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Cancer Investigation, 10(5), 471-476 (1992)
Patient Selection for Treatment with Conservative Surgery and Radiation Therapy Abram Recht, M.D. Joint Center for Radiation Therapy Department of Radiation Oncology Harvard Medical School Beth Israel Hospital 330 Brookline Avenue Boston, Massachusetts
ABSTRACT There is now general agreement that treatment with conservative surgery and radiation therapy yields survival equal to mastectomy with the advantage of organ preservation for properly selected patients. When competently performed, such treatment gives highly satisfactory cosmetic results and acceptably low rates of local tumor recurrence. However, there remain numerous controversies concerning patient selection for this treatment option. The factors involved in patient selection may be grouped into three categories: patient factors; clinical factors; and pathologic factors. This article reviews their use. Because breast cancer has a long natural history, long follow up of patients is required for ultimate proof of the relative merits of different selection or treatment policies. However, due to the increasing numbers of patients being treated with conservative surgery and radiotherapy, it appears likely that many of these questions will be answered within the next decade.
there remain numerous controversies concerning patient selection for this treatment option. In this article some of the generally accepted principles and controversies surrounding patient selection will be addressed. Further discussion of these issues and others may be found elsewhere (2).
INTRODUCTION There is now general agreement that treatment with conservative surgery and radiation therapy yields survival equal to mastectomy with the advantage of organ preservation for properly selected patients (1). However, 47 1 Copyright 0 1992 by Marcel Dekker, Inc.
Recht
412
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PATIENT FACTORS The factors involved in patient selection may be grouped into three categories: patient factors; clinical factors; and pathologic factors. Pregnancy is an absolute contraindication to treatment with radiotherapy, unless terminated, because of the possible teratogenic and carcinogenic effects on the fetus. Several patients with pre-existing collagen-vascular disease who had unusually severe acute and chronic reactions to treatment have been reported by one group (3,4), but whether all such patients treated without complications were identified is not certain in this retrospective analysis. Thus, caution appears indicated in assessing whether to treat such individuals with radiotherapy, but we do not view the presence of collagen-vascular disease by itself as an absolute contraindication to treatment. A controversial factor in patient selection is age at diagnosis. Reports from the Joint Center for Radiation Therapy (JCRT) (5) and other centers in the early and middle 1980s found that patients younger than 35 years old at diagnosis had a substantially higher risk of local recurrence of breast cancer than older patients. However, more recent series (6) have failed to show such dramatic differences in local recurrence rates. These conflicting results may be explained in part by marked changes in patient selection criteria and techniques of mammography, surgery, pathologic assessment of specimens, radiotherapy, and systemic therapy over the past decades. For example, the 5-year actuarial incidence of local failure in patients age 34 or younger was 21% for 65 patients treated at the JCRT from 1968 to 1982, compared with 12% in 44 patients from 1983 to 1985 (7). One of the many changes in treatment practices which occurred between these two time periods was an increase in the use of re-excision of the primary tumor site following initial biopsy. Only 22% of patients in the earlier cohort underwent a re-excision, compared with 64% of those in the latter group. The 8-year rate of local failure was 10% for the 42 patients in both cohorts who underwent re-excision, compared with 32% for the 67 patients who did not. Therefore, very young patients may be at little or no increased risk of local recurrence, compared with older patients, when current evaluation and treatment techniques are employed. Even if a slight increased risk does exist for this patient group, it is not clear whether this adversely affects overall survival, compared with initial treatment by mastectomy. Hence, we do not believe that
young patient age is a contraindication to breast-conserving management. Although there often has been a reluctance in many communities to treat older patients with radiotherapy (8), in our experience older patients tolerate treatment extremely well and have excellent local control (5). The greatest obstacle to treating elderly patients is often the daily transportation to and from the radiation oncology department, which can be solved with more or less difficulty. Since inadequate treatment may result in an increased likelihood of local or even distant failure, doing a patient the “kindness” of minimal initial therapy may well backfire.
