0360.3016/91 $3.00 + .Yl Copyright 0 199 Pergamon Press plc
Inl. J Radialron Oncology Biol Phys.. Vol. 21, pp. 331-338 Printed I” the LISA. All rights reserved.
I
l Original Contribution
COSMETIC RESULTS AFTER SURGERY, CHEMOTHERAPY, RADIATION THERAPY FOR EARLY BREAST CANCER ANTHONY
L. ABNER,
BARBARA
SILVER,
M.D.,’ ABRAM RECHT, M.D.,’
FRANK
A. VICINI,
B.A.,’
STEVEN
COME,
DANIEL
HAYES,
AND JAY R. HARRIS,
M.D.,3
AND
M.D.,2
M.D.4
M.D.’
‘Joint Center for Radiation Therapy, Department of Radiation Therapy, Harvard Medical School, Boston, MA; 2Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI; 3Department of Medicine, Harvard Medical School, and Breast Evaluation Center, Dana-Farber Cancer Institute, Boston, MA; and 4Department of Medicine, Harvard Medical School, and Division of Hematology/Oncology, Beth Israel Hospital, Boston, MA Adjuvant chemotherapy (CT) is increasingly being used in conjunction with radiation therapy (RT) in the treatment of early stage breast cancer. To assess the effect of CT on the cosmetic outcome of the irradiated breast, we retrospectively reviewed the cosmetic results of patients who received either cyclophosphamide-methotrexatefluorouracil (CMF) or doxorubicin-based chemotherapy in conjunction with breast irradiation between 1968 and 1985. The overall cosmetic results were evaluated by the physician as “excellent,” “good,” “fair,” or “poor” using a standardii scale. The Cl group consisted of 170 patients treated with CT and RT administered either concurrently or sequentially (Cl before RT, after RT, or both) with a minimum of 24 months of cosmetic follow-up. These were compared to an RT alone control group of 170 patients who did not receive CT and were matched by tumor size, radiation technique, and year of treatment. At 36 months, the cosmetic scores for the Cf group compared to RT alone were 47% versus 71% excellent (p < O.Ol), 36% versus 19% good, and 17% versus 9% fair or poor. For the 50 patients treated with concurrent CMF and RT, the scores were 31% excellent, 45% good, and 24% fair/poor, whereas for the 118 patients treated with sequential RT and CT they were 54%, 318, and 14%, respectively. There was no difference between those patients who received sequential CMF and those treated with doxorubicin. We conclude that adjuvant chemotherapy adversely affects the cosmetic outcome of breast irradiation, but that this effect is not clinically significant unless CMF is administered concurrently with RT. Patients treated with either sequential CMF or doxorubicin-based CT had only a slight decrement in their cosmetic result compared to patients treated without CT. Breast cancer, Conservative
surgery and radiotherapy, Chemotherapy,
INTRODUaION
Cosmesis.
in the cosmetic outcome when CT is added. Further, the sequence of administration of CT and RT requires additional investigation into its effect on local control, distant failure, and complications, as well as on cosmesis. Previous reports from the Joint Center for Radiation Therapy (JCRT) have used a standard cosmetic evaluation of treated patients, in which the physician routinely scored the overall cosmetic result and the extent of breast edema, telangiectasia, and retraction. We have recently published studies of the late cosmetic outcome after RT (18) and factors that influence this outcome ( 16). In an earlier report with a smaller number of patients, we investigated the effect of concurrent versus sequential administration of CT and RT (11). In this paper, we have enlarged our previous study population and updated our results in order to answer three questions: a) Does CT influence the cosmetic result in patients treated with RT?; b) Is the influ-
In recent years, two major developments have occurred in the management of early stage breast cancer: the use of less extensive surgery followed by radiation therapy (RT) for local control and the administration of adjuvant chemotherapy (CT) or hormonal therapy to reduce the risk of distant me&stases. The results of studies using these approaches were presented in June 1990 at a Consensus Development Conference of the National Cancer Institute ( 15). The conclusions reached at this conference will likely result in increased use of both modalities. However, the precise effect of adjuvant chemotherapy on the cosmetic outcome of the breast after radiation therapy has not been fully determined. Contradictory results have been reported from retrospective series, with some finding significant differences ( 11, 18) but others finding no change ( 1, 2, 8) Reprint requests to: Anthony Abner, M.D., Joint Center for Radiation Therapy, 50 Binney St., Boston, MA 02115.
