCT) might have residual tumor within the breast. This analysis justified the concept that whole-breast treatment, either with surgery or RT, was necessary to achieve local control. It was also one of the main sources of pathologic information that supported the use of whole-breast RT as a com- ponent of standard BCT in the 1980s (Faverly et al. 1992; Holland et al. 1985).

However, since the publication of these data, there have been significant advances in the detection, selection, and management process of patients receiving BCT, and it is un- certain how many of the patients included in the study of Holland et al. would have been eligible for BCT by modern standards. In addition, this study suggested that residual disease could be found in the breast after simulated gross excisions >2 cm from the pri- mary tumor in >29% of patients (with no extensive intraductal component). However, a review of the study details shows that in the majority of patients tumor was clinically detected (>80%) with a median size of almost 4 cm. Additionally, the extensive mapping procedure that was used was described as having an error of “less than 15 mm”, which is significant when considering the possibility of performing PBI. The most important as- pect to consider is that it is impossible to extrapolate the data generated from the “gross simulated excision” used in this study to a lumpectomy with negative microscopic mar- gins routinely achieved in the clinic today. For example, in the analysis from William Beaumont Hospital, disease extended more than 10 mm into the breast in approximately 26% of patients after an initial lumpectomy with positive margins vs. only 10% in pa- tients with initial negative margins (Goldstein et al. 2003). As a result, it is difficult to know whether the findings of Holland et al. can be applied to patients selected for BCT with modern mammographic evaluation and rigorous pathologic evaluation.

Contrary to the data of Holland et al., recent studies applying thorough pathologic processing of quadrantectomy and mastectomy specimens from women considered ap- propriate for BCT by modern standards reveal that the microscopic extension of ma- lignant cells is much less likely to be beyond 1 cm. For example, Ohtake et al. used a subgross and stereomicroscopic technique to examine the extent of residual ductal car- cinoma in situ (DCIS) remaining in the breast after actual quadrantectomies in 20 pa- tients with invasive cancer. Using a computer graphic three-dimensional reconstruction of the mammary duct–lobular system, the average maximum distance of extension was 11.9 mm. Patients >50 years of age had a maximum extension of <8 mm. In contrast to the study of Holland et al., the mean tumor size in this contemporary study was 1.7 cm (Ohtake et al. 1995).

In a related study, Imamura et al. measured the maximal DCIS extension in 253 mas- tectomy specimens in women with invasive breast cancer. The authors found that the median DCIS extension was only 9 mm and was related to patient age. The maximum disease extension was measured in relation to the edge of the invasive tumor. In pa- tients ≥40 years of age, the maximum extension was <9 mm in all cases (Imamura et al.

2000).

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3. Pathologic Anatomy of Early-Stage Breast Cancer 

Table 3.1 Factors in initial excision specimens and the presence of ≥1 cm extension of carcinoma in re- excision specimens (combining margin status with invasive carcinoma/specimen dimension ratio)

Initial excision specimen margin group

Percentage of re-excision specimens with >1 cm maximum extension (no.

of patients)

Initial excision specimen invasive carcinoma:specimen dimension ratio

Totals

<0.3 0.3–<0.6 ≥0.6

Negative 0% (0/13) 0% (0/3) 100% (2/2) 28% (2/18)

Near:least amount 0% (0/40) 0% (0/13) 40% (2/5) 3% (2/58) Near:intermedi-

ate amount

0% (0/10) 5% (1/20) 0% (0/4) 3% (1/34)

Near:great- est amount

36% (4/11) 57% (4/7) 0% (0/5) 35% (8/23)

Totals (>1.0 cm extension)

5% (4/74) 12% (5/43) 25% (4/16) 9.7% (13/133)

Fig. 3.1 Example of radial extension from re-excision analysis data from William Beaumont Hospital

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The results of these studies point out two key issues. First, it is unlikely that the dis- tribution of cancer in a breast in contemporary cases detected through screening mam- mography is similar to the findings in clinically detected cases from the early 1980s re- ported by Holland et al. Second, selection criteria for PBI clearly identify patients with smaller tumors and negative margins whose patterns of disease distribution in the breast are more likely to mirror those described in the studies of Imamura et al. and Ohtake et al., and current studies. Hopefully, additional pathologic analyses using contemporary patients will help to further clarify these issues.

3.1.2 Re-Excision Pathologic Studies

One primary re-excision study of patients treated at William Beaumont Hospital, Royal Oak, Michigan, was conducted to help define the CTV for APBI. The study population comprised 441 patients derived from a dataset of 607 consecutive patients (reviewed by one pathologist) who underwent re-excision before RT (as part of their standard BCT).

The surgical treatment in all patients included an initial excisional resection with a rim of normal breast parenchyma around the clinically apparent tumor or the tissue around the tip of the needle localization wire. Patients underwent a re-excision of the primary tumor site for inadequate margin distances or questionable post-surgical mammog- raphy results at the discretion of the surgeon or radiation oncologist. The re-excision specimens were reviewed for presence, type, amount, and linear (radial) extension of cancer cells from the edge of the original margin (see Fig. 3.1) (Goldstein et al. 2003;

Vicini et al. 2004).