CLINICAL FACTORS One of the major criteria or patient selection is the ability to resect the primary without causing major cosmetic deformities. This is determined by several factors, such as the size of the primary tumor, the size of the breast, the location of the tumor, and the extent of the surgical margin felt to be necessary. As there is no difference in recurrence rates based on the size of the tumor itself (9), this is a matter of judgement. Women with very large breasts may have greater breast retraction following therapy than patients with smaller breasts (10). Nonetheless, most patients find the degree of change acceptable. Although the treatment of such patients is often technically challenging to the radiation oncologist, careful attention to technical details usually can minimize the extent of this problem. Patients with two nonadjacent primary cancers in the same breast (demonstrated by palpation or mammographically) are poor candidates for breast conserving treatment. The cosmetic results of multiple wide local excisions and radiation boosts are likely to be undesirable. Further, such patients appear to have a risk of local recurrence of 25 to 40%, substantially higher than what is usually considered acceptable ( I I , 12). The prognosis of these patients with initial mastectomy however is not known. Another group of patients in whom similar concerns obtain is that in which mammograms reveal extensive malignant microcalcifications. Over half of the patients in each of these groups will have more than one quadrant of the breast involved pathologically when mastectomy is performed (13). The need to rule out true multicentric or diffuse tumor is one reason why modern film-screen mammography often provides critical information in the initial evaluation
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Patient Selection for Surgery and RT
473
of patients (14). In a study of 200 consecutive patients presenting with a palpable invasive cancer at the University of Edinburgh, 17 patients (8.5%) had significant changes in their management due to abnormalities not suspected on physical examination ( I 5). Twelve patients had findings suggestive of diffuse or multicentric ipsilateral cancers and underwent .mastectomy as a result. Five patients were found to have a contralateral breast cancer. Two additional patients had contralateral lesions which required biopsy but were benign. Mammography with magnification views of suspicious or equivocal areas should be performed before biopsy if possible, in order to avoid obscuring potentially important details by postoperative scarring or hematoma. Postbiopsy mammograms are often useful to assess the completeness of resection in those tumors with microcalcifications. The location of the tumor is a concern for patients with subareolar primaries. In one mastectomy series, many of these patients were found to have extensive tumor spread along the ducts (13). We feel that such patients should undergo resection of the nipple-areola complex. Not all patients are willing to accept this surgery. However, the appearance and texture of the remaining breast is as good as that after most reconstruction procedures, and sensation in the remaining breast is preserved (unlike following a reconstruction). Patients with bilateral breast cancer (either synchronous or metachronous) can also be treated successfully with conservative surgery and radiation therapy without an increased risk of complications (16).
PATHOLOGIC FACTORS A heated controversy has existed as to whether patients who have microscopically involved (or “positive”) margins can be treated as successfully as can patients with microscopically uninvolved margins. One reason for this uncertainty is that there are technical problems in assessing the margins. It is essential that the pathologist ink the margins of resection prior to cutting the specimen so that they can be clearly identified on microscopic examination. However, there is no clear definition of what constitutes “involved margins.” This can imply that cancer is seen either directly at an inked surface or within some arbitrary distance from an inked margin. Such a definition obviously is influenced by the number of sections assessed for involvement. It may also be clinically important to distinguish between “focal” or “minimal” involvement of the margins and more extensive involvement. Limited data from several centers suggest that recurrence rates are lower when margins are “negative” rather than “positive” or “indeterminate.” However, margin involvement was nor an independent risk factor for recurrence in other studies (Table 1). The type of resection performed and the histologic features of the tumor may also influence the clinical implications of margin involvement. For example, in a randomized study performed in Milan comparing quadrantectomy plus radiotherapy to tumorectomy (a much narrower excision) and radiotherapy, the incidence of local recurrence in patients with positive margins was
Table I Risk qf Local Recurrence and Margin Status
Negative
Close
Positive
Indeterminate/ unknown
Reference
Marseille
8% (221283)
-
24% (12/49)
16% (27/ 164)
17
Gustave-Roussy
5% (12/262)
-
10% (8/80)
-
18
City of Hope
2% (1/63)
-
13% (1/8)
Cincinnati”
7% (23)
-
18% (23)
Amsterdam
1% (11242)
2% (2/95)
Penn
9% (l9/203)
Kaiser Tufts
Series
,‘Actuarial S-year rate
11% (3128)
19
-
20
3% (1/32)
I % (1/216)
21
I I % (4/37)
4% (2157)
10% (36/346)
22
6% (161283)
8% (7187)
13% (3/23)
-
23
0% (0/22)
0% (0/II)
0% (0/61)
-
24
Recht
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0% (0 of 7) in the quadrantectomy arm and 13% (6 of 46) in the tumorectomy arm. The respective rates of local failure were 2% (4 of 169) and 5% (13 of 237) in evaluable patients with negative margins (25). A re-excision study from the JCRT (26) found that the likelihood of having involvement of the margins following limited resection depended on the histology of the primary tumor. Similar findings concerning the distribution and amount of residual tumor in mastectomy specimens has also been reported (27). Thus, the status of the specimen margins must be considered in relationship to the biological behavior of the primary tumor and the extent of surgery, rather than as an isolated factor, in selection of patients and treatment techniques. The experiences at the JCRT (28), the Institut Gustave Roussy (18), the University of Pennsylvania (22), and the Kaiser-Permanente Group (23) suggest that a high rate of local tumor control can be achieved in patients with close or involved margins by using a “boost” dose of radiation to bring the primary tumor site to a minimum dose of 60 Gy or higher. Whether a boost is needed in patients with uninvolved margins is not known. The histologic factor that most investigators have found to have the greatest impact on the risk of recurrence (for infiltrating ductal carcinomas) has been the presence or absence of an extensive intraductal component, or EIC (Table 2). Tumors are described as being in the EIC+ category when two features are simultaneously present: intraductal carcinoma comprising a prominant portion of the area of the primary mass; and intraductal carcinoma clearly extending beyond the infiltrating margin of the tumor or present in sections of grossly normal adjacent breast tissue. (Predominantly noninvasive tumors, with only focal areas of invasion, were also included in this category.) Table 2 Risk o/’Locnl Recurrence and Extensive Intraductal Component (EIC)