Accepted for publication 331
25 January 199 1
332
I. J. Radiation Oncology 0 Biology 0 Physics
ence of CT related to the timing (i.e., sequential versus concurrent) of CT and RT?; and c) What is the effect of doxorubicin (Adriamycin*)- containing regimens compared to CMF? METHODS
AND MATERIALS
One thousand six hundred twenty-four women with UICC-AJC clinical Stage I-II invasive breast carcinomas were treated at the JCRT from 1968-1985. This study excludes patients with a history of prior malignancy (other than non-melanoma skin cancers or carcinoma in situ of the cervix) and women who presented with simultaneous bilateral breast primaries. Of these 1624 patients, 390 received adjuvant chemotherapy. Patients were excluded from this study for the following reasons: 42 patients did not receive CMF or doxorubicin-based CT; 6 had local recurrence and 39 had distant failure within 24 months of completion of RT; and 33 patients had less than 24 months cosmetic follow-up at the JCRT. The study population for this analysis thus consists of 170 of these 390 women who had a minimum of 2 years of cosmetic followup at the JCRT without local or distant relapse during that time. All patients received either CMF- or doxorubicin-based chemotherapy, underwent complete gross excision of the tumor, and received a minimum of 60 Gy to the tumor bed. Follow-up was generally recorded at 6-month intervals, using a standardized scale to evaluate the overall appearance, breast edema, telangiectasia, retraction, and arm edema. The overall result was classified as “excellent” when the treated breast was virtually indistinguishable from the opposite breast, “good” when there were small but noticeable effects of RT, “fair” if there were significant variations, and “poor” if there were severe sequelae. Breast and arm edema, telangiectasia, and retraction were independently evaluated and assigned a score of O-3 corresponding to none, minimal, moderate, or severe degrees. These results were grouped into 12-month intervals from the time of completion of RT. If there was more than one evaluation in a given interval, the worse score was used. Evaluations within 6 months of the time-point were considered to occur at the midpoint of the interval. The first interval consisted of evaluations from 0 to 6 months after completion of RT. Cosmetic follow-up ranged from 24-134 months, with a median of 60 months. One hundred seven patients (63%) had follow-up greater than 4 years. Patients were censored at the time of local or distant failure since subsequent treatment may have affected the cosmetic results. Cosmetic results were followed to 96 months or until a subgroup had fewer than 10 patients within the given interval.
* Adria Laboratories, Columbus, OH.
July 1991. Volume 21. Number 2
Table 1. Characteristics of concurrent CMF, sequential CT, and RT alone cohorts Concurrent CMF Sequential Number of patients Axillary node status Performed Node positive T Stage Tl T2 Machine energy 4MV 6-8 MV Treatment fields Breast tangents only Breast and medial SC Breast, medial SC, and axilla Dose to breast (Gy) Median Range Total dose to primary (GY) Median Range Boost technique Implants Mean no. seeds
50 50 (100%) 50 (100%)
118
RT alone 170
115 (97%) I IO (95%)
116 (68%) 5 (4%)
22 (44%) 28 (56%)
53 (45%) 65 (55%)
78 (45%) 92 (55%)
43 (86%) 7 (14%)
96 (81%) 22 (19%)
144 (85%) 26 (15%)
2 (4%) 23 (46%) 25 (50%)
24 (20%) 31 (26%) 63 (53%)
27 (16%) 33 (19%) I IO (65%)
46.0 46.0-50.0
46.0 42.0-5 I .8
46.0 37.8-50.0
67.6 60.7-72.0
66.0 60.0-83.7
66.7 60.0-78.8
43 (86%) 68. I
91 (77%) 76.9
134 (79%) 71.1
SC = supraclavicular.