In the specimens from 333 of these 441 patients, it was possible to measure the great- est perpendicular extension of any residual disease (DCIS or invasive cancer) from the edge of the original lumpectomy specimen. Because no PBI protocols allow patients with positive margins to be enrolled, only 134 patients with initial negative margins (per NSABP criteria) were studied (199 patients had initial positive margins). In more than 90% of these 134 patients, if any residual disease was present (38% of patients) it was limited to <10 mm from the edge of the original lumpectomy margin. If more restrictive criteria were used (e.g., initial excision specimens with margins that were negative, near:

least-amount, or near:intermediate-amount with invasive carcinoma:specimen maxi- mum dimension ratios of <0.3 or margins that are negative or near:least-amount with invasive carcinoma:specimen maximum dimension ratios of <0.6), it was possible to ac- curately identify all 13 patients (9.7%) with disease extending ≥10 mm from the edge of the margin (Table 3.1).

These results suggest that using NSABP criteria for negative margins (no tumor on

ink), a margin of 10 mm beyond the tumor bed is adequate to cover any residual disease

remaining in the breast in >90% of patients treated with PBI. In addition, it is possible to

accurately identify all patients with disease extending beyond 10 mm using more restric-

tive pathologic criteria.

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3. Pathologic Anatomy of Early-Stage Breast Cancer 

3.1.2.1 Concerns Regarding Re-Excision Analysis

Although the results in the current re-excision analysis suggest that a 1.0-cm margin beyond the lumpectomy cavity provides an adequate CTV for PBI (with negative mar- gins per NSABP criteria), they are by no means conclusive. Clearly, it is not certain if the assumption that the maximal, perpendicular extension distance of invasive carcinoma or DCIS measured from the inner edge of the granulation tissue reaction in the re-exci- sion specimen provides an accurate representation of residual cancer distribution in the breast. Because a variable amount of breast tissue is removed (or destroyed) around the lumpectomy edges through electrocautery or tissue processing, the actual extension of disease in some patients may be underestimated. However, the results obtained were from numerous surgeons using various surgical techniques. Despite obvious inconsis- tencies, the range and standard deviation of the maximal extension in all 333 patients were very small. Combined with the clinical results obtained with PBI, this pathologic analysis does provide some assurance that a 1.0-cm margin beyond the lumpectomy cavity may be sufficient for most patients treated with PBI. Additional similar pathologic studies and long-term clinical PBI data are needed to help clarify this issue.

3.1.3 Recurrence Patterns in PBI

The only clinical treatment data that can be used to correlate the volume of tissue irradi- ated (e.g., CTV) with local recurrence after PBI has been reported by Vicini et al. (Vicini et al. 1999; Kestin et al. 2000). In their analysis, 21 patients treated with PBI using high- dose-rate (HDR) brachytherapy who had surgical clips outlining the lumpectomy cavity and underwent computed tomography (CT) scanning after implant placement were an- alyzed. For each patient, the postimplant CT dataset was transferred to a three-dimen- sional treatment planning system. The lumpectomy cavity, target volume (lumpectomy cavity plus a 1-cm margin), and entire breast were outlined. The programmed HDR brachytherapy source positions and dwell times were then imported into the three-di- mensional planning system. The implant dataset was then registered to the visible im- plant template in the CT dataset. The distribution of the implant dose was analyzed with respect to defined volumes via dose–volume histograms. Despite visual verification by the treating physician that surgical clips (with an appropriate margin) were within the boundaries of the implant needles, the median proportion of the lumpectomy cavity that received the prescribed dose was only 87% (range 73–98%). With respect to the CTV, a median of only 68% (range 56–81%) of this volume received 100% of the prescribed dose.

The minimum follow-up for the 21 patients in the analysis was 62 months, and the

5-year actuarial rate of local recurrence was 0.5%. The overall experience in 199 patients

treated with PBI using the same CTV margins from the same group has recently been

published. With a median follow-up of 5.4 years for all patients, the 5-year actuarial rate

of local recurrence reported was 1.2%. Although no direct relationship between the pre-

cise volume of breast tissue receiving full-dose RT and outcome in all patients can be

obtained, these findings suggest that a CTV of only the lumpectomy cavity plus 1.0 cm

should be adequate in most patients and supports the conclusions from this re-excision

analysis.

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3.1.4 Composite Disease Extension

Using the above studies to delineate the target volume for partial breast irradiation, the composite maximum intraductal extension can be estimated. Imamura et al. and Ohtake et al. concluded the average maximum intraductal extension was 9 mm and 11.9 mm, respectively. The William Beaumont Hospital data using re-excision analysis revealed a maximum radial extension of <10 mm in 90% of patients. Therefore, if the radiation dose of PBI is prescribed to 1 cm around the lumpectomy cavity, the pathologic area of risk should be covered.