Scrics
EIC Absent
EIC Present
Reference
JCRT
7% (29/418)
26% (43/166)
28
10% (391380)
19% (22/ 116)
17
Curie Institute
9% (33/361)
19% (12/63)
29
Wcstminster Hospital
2% (5/234)
15% (9159)
30
Amsterdam
1% (1/208)
4% (3179)
21
10%(211214)
22% (13/59)
31
Marscillc
Iowa
The most recent update of the effect of EIC in patients treated at the JCRT examined the risk of local recurrence in 684 breasts with infiltrating ductal histology treated from 1968 to 1982 in whom there were sufficient adjacent breast tissue for pathologic review and in whom a boost dose was used to give the tumor bed a minimum dose of 60 Gy (28). The median follow up in this group was 75 months. In the large majority of patients the tumor was excised grossly with a small rim of adjacent breast tissue wirhout regard to the microscopic margins of resection. The margins of resection were not routinely inked or labelled during this period and therefore were not evaluable in most cases on review. The group with extensive intraductal involvement had a 24% actuarial risk of breast recurrence at 5 years and 32% at 10 years, compared with only 6% at 5 years and 14% at 10 years for other patients. Of importance, the five-year risk of distant failure was similar for patients either with or without EIC, despite the much higher breast failure rate in the former group. Not all investigators looking at the influence of EIC have found exactly the same impact in all patient groups. The presence of an EIC was found to affect local failure rates in premenopausal patients, but not in postmenopausal patients, in a series from Marseille (17). In the Curie Institute series EIC was a significant factor on univariate analysis but not multivariate analysis (29). It seems likely that patients with an EIC have a greater residual tumor burden following gross excision than do other patients. Re-excision specimens from patients with an EIC who initially undergo only limited gross excision frequently contain substantial residual disease (26,32). A review of 217 mastectomy specimens from the Netherlands found that the presence of an EIC was associated with a substantial likelihood that significant residual disease would be located beyond the boundaries of a cosmetically acceptable excision (27). These pathologic findings suggest that the risk of recurrence in patients with an EIC may be reduced by a more extensive surgical resection than was often used in the past. In a recent analysis correlating the volume of resection with the incidence of local failure, the actuarial 5-year risk of recurrence at or near the primary tumor site was dependent both on the volume of excised tissue and on the histology of the primary tumor (Table 3) (33). Similar conclusions may be drawn from the results of treatment in Amsterdam, where the use of very wide excision and high radiotherapy doses resulted in a low risk of recurrence in patients with an EIC (21). The results at the JCRT and other centers thus suggest that the optimal extent of resection may depend on the
Patient Selection for Surgery and RT
475
Table 3
recurrence (401, regardless of its overall prognostic implications.
Actuarial 5-Year Risk of Recurrence at or Near the Primary Tumor Site Related to Tumor Histology and Volume of Excision
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NO.
Size of excision (CM3) 48
CONCLUSIONS P
TI EIC-
182
9%
2%
0%
0.02
TI EIC+
83
29%
22%
10%
0.07
75
T2 EIC-
164
6%
2%
3%
NS
T2 EIC+
78
36%
26%
9%
0.04
P-values compare the smallest and largest excisions. Source: Adapted from Ref. 33.
extent of associated intraductal carcinoma. Patients without an EIC are well treated with excisional biopsy with narrow gross tissue margins; if the margins are heavily involved or inevaluable, we then perform a re-excision prior to radiotherapy. If an EIC is present and the margins are microscopically involved or equivocal, then a reexcision of the biopsy site should be done. In most patients a cosmetically and pathologically satisfactory re-excision can be performed. If the margins of the re-excision specimen are still involved, mastectomy may be preferable. Experience with other histologic subtypes of breast neoplasms is much more limited in all series, but in general results appear similar to those achieved in infiltrating ductal carcinomas (34-36). Other factors which may affect the likelihood of breast failure are blood or lymphatic vessel invasion (28,29), histologic grade ( 18,37,38), estrogen receptor level (23), aneuploidy (39), and a major mononuclear cell reaction or lymphocytic infiltrate ( 17). For example, in the JCRT series (28) the presence of lymphatic vessel invasion (LVI) was slightly higher in the EIC + group (31%) than the EIC group (25%). By itself, LVI did not affect local recurrence rates; however, there was a statistically significant increase in the 5-year actuarial breast failure rate in the EIC + /LVI + subgroup (34%) compared with the EIC + /LVI - subgroup (20%). (The respective rates in the EIC - subgroups were 9% and 5% .) The impact of most of these pathologic factors have not yet been confirmed by other groups. Other factors, such as oncogene expression, are only beginning to be examined. For example, in one small study expression of the c-erbB-2 oncogene did not appear to influence the risk of local
The results to date from prospective randomized trials indicate that survival following conservative surgery and radiotherapy for early breast cancer is equivalent to that following mastectomy. When competently performed, such treatment gives highly satisfactory cosmetic results and acceptably low rates of local tumor recurrence. A number of controversial issues remain concerning patient selection as well as other aspects of this treatment approach. Because breast cancer has a long natural history, long follow up of patients is required for ultimate proof of the relative merits of different selection or treatment policies. However, due to the increasing numbers of patients being treated with conservative surgery and radiotherapy, it appears likely that many of these questions will be answered within the next decade.