External beam techniques at the JCRT have been described previously (19). Details of treatment fields are shown in Table 1. The medial supraclavicular and axillary fields were matched to the breast tangential fields using the “hanging block” or “corner block” technique (3). The majority of patients received 45 Gy to 50 Gy to the entire breast (range, 42.00 Gy-5 1.82 Gy). Most were treated on a 4 MV or 6 MV linear accelerator, but 14 patients with very large breasts were treated on an 8 MV accelerator to minimize dose inhomogeneities. Boost doses to the primary site were delivered with interstitial iridium- 192 implantation alone in 125 patients, and implantation combined with either photons or electrons in nine patients; electrons alone were used for the boost in 36 patients. No patient in this group received a boost with external photons alone. All patients in this study received either CMF- or doxorubicin-based chemotherapy (Table 2). Fifty-two patients received CT concurrently with RT, of whom 50 received CMF without modification; the 2 patients who had methotrexate ommitted during RT have been excluded from analysis in the concurrent group but are included in the overall CT group. Fourteen received all CT prior to RT (“CT- first”), whereas 61 had all RT before CT (“RT-
Cosmetic results after surgery0 Table 2. Chemotherapy CMF-based CMF CMFVP CMF-melphalan Doxorubicin-based CAMFP CAMF CA
A.
L. ABNER
333
ef u/.
found to be associated with a poorer cosmetic outcome: tumor size (Tl vs T2); boost technique (electrons versus interstitial implant); and external beam technique (three-field RT vs tangents only). Matching by the year of treatment was also used to minimize variations in technical factors. In a few cases, an exact match could not be made in the designated year, requiring a match from the preceeding year. Other factors, including breast size and volume of excision, were not considered in the match. Statistical comparisons were made using the chisquared test at 36 months. P values of 0.05 or less were considered to be significant.
previously
regimens
133 4 4 20 5 4
C = Cyclophosphamide; M = Methotrexate; F = Fluorouracil; V = Vincristine; P = Prednisone; A = Doxorubicin.
first”). Twenty-six had at least one cycle of CT prior to RT with additional CT following the completion of RT
(“sandwich” therapy). Seventeen patients had an interstitial implant followed by some CT, then had external beam RT with additional CT following the completion of RT (“interval” therapy). Since external beam RT and CT were delivered with similar timing relative to each other in the sandwich and interval groups, they are considered together in subsequent analyses. No patient received doxorubicin concurrently with RT. To explore further the effect of chemotherapy, a casecontrol method was used. A one-to-one match of study patients with a cohort of patients who did not receive chemotherapy was made by matching for factors we have
RESULTS The overall cosmetic outcome for the 170 patients treated with CT and RT and the 170 matched-pair patients treated with RT alone is shown in Figure 1. At 36 months, cosmetic results in the patients receiving CT were classified as excellent in 47% of the patients, good in 36%, and fair/ poor in 17% compared to 7 l%, 19%, and 9%, respectively, for the matched pair control population. The difference in the percentage of patients judged as excellent between the CT and control groups was statistically significant (p < 0.0000 1). The primary effect of adjuvant CT appeared to be a shift of the results from excellent to good. There
RT
ALONE
p=A
EXCELLENT
b?$w
GOOD FAIR/POOR
RT
AND
CT
m
EXCELLENT
I]
GOOD
m
FAIR/POOR
MONTHS
Fig. 1. Overall cosmetic results over time for the RT alone group and for the RT and CT group. For each time point, the RT alone group is on the left and combined RT and CT on the right. Excellent and good scores are above the axis, while fair and poor scores are shown below.