3.2 Impact of Radiation on Elsewhere Failures

The rationale for giving adjuvant whole-breast RT after lumpectomy in patients receiving BCT is that even after tumor excision with negative margins, many patients may har- bor significant areas of occult, residual microscopic disease in the breast (see Table 3.2).

Therefore, whole-breast radiation must be delivered to the lumpectomy cavity and the entire breast in an effort to “sterilize” any residual foci of cancer. There are multiple ran- domized trials comparing breast-conserving surgery alone versus breast-conserving surgery plus RT (see Table 3.3). The percentage of patients with elsewhere failures is not impacted by the addition of RT. In the study by Veronesi et al. (Veronesi et al. 2002), with 20 years of follow-up, the overall rate of ipsilateral breast recurrence was nearly identical to the rate of contralateral carcinomas in women who received postoperative whole-breast RT. Patterns of failure after standard BCT and after excision alone (without adjuvant radiation) show that the large majority of recurrences are in the immediate vicinity of the tumor bed. This suggests that the major value of post-lumpectomy RT is to eradicate residual disease in the region of the tumor bed and that areas of occult disease in the remainder of the breast may be of little practical significance in many patients.

A study from Yale (Smith et al. 2000) analyzed true recurrences vs. new primary ip- silateral breast tumor relapses. It was found that in 1152 patients treated with standard breast-conserving therapy utilizing whole-breast RT, at 15 years the elsewhere failure and contralateral failure rates were 13.1% and 10%, respectively. It was shown that a significant proportion of patients who experienced ipsilateral breast tumor relapses fol- lowing conservative surgery and RT may have new primary tumors as opposed to true local recurrences.

Krauss et al. studied the rates and patterns of tumor recurrence following BCT. Their analysis showed that after 5 years the ipsilateral breast tumor recurrence rates approach the rates of development of a contralateral breast cancer. While elsewhere failures were less frequent than true recurrences, they more often contributed to the ipsilateral breast tumor recurrence rate (Krauss et al. 2004). This further emphasizes that elsewhere fail- ures may increasingly represent new primary tumors rather than recurrences.

There are inherent inconsistencies in reporting recurrences following BCT. The rates

of elsewhere failures vs. true recurrences vary depending on the classification scheme

employed. The use of molecular techniques to identify markers, such as deletion/loss of

heterozygosity analysis, may provide additional insight in determining whether geneti-

cally the ipsilateral tumor bed recurrences noted are secondary to new primary tumors

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3. Pathologic Anatomy of Early-Stage Breast Cancer 

or an actual recurrence (Tsuda et al. 1999). Nonetheless, the above data suggest that there is a rate of developing new disease within the breast that whole-breast RT may not be able to prevent. The key benefit of whole-breast RT seems to be reduction of failures in the breast tissue immediately surrounding the lumpectomy cavity.

3.3 Conclusions

The optimal margin of tissue requiring RT after lumpectomy in patients treated with PBI remains controversial. However, recent radiographic and pathologic data suggest that a margin of 10 mm around the tumor bed appears adequate for coverage of any disease remaining in the breast after lumpectomy in most (>90%) patients treated with PBI, pro- vided the final negative margins are negative using the NSABP criteria. More restrictive

Table 3.2 Prospective randomized trials of lumpectomy with/without RT (CS conserving surgery)

Trial Reference No. of patients

Tumor size (cm)

Surgery Patients with recurrence (%)

Reduction in recur- rence, CS vs. CS + RT (%) CS alone CS + RT

NSABP B06

Fisher et al. 2002

1265 <4.0 Wide

excision

36 12 67

Milan III Veronesi et al. 1993

601 <2.5 Quadran-

tectomy

24 6 75

Scottish Forrest et al. 1996

584 <4.0 Wide

excision

5 6 75

Sweden Liljegren et al. 1994

381 <2.0 Quadran-

tectomy

24 9 63

Ontario Clark et al. 1996

837 <4.0 Wide

excision

35 11 69

British Renton et al. 1996

399 <5.0 Wide

excision

35 13 63

Table 3.3 The impact of whole-breast radiation therapy on elsewhere failures (CS conserving surgery)

Trial Reference Elsewhere failures (%)

CS alone CS + RT

NSABP B06 Fisher et al. 2002 2.7 (17/636) 3.8 (24/629)

Ontario Clark et al. 1992 3.5 (15/421) 0.9 (4/416)

Milan Veronesi et al. 2002 2.8 (8/280) 0.6 (2/299)

Sweden Liljegren et al. 1994 1.5 (3/194) 0.5 (1/187)

Range 1.5–3.5 0.5–3.8

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pathologic criteria can be used to identify patients with disease beyond 10 mm. Addi- tional pathologic analysis as well as long-term clinical data on patients treated with PBI are required to provide stricter guidelines in establishing the optimal CTV for PBI.

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