REFERENCES I. 2. 3.
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NIH Consensus Conference: Treatment of early-stage breast cancer. J Am Med Assoc 265391-395. 1991. Harris JR, Hellman S, Henderson IC et al: Breast Diseases. 2nd ed. Philadelphia, JB Lippincott, 1991. Fleck RS, McNeese M, Ellerbroek NA et al: Consequences of breast irradiation in patients with pre-existing collagen vascular diseases. Int J Radiat Oncol Biol Phys 17:829-833, 1989. Robertson JM, Clarke DH, Pevzner MM et al: Breast conservation therapy: severe breast fibrosis after radiation therapy in patients with collagen vascular disease. Cancer 68502-508, 1991. Recht A, Connolly JL, Schnitt SJ et al: The effect of young age on tumor recurrence in the breast after conservative surgery and radiotherapy for early stage breast cancer. Int J Radiat Oncol Biol Phys 14:3-10, 1988. Solin LJ, Fowble B, Schultz DJ et al: Age of prognostic factor for patients treated with definitive irradiation for early stage breast cancer. Int J Radiat Oncol Biol Phys 16:373-381. 1989. Vicini F, Recht A, Abner A et al: The association between very young age and recurrence in the breast in pts treated with conservative surgery (CS) and radiation therapy (RT) (abstr). Int J Radiat Oncol Biol Phys I9(Suppl 1):132, 1990. Kantorowitz DA, Poulter CA, Sischy B et al: Treatment of breast cancer among elderly women with segmental mastectomy or segmental mastectomy plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys 15:263-270, 1988. Eberlein TJ, Connolly JL, Schnitt SJ et al: Predictors of local recurrence following conservative breast surgery and radiation therapy: the influence of tumor size. Arch Surg 125:771-777, 1990. Gray JR, McCormick B, Cox L et al: Primary breast irradiation
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in large-breasted or heavy women: analysis of cosmetic outcome. Int J Radiat Oncol Biol Phys 21:347-354, 1991. Leopold KA, Recht A, Schnitt SJ et al: Results of conservative surgery and radiation therapy for multiple synchronous cancers of one breast. Int J Radiat Oncol Biol Phys 16: 11-16. 1989. Kurtz J, Jacquemier J , Amalric R et al: Breast-conserving therapy for macroscopically multiple cancers. Ann Surg 212:38-44, 1990. Danoff B, Goodman RL: Identification of a subgroup of patients with breast cancer in whom conservative surgery and radiation is contraindicated (abstr). Int J Radiat Oncol Biol Phys I I(Supp. 1):104, 1985. Sadowsky NL. Semine A, Harris JR: Breast imaging-a critical aspect of breast conserving treatment. Cancer 65:2113-2118, 1990. Dixon JM, Chetty U: Mammography in the management of patients with small breast cancers. Br J Surg 78:218-219, 1991. Solin LJ, Fowble BL, Schultz DJ et al: Bilateral breast carcinoma treated with definitive irradiation. Int J Radiat Oncol Biol Phys 17:263-271, 1989. Kurtz J, Jacquemier J, Amalric R et al: Why are local recurrences after breast-conserving surgery more frequent in young patients? J Clin Oncol 8:591-598, 1990. Clarke DH, Le MG, Sarrazin D et al: Analysis of local-regional relapses in patients with early breast cancers treated by excision and radiotherapy: experience of the Institut Gustave-Roussy. Int J Radiat Oncol Biol Phys 11:137-145, 1985. Pezner RD, Terz J, Ben-Ezra J et al: Now there are two effective conservation approaches for patients with stage I and Stage 11 breast cancer: how pathological assessment of inked resection margins can provide valuable information for the radiation oncologist. Am J Clin Oncol (CCT) 13:175-179, 1990. Cross MA, Wirman JA, Compaan PJ et al: Pathologic parameters in breast conservation therapy (abstr). Breast Cancer Res Treat 14:140. 1989. Bartelink H. Borger JH, Van Dongen JA et al: The impact of tumor size and histology on local control after breast-conserving therapy. Radiother Oncol I1:297-303, 1988. Solin W. Fowble BL. Schultz DJ et al: The significance of the pathology margins of tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer. Int J Radiat Oncol Biol Phys 21:279-287, 1991. Ryoo MC. Kagan AR. Wollin M et al: Prognostic factors for recurrence and cosmesis in 393 patients after radiation therapy for early mammary carcinoma. Radiology 172:555-559, 1989. Schmidt-Ullrich R. Wazer DE, Tercilla 0 et al: Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma. Int J Radiat Oncol Biol Phys I7:733-738. 1989. Veronesi U. Volterrani F, Luini A et al: Quadrantectomy versus lumpectomy for small size breast cancer. Eur J Cancer 26:671673. 1990.