334
I. J. Radiation Oncology 0 Biology 0 Physics
July 1991, Volume 2 I, Number 2
90 80
-m-
-.-
0
12
24
36
48
60
72
84
RT RT
ALONE AND CT
(N1170) (Nx170)
96
MONTHS
Fig. 2. Percent of patients with breast edema over time for the RT alone group and the combined CT and RT group.
was also a trend toward more fair/poor results in the CT group but this did not reach statistical significance (p = 0.06). We examined the contributions of breast edema, retraction, and telangiectasia to the overall cosmetic outcome for the two groups. Breast edema was found to be greatest in both groups at the time of initial evaluation, and then decreased over the interval studied. Breast edema was more common in patients treated with RT and CT compared to RT alone (Fig. 2).At 36 months, 36% of the CT group had evidence of edema compared to 18% of the controls (p = 0.04). Breast retraction was found to increase with time for both groups, and was also more common in patients treated with both CT and RT (Fig. 3);at 36 months 7 1% of the CT patients had evidence of retraction compared to 49% of the controls (p = 0.000 1). Telangiectasia was not found to be affected by the addition of CT (data not shown). We then examined the effect of timing of CT by comparing patients who received concurrent CMF and RT with patients treated with sequential CT and RT. The patient characteristics of these two groups are shown in Table 1, demonstrating that treatment techniques were similar. Compared with controls, the proportion of excellent results decreased when CT was administered in either manner, but patients treated with concurrent CT and RT were less likely to have an excellent result than patients treated with sequential CT and RT (Fig. 4). At 36 months, 3 1% of patients treated with concurrent CT
had an excellent result compared to 54% for patients treated with sequential CT and 7 1% for the controls (p < 0.000 1, concurrent CMF versus control; p = 0.002, sequential versus control; p = 0.009,concurrent CMF versus sequential). Fair/poor results were somewhat more common in the concurrent group than the sequential group. At 36 months, 24% of the concurrent CMF group had a fair/poor result compared to 14% of the sequential group and 9% of the control group (p = 0.01, concurrent CMF versus control; p = 0.2,sequential versus control; p = 0.3, concurrent CMF versus sequential). The extent of breast edema was similar in the two groups, with 42% of the concurrent group and 34% of the sequential group demonstrating clinically significant edema. Retraction was noted in 76% of the patients treated with concurrent CMF and 68% of those who received sequential CT compared with 49% of the controls. The incidence of telangiectasia was increased only in the concurrent group (data not shown). Within the group treated with sequential CT and RT, we compared outcome in patients treated with all CT first, patients treated with all RT followed by CT, and the “sandwich/interval” group as defined above. The percentage of excellent scores was similar in all groups (data not shown); however, these comparisons were limited by the small numbers in the subgroups. We also examined the effect of different chemotherapeutic agents on the cosmetic outcome to determine if doxorubicin had a greater impact on the cosmetic result
335
Cosmetic results after surgery 0 A. L. ABNERd a/
%
60 -m-o-
50
RT RT
ALONE and CT
(N=l70) (N=170)
40
10
t
01
I I
I
12
0
I
24
36
48
60
72
84
96
MONTHS Fig. 3. Percent group.
of patients
with breast retraction
over time for the RT alone group and the combined
-•RT ALONE -*SEQUENTIAL .-----A------ CONCURRENT
CT CMF
RT and CT
(N=170) (N=118) (N-50)
‘..
01
0
I 1
12
24
L I
36
L ,
48
60
72
84
96
MONTHS Fig. 4. Percent of patients with an excellent cosmetic score over time for the RT alone group, the RT and CT (sequential) group, and the RT and CT (concurrent CMF) group.