26. Schnitt SJ, Connolly JL, Khettry U et al: Pathologic findings on re-excision of the primary site in breast cancer patients considered for treatment by primary radiation therapy. Cancer 59:675-681, 1987. 27. Holland R, Connolly JL, Gelman R et al: The presence of an extensive intraductal component (EIC) following a limited excision predicts for prominent residual disease in the remainder of the breast. J Clin Oncol 8.1 13-1 18, 1990. 28. Boyages J, Recht A, Connolly J et al: Early breast cancer: predictors of breast recurrence for patients treated with conservative surgery and radiation therapy. Radiother Oncol 19:29-41, 1990. 29. Fourquet A, Campana F, Zafrani B et al: Prognostic factors of breast recurrence in the conservative management of early breast cancer: a 25-year follow-up. Int J Radiat Oncol Biol Phys 17:7 19725, 1989. 30. Lindley R, Bulman A, Parsons P et al: Histologic features predictive of an-increased risk of early local recurrence after treatment of breast cancer by local tumor excision and radical radiotherapy. Surgery 105:13-20, 1989. 31. Mayr NA, Staples JJ, Robinson RA et al: Morphometric studies in intraductal breast carcinoma using computerized image analysis. Cancer 67:2805-2812, 1991. 32. Solin LJ, Fowble B, Martz K et al: Results of re-excisional biopsy of the primary tumor in preparation for definitive irradiation of patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 12:721-725, 1986. 33. Vicini FA, Eberlein TJ, Connolly JL et al: Extent of resection for patients with Stage 1-11 breast cancer treated with conservative surgery and radiotherapy. Ann Surg 214:200-204, 1991. 34. Kurtz JM, Jacquemier J, Torhorst J et al: Conservation therapy for breast cancers other than infiltrating ductal carcinoma. Cancer 63:1630-1635, 1989. 35. Schnitt SJ, Connolly JL, Recht A et al: Influence of infiltrating lobular histology on local tumor control in breast cancer patients treated with conservative surgery and radiotherapy. Cancer 64: 448-454, 1989. 36. Ucla L, Fenton J, Mathieu G et al: Cancer colloides du seininteret de la radiotherapie-serie de 138 cas traites a I’Institut Curie. Bull Cancer 75:783-787, 1988. 37. Kurtz JM, Amalric R, Brandone H et al: Local recurrence after breast-conserving surgery and radiotherapy: frequency, time course, and prognosis. Cancer 63:1912-1917, 1989. 38. Stadler B, Staffen A, Strasser K et al: Prognostic factors for local recurrence in patients with limited surgery and irradiation of breast cancer. Strahlenther Onkol 166:453-456, 1990. 39. Beerman H, Bonsing BA, van de Vijver MJ et al: DNA ploidy of primary breast cancer and local recurrence after breast-conserving therapy. Br J Cancer 64:139-143, 1991. 40. Schwartz L, Thor AD, Edgerton SM et al: Retrospective analysis of c-erbB-2 and PS2 in early breast cancer before and after local failure (abstr). Int J Radiat Oncol Biol Phys 19(supp. 1):212. 1990.
Cancer Investigation, 10(5), 471-476 (1992)
Patient Selection for Treatment with Conservative Surgery and Radiation Therapy Abram Recht, M.D. Joint Center for Radiation Therapy Department of Radiation Oncology Harvard Medical School Beth Israel Hospital 330 Brookline Avenue Boston, Massachusetts
ABSTRACT There is now general agreement that treatment with conservative surgery and radiation therapy yields survival equal to mastectomy with the advantage of organ preservation for properly selected patients. When competently performed, such treatment gives highly satisfactory cosmetic results and acceptably low rates of local tumor recurrence. However, there remain numerous controversies concerning patient selection for this treatment option. The factors involved in patient selection may be grouped into three categories: patient factors; clinical factors; and pathologic factors. This article reviews their use. Because breast cancer has a long natural history, long follow up of patients is required for ultimate proof of the relative merits of different selection or treatment policies. However, due to the increasing numbers of patients being treated with conservative surgery and radiotherapy, it appears likely that many of these questions will be answered within the next decade.
there remain numerous controversies concerning patient selection for this treatment option. In this article some of the generally accepted principles and controversies surrounding patient selection will be addressed. Further discussion of these issues and others may be found elsewhere (2).
INTRODUCTION There is now general agreement that treatment with conservative surgery and radiation therapy yields survival equal to mastectomy with the advantage of organ preservation for properly selected patients (1). However, 47 1 Copyright 0 1992 by Marcel Dekker, Inc.
Recht
412
Cancer Invest Downloaded from informahealthcare.com by McMaster University on 11/03/14 For personal use only.
PATIENT FACTORS The factors involved in patient selection may be grouped into three categories: patient factors; clinical factors; and pathologic factors. Pregnancy is an absolute contraindication to treatment with radiotherapy, unless terminated, because of the possible teratogenic and carcinogenic effects on the fetus. Several patients with pre-existing collagen-vascular disease who had unusually severe acute and chronic reactions to treatment have been reported by one group (3,4), but whether all such patients treated without complications were identified is not certain in this retrospective analysis. Thus, caution appears indicated in assessing whether to treat such individuals with radiotherapy, but we do not view the presence of collagen-vascular disease by itself as an absolute contraindication to treatment. A controversial factor in patient selection is age at diagnosis. Reports from the Joint Center for Radiation Therapy (JCRT) (5) and other centers in the early and middle 1980s found that patients younger than 35 years old at diagnosis had a substantially higher risk of local recurrence of breast cancer than older patients. However, more recent series (6) have failed to show such dramatic differences in local recurrence rates. These conflicting results may be explained in part by marked changes in patient selection criteria and techniques of mammography, surgery, pathologic assessment of specimens, radiotherapy, and systemic therapy over the past decades. For example, the 5-year actuarial incidence of local failure in patients age 34 or younger was 21% for 65 patients treated at the JCRT from 1968 to 1982, compared with 12% in 44 patients from 1983 to 1985 (7). One of the many changes in treatment practices which occurred between these two time periods was an increase in the use of re-excision of the primary tumor site following initial biopsy. Only 22% of patients in the earlier cohort underwent a re-excision, compared with 64% of those in the latter group. The 8-year rate of local failure was 10% for the 42 patients in both cohorts who underwent re-excision, compared with 32% for the 67 patients who did not. Therefore, very young patients may be at little or no increased risk of local recurrence, compared with older patients, when current evaluation and treatment techniques are employed. Even if a slight increased risk does exist for this patient group, it is not clear whether this adversely affects overall survival, compared with initial treatment by mastectomy. Hence, we do not believe that
young patient age is a contraindication to breast-conserving management. Although there often has been a reluctance in many communities to treat older patients with radiotherapy (8), in our experience older patients tolerate treatment extremely well and have excellent local control (5). The greatest obstacle to treating elderly patients is often the daily transportation to and from the radiation oncology department, which can be solved with more or less difficulty. Since inadequate treatment may result in an increased likelihood of local or even distant failure, doing a patient the “kindness” of minimal initial therapy may well backfire.
CLINICAL FACTORS One of the major criteria or patient selection is the ability to resect the primary without causing major cosmetic deformities. This is determined by several factors, such as the size of the primary tumor, the size of the breast, the location of the tumor, and the extent of the surgical margin felt to be necessary. As there is no difference in recurrence rates based on the size of the tumor itself (9), this is a matter of judgement. Women with very large breasts may have greater breast retraction following therapy than patients with smaller breasts (10). Nonetheless, most patients find the degree of change acceptable. Although the treatment of such patients is often technically challenging to the radiation oncologist, careful attention to technical details usually can minimize the extent of this problem. Patients with two nonadjacent primary cancers in the same breast (demonstrated by palpation or mammographically) are poor candidates for breast conserving treatment. The cosmetic results of multiple wide local excisions and radiation boosts are likely to be undesirable. Further, such patients appear to have a risk of local recurrence of 25 to 40%, substantially higher than what is usually considered acceptable ( I I , 12). The prognosis of these patients with initial mastectomy however is not known. Another group of patients in whom similar concerns obtain is that in which mammograms reveal extensive malignant microcalcifications. Over half of the patients in each of these groups will have more than one quadrant of the breast involved pathologically when mastectomy is performed (13). The need to rule out true multicentric or diffuse tumor is one reason why modern film-screen mammography often provides critical information in the initial evaluation
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Patient Selection for Surgery and RT
473
of patients (14). In a study of 200 consecutive patients presenting with a palpable invasive cancer at the University of Edinburgh, 17 patients (8.5%) had significant changes in their management due to abnormalities not suspected on physical examination ( I 5). Twelve patients had findings suggestive of diffuse or multicentric ipsilateral cancers and underwent .mastectomy as a result. Five patients were found to have a contralateral breast cancer. Two additional patients had contralateral lesions which required biopsy but were benign. Mammography with magnification views of suspicious or equivocal areas should be performed before biopsy if possible, in order to avoid obscuring potentially important details by postoperative scarring or hematoma. Postbiopsy mammograms are often useful to assess the completeness of resection in those tumors with microcalcifications. The location of the tumor is a concern for patients with subareolar primaries. In one mastectomy series, many of these patients were found to have extensive tumor spread along the ducts (13). We feel that such patients should undergo resection of the nipple-areola complex. Not all patients are willing to accept this surgery. However, the appearance and texture of the remaining breast is as good as that after most reconstruction procedures, and sensation in the remaining breast is preserved (unlike following a reconstruction). Patients with bilateral breast cancer (either synchronous or metachronous) can also be treated successfully with conservative surgery and radiation therapy without an increased risk of complications (16).