336
1. J. Radiation Oncology 0 Biology 0 Physics
than CMF. Since all patients who received doxorubicin were treated with sequential CT and RT, the comparison was limited to those patients who received sequential CMF-based regimens and RT. The two groups differed in two important respects: 66% of the doxorubicin group received an interstitial implant compared to 82% of the sequential CMF group, while a three-field external beam RT technique was used in 84% of the sequential CMF patients compared with 66% of those who received doxorubicin CT. Other factors, including machine energy, varied between these groups, limiting interpretation of these results. Figure 5 shows the proportion of acceptable (good plus excellent) results for the two groups. There was no statistically significant difference. Similarly, no differences in breast edema, telangiectasia, or retraction were identified for the two chemotherapeutic regimens. DISCUSSION The results of this study confirm and expand our previous reports of the effect of CT on the cosmetic results following breast-conserving surgery and RT. These may be summarized as follows: a) breast cosmesis is adversely affected by CT; b) concurrent external beam RT and CT using unmodified CMF are more likely than sequential CT and RT to be associated with a fair or poor result and less likely to be associated with an excellent one; and c) the effects of sequential administration of RT and doxorubicin are similar to those of sequential administration
% E X C E L
July 1991, Volume 21, Number 2
of RT and CMF, and the majority of patients treated with sequential CT have an excellent/good cosmetic result. Several factors have been shown to influence the cosmetic result after conservative surgery and RT for early stage breast cancer. Tumor size (6, 9), breast size (6, 17) extent of resection ( 16), external beam radiation technique (12, 14) and boost type (I 6) have all been shown in retrospective studies to contribute to the subsequent texture and appearance of the breast. However, considerable controversy exists regarding the effect of adjuvant CT on the cosmetic outcome. Previous reports from the JCRT (11) have demonstrated that adjuvant chemotherapy is less likely to be associated with an excellent cosmetic result. This effect was reported by Gore et al. (11) to be most significant when CT and RT were administered concurrently. This finding was not corroborated by investigators at the University of Pennsylvania (8) in a group of 27 patients who received CMF or CMFP chemotherapy who were compared to a control group of 19 patients who received no adjuvant treatment. Of note, the chemotherapy was modified to delete methotrexate during RT, based on the empiric observation that concurrent use of methotrexate and prednisone with RT caused an increased skin reaction. There was no significant difference in the number of excellent and good results between the patients who received this chemotherapy regimen and those who had no adjuvant therapy. A study conducted at the National Cancer Institute (1) demonstrated no effect on the cosmetic effects from sequential administration of doxoru-
!!ip=&
70--
60--
;
50--
N T t
40--
:
30--
-.-.-
OOXORU6ICIN SEQUENTIAL
CMF
(N=29) (N=93)
0 o
20-r 10 i 01
0
I
1
12
24
36
40
MONTHS Fig. 5. Percent of patients with an excellent or good cosmetic score for patients CMF and patients treated with sequential RT and doxorubicin-based regimens.
treated
with sequential
RT and
Cosmetic results after surgery 0 A. L.
bicin and cyclophosphamide when compared to patients treated with RT alone. However, the overall cosmetic results in both groups in this study were worse than those seen in other series. The optimal method of combining chemotherapy and radiation therapy remains uncertain. Chemotherapy appears to have little effect on the risk of local failure following breast-conserving surgery when RT is not used (lo), but may improve local control in patients who do receive RT. Results from the NSABP B-06 trial appear to demonstrate an additive or synergistic effect of radiation therapy and chemotherapy in reducing the rate of local failure (lo), but patients in this study who received CT were node-positive, whereas those who did not were nodenegative, which may bias the conclusions reached. Randomized studies of node-negative patients comparing RT alone to RT and CT or tamoxifen after breast-conserving surgery have been conducted by the NSABP, but meaningful results on local control will not be available for several years. We would like to stress that the cosmetic result is only one factor in determining the optimum sequencing of RT and CT. Of more importance, local and distant control may be affected by a lengthy delay in beginning either RT or CT. Ultimately, the sequence that provides the best likelihood of survival will likely be favored. There are concerns that giving all CT prior to RT delays the start of RT by at least several months. A study by Clarke et al. (5) has shown that, in patients who did not receive CT, an interval of 7 weeks or more between surgery and radiation therapy increased the risk of failure in the breast,
337
ABNER rt a/.
although this was not significant on multivariate analysis. There are perhaps even greater concerns regarding delays in starting chemotherapy. Buzdar et al. (4), however, found no effect of a period of 18 weeks between excision and systemic treatment. An opposite finding was reached by Dalton et al. (7) in a study of patients having 1-3 positive nodes. Lara et al. (13) found a greater risk of distant failure in patients who completed RT before beginning CT; however, the interval was not stated. Until further data become available, the influence of timing of CT and RT will remain controversial. This study confirms our previous findings that both sequential and concurrent administration of CT result in fewer excellent cosmetic results after RT. This effect was most prominent in the group that received concurrent treatment with unmodified CMF. Among those patients who received sequential RT and CT, there was no significant difference in cosmesis between those who received all RT first, all CT first, or sandwich therapy. Although the percentage of excellent results was decreased in all groups, 83% of the women treated with CT and RT were found to have an excellent or good result. Given the widespread use of combined CT and RT and the paucity of information regarding sequencing of these modalities, further study, especially using randomized clinical trials, will be required to determine the optimal sequence of administration. Our institution has initiated one such trial comparing chemotherapy (using four cycles of CAMFP given over a 12-week period) either before or after radiation not be available
therapy.