PATHOLOGIC FACTORS A heated controversy has existed as to whether patients who have microscopically involved (or “positive”) margins can be treated as successfully as can patients with microscopically uninvolved margins. One reason for this uncertainty is that there are technical problems in assessing the margins. It is essential that the pathologist ink the margins of resection prior to cutting the specimen so that they can be clearly identified on microscopic examination. However, there is no clear definition of what constitutes “involved margins.” This can imply that cancer is seen either directly at an inked surface or within some arbitrary distance from an inked margin. Such a definition obviously is influenced by the number of sections assessed for involvement. It may also be clinically important to distinguish between “focal” or “minimal” involvement of the margins and more extensive involvement. Limited data from several centers suggest that recurrence rates are lower when margins are “negative” rather than “positive” or “indeterminate.” However, margin involvement was nor an independent risk factor for recurrence in other studies (Table 1). The type of resection performed and the histologic features of the tumor may also influence the clinical implications of margin involvement. For example, in a randomized study performed in Milan comparing quadrantectomy plus radiotherapy to tumorectomy (a much narrower excision) and radiotherapy, the incidence of local recurrence in patients with positive margins was
Table I Risk qf Local Recurrence and Margin Status
Negative
Close
Positive
Indeterminate/ unknown
Reference
Marseille
8% (221283)
-
24% (12/49)
16% (27/ 164)
17
Gustave-Roussy
5% (12/262)
-
10% (8/80)
-
18
City of Hope
2% (1/63)
-
13% (1/8)
Cincinnati”
7% (23)
-
18% (23)
Amsterdam
1% (11242)
2% (2/95)
Penn
9% (l9/203)
Kaiser Tufts
Series
,‘Actuarial S-year rate
11% (3128)
19
-
20
3% (1/32)
I % (1/216)
21
I I % (4/37)
4% (2157)
10% (36/346)
22
6% (161283)
8% (7187)
13% (3/23)
-
23
0% (0/22)
0% (0/II)
0% (0/61)
-
24
Recht
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0% (0 of 7) in the quadrantectomy arm and 13% (6 of 46) in the tumorectomy arm. The respective rates of local failure were 2% (4 of 169) and 5% (13 of 237) in evaluable patients with negative margins (25). A re-excision study from the JCRT (26) found that the likelihood of having involvement of the margins following limited resection depended on the histology of the primary tumor. Similar findings concerning the distribution and amount of residual tumor in mastectomy specimens has also been reported (27). Thus, the status of the specimen margins must be considered in relationship to the biological behavior of the primary tumor and the extent of surgery, rather than as an isolated factor, in selection of patients and treatment techniques. The experiences at the JCRT (28), the Institut Gustave Roussy (18), the University of Pennsylvania (22), and the Kaiser-Permanente Group (23) suggest that a high rate of local tumor control can be achieved in patients with close or involved margins by using a “boost” dose of radiation to bring the primary tumor site to a minimum dose of 60 Gy or higher. Whether a boost is needed in patients with uninvolved margins is not known. The histologic factor that most investigators have found to have the greatest impact on the risk of recurrence (for infiltrating ductal carcinomas) has been the presence or absence of an extensive intraductal component, or EIC (Table 2). Tumors are described as being in the EIC+ category when two features are simultaneously present: intraductal carcinoma comprising a prominant portion of the area of the primary mass; and intraductal carcinoma clearly extending beyond the infiltrating margin of the tumor or present in sections of grossly normal adjacent breast tissue. (Predominantly noninvasive tumors, with only focal areas of invasion, were also included in this category.) Table 2 Risk o/’Locnl Recurrence and Extensive Intraductal Component (EIC)
Scrics
EIC Absent
EIC Present
Reference
JCRT
7% (29/418)
26% (43/166)
28
10% (391380)
19% (22/ 116)
17
Curie Institute
9% (33/361)
19% (12/63)
29
Wcstminster Hospital
2% (5/234)
15% (9159)
30
Amsterdam
1% (1/208)
4% (3179)
21
10%(211214)
22% (13/59)
31
Marscillc
Iowa
The most recent update of the effect of EIC in patients treated at the JCRT examined the risk of local recurrence in 684 breasts with infiltrating ductal histology treated from 1968 to 1982 in whom there were sufficient adjacent breast tissue for pathologic review and in whom a boost dose was used to give the tumor bed a minimum dose of 60 Gy (28). The median follow up in this group was 75 months. In the large majority of patients the tumor was excised grossly with a small rim of adjacent breast tissue wirhout regard to the microscopic margins of resection. The margins of resection were not routinely inked or labelled during this period and therefore were not evaluable in most cases on review. The group with extensive intraductal involvement had a 24% actuarial risk of breast recurrence at 5 years