Definitive
for several
results
of this trial will
years.
REFERENCES I. Bader, J. L.; Lippman, M. E.; Swain, S. Cosmetic evaluation (CE) following lumpectomy and radiation (XRT) for early breast cancer (BC) is similar with and without adjuvant adriamycin/cytoxan (AC) (Abstract). Proc. Am. Sot. Clin. Oncol. 6:62; 1987. 2. Borger, J. H.; Keijser, A. H. Conservative breast cancer treatment: analysis of cosmetic results and the role of concomitant adjuvant chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 13:1173-1177; 1987. 3. Buck, B. A.; Siddon, R. L.; Svensson, G. K. A beam alignment device for matching fields. Int. J. Radiat. Oncol. Biol. Phys. Il:1039-1043; 1985. 4. Buzdar. A. U.; Smith, T. L.; Powell, K. C.; Blumenschein, G. R.; Gehan, E. A. Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res. Treat. 2: 163-169; 1982. 5. Clarke, D. H.; Lee, M. G.; Sarrazin, D.; Lacombe, M. J.; Fontaine, F.; Travagli, J. P.; May-Levin, F.; Contesso, G.; Arriagada, R. Analysis of local-regional relapses in patients with early breast cancer treated with excision and radiotherapy: experience of the Institut Gustave-Roussy. Int. J. Radiol. Oncol. Biol. Phys. 11:137-145; 1985. 6. Clarke, D.; Martinez, A.; Cox, R. S. Analysis of cosmetic results and complications in patients with Stage I and II breast cancer treated by biopsy and irradiation. Int. J. Radiat. Oncol. Biol. Phys. 9: 1807-l 8 13; 1983.
7. Dalton, W. S.; Brooks, R. J.; Jones, S. E. Breast cancer adjuvant therapy trials at the Arizona Cancer Center using Adriamycin and cyclophosphamide. In: Salmon, S. E., ed. Adjuvant therapy of cancer V. Orlando: Grune & Stratton: 1987:263-269. 8. Danoff, B. F.; Goodman, R. L.; Glick, J. H.; Haller, D. G.; Pajak, T. F. The effect of adjuvant chemotherapy on cosmesis and complications in patients with breast cancer treated by definitive irradiation. Int. J. Radiat. Oncol. Biol. Phys. 9:1625-1630; 1983. 9. Dewar, J. A.; Benhamou, S.; Benhamou, E. Cosmetic results following lumpectomy, axillary dissection and radiotherapy for small breast cancers. Radiother. Oncol. 12:273-280; 1988. 10. Fisher, B.; Bauer, M.; Margolese, R.; Poisson, R.: Pilch, Y .; Redmond, C.; Fisher, E.; Wolmark, N.; Deutsch, M.; Montague, E. Five year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N. Eng. J. Med. 312:665-673; 1985. Il. Gore, S. M.; Come, S. E.; Griem, K.; Harris, J. R. Influence of sequencing of chemotherapy and radiation therapy in node-negative breast cancer patients treated with conservative surgery and radiation therapy. In: Salmon, S. E., ed. Adjuvant therapy of cancer V. Orlando, Grune & Stratton; 1987:365-373.