and 32% at 10 years, compared with only 6% at 5 years and 14% at 10 years for other patients. Of importance, the five-year risk of distant failure was similar for patients either with or without EIC, despite the much higher breast failure rate in the former group. Not all investigators looking at the influence of EIC have found exactly the same impact in all patient groups. The presence of an EIC was found to affect local failure rates in premenopausal patients, but not in postmenopausal patients, in a series from Marseille (17). In the Curie Institute series EIC was a significant factor on univariate analysis but not multivariate analysis (29). It seems likely that patients with an EIC have a greater residual tumor burden following gross excision than do other patients. Re-excision specimens from patients with an EIC who initially undergo only limited gross excision frequently contain substantial residual disease (26,32). A review of 217 mastectomy specimens from the Netherlands found that the presence of an EIC was associated with a substantial likelihood that significant residual disease would be located beyond the boundaries of a cosmetically acceptable excision (27). These pathologic findings suggest that the risk of recurrence in patients with an EIC may be reduced by a more extensive surgical resection than was often used in the past. In a recent analysis correlating the volume of resection with the incidence of local failure, the actuarial 5-year risk of recurrence at or near the primary tumor site was dependent both on the volume of excised tissue and on the histology of the primary tumor (Table 3) (33). Similar conclusions may be drawn from the results of treatment in Amsterdam, where the use of very wide excision and high radiotherapy doses resulted in a low risk of recurrence in patients with an EIC (21). The results at the JCRT and other centers thus suggest that the optimal extent of resection may depend on the
Patient Selection for Surgery and RT
475
Table 3
recurrence (401, regardless of its overall prognostic implications.
Actuarial 5-Year Risk of Recurrence at or Near the Primary Tumor Site Related to Tumor Histology and Volume of Excision
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NO.
Size of excision (CM3) 48
CONCLUSIONS P
TI EIC-
182
9%
2%
0%
0.02
TI EIC+
83
29%
22%
10%
0.07
75
T2 EIC-
164
6%
2%
3%
NS
T2 EIC+
78
36%
26%
9%
0.04
P-values compare the smallest and largest excisions. Source: Adapted from Ref. 33.
extent of associated intraductal carcinoma. Patients without an EIC are well treated with excisional biopsy with narrow gross tissue margins; if the margins are heavily involved or inevaluable, we then perform a re-excision prior to radiotherapy. If an EIC is present and the margins are microscopically involved or equivocal, then a reexcision of the biopsy site should be done. In most patients a cosmetically and pathologically satisfactory re-excision can be performed. If the margins of the re-excision specimen are still involved, mastectomy may be preferable. Experience with other histologic subtypes of breast neoplasms is much more limited in all series, but in general results appear similar to those achieved in infiltrating ductal carcinomas (34-36). Other factors which may affect the likelihood of breast failure are blood or lymphatic vessel invasion (28,29), histologic grade ( 18,37,38), estrogen receptor level (23), aneuploidy (39), and a major mononuclear cell reaction or lymphocytic infiltrate ( 17). For example, in the JCRT series (28) the presence of lymphatic vessel invasion (LVI) was slightly higher in the EIC + group (31%) than the EIC group (25%). By itself, LVI did not affect local recurrence rates; however, there was a statistically significant increase in the 5-year actuarial breast failure rate in the EIC + /LVI + subgroup (34%) compared with the EIC + /LVI - subgroup (20%). (The respective rates in the EIC - subgroups were 9% and 5% .) The impact of most of these pathologic factors have not yet been confirmed by other groups. Other factors, such as oncogene expression, are only beginning to be examined. For example, in one small study expression of the c-erbB-2 oncogene did not appear to influence the risk of local
The results to date from prospective randomized trials indicate that survival following conservative surgery and radiotherapy for early breast cancer is equivalent to that following mastectomy. When competently performed, such treatment gives highly satisfactory cosmetic results and acceptably low rates of local tumor recurrence. A number of controversial issues remain concerning patient selection as well as other aspects of this treatment approach. Because breast cancer has a long natural history, long follow up of patients is required for ultimate proof of the relative merits of different selection or treatment policies. However, due to the increasing numbers of patients being treated with conservative surgery and radiotherapy, it appears likely that many of these questions will be answered within the next decade.
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