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12. Harris, J. R.; Levene, M. B.; Svensson, G.; Hellman, S. Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int. J. Radiat. Oncol. Biol. Phys. 5:257-261; 1979. 13. Lara, P.; Soler, M.; Asenio, C. Combined postoperative radiotherapy and chemotherapy in poor prognosis breast cancer patients: comparison of three different schedules (Abstract). Proc. 5th Europ. Conf. Clin. Oncol. P-0940, London, 1989. 14. van Limbergen, E.; Rijnders, A.; van der Schueren, E.; Lerut, T.; Christiaens, R. Cosmetic evaluation of breast conserving treatment for mammary cancer 2: a quantitative analysis of the influence of radiation dose, fractionation schedules, and surgical treatment techniques on cosmetic results. Radiother. Oncol. 16:253-267; 1989. 15. National Institutes of Health Consensus Development Conference Statement: treatment of early-stage breast cancer. JAMA 265:39 l-395; 199 1.
July 1991, Volume 21. Number 2
16. Olivotto, I.; Rose, M. A.; Osteen, R. T.; Love, S.; Cady, B.: Silver, B.; Recht, A.; Harris, J. R. Late cosmetic outcome after conservative surgery and radiation therapy: analysis of causes of cosmetic failure. Int. J. Radiat. Oncol. Biol. Phys. 17:747-753; 1989. 17. Ray, G.; Fish, V. J. Biopsy and definitive radiation therapy in stage I and II adenocarcinoma of the female breast: analysis of cosmesis and the role of electron beam supplementation. Int. J. Radiat. Oncol. Biol. Phys. 9:813-819; 1983. 18. Rose, M. A.; Olivotto, I.; Cady, B.; Koufman, C.; Osteen, R.; Silver, B.; Recht, A.; Harris, J. R. Conservative surgery and radiation therapy for early breast cancer. Long-term cosmetic results. Arch. Surg. 124: 153- 157; 1989. 19. Siddon, R. L.; Buck, B. A.; Harris, J. R.; Svensson, G. K. Three-field technique for breast irradiation using tangential fields corner blocks. Int. J. Radiat. Oncol. Biol. Phys. 6: 689-694; 1980.
Inl. J Radialron Oncology Biol Phys.. Vol. 21, pp. 331-338 Printed I” the LISA. All rights reserved.
I
l Original Contribution
COSMETIC RESULTS AFTER SURGERY, CHEMOTHERAPY, RADIATION THERAPY FOR EARLY BREAST CANCER ANTHONY
L. ABNER,
BARBARA
SILVER,
M.D.,’ ABRAM RECHT, M.D.,’
FRANK
A. VICINI,
B.A.,’
STEVEN
COME,
DANIEL
HAYES,
AND JAY R. HARRIS,
M.D.,3
AND
M.D.,2
M.D.4
M.D.’
‘Joint Center for Radiation Therapy, Department of Radiation Therapy, Harvard Medical School, Boston, MA; 2Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI; 3Department of Medicine, Harvard Medical School, and Breast Evaluation Center, Dana-Farber Cancer Institute, Boston, MA; and 4Department of Medicine, Harvard Medical School, and Division of Hematology/Oncology, Beth Israel Hospital, Boston, MA Adjuvant chemotherapy (CT) is increasingly being used in conjunction with radiation therapy (RT) in the treatment of early stage breast cancer. To assess the effect of CT on the cosmetic outcome of the irradiated breast, we retrospectively reviewed the cosmetic results of patients who received either cyclophosphamide-methotrexatefluorouracil (CMF) or doxorubicin-based chemotherapy in conjunction with breast irradiation between 1968 and 1985. The overall cosmetic results were evaluated by the physician as “excellent,” “good,” “fair,” or “poor” using a standardii scale. The Cl group consisted of 170 patients treated with CT and RT administered either concurrently or sequentially (Cl before RT, after RT, or both) with a minimum of 24 months of cosmetic follow-up. These were compared to an RT alone control group of 170 patients who did not receive CT and were matched by tumor size, radiation technique, and year of treatment. At 36 months, the cosmetic scores for the Cf group compared to RT alone were 47% versus 71% excellent (p < O.Ol), 36% versus 19% good, and 17% versus 9% fair or poor. For the 50 patients treated with concurrent CMF and RT, the scores were 31% excellent, 45% good, and 24% fair/poor, whereas for the 118 patients treated with sequential RT and CT they were 54%, 318, and 14%, respectively. There was no difference between those patients who received sequential CMF and those treated with doxorubicin. We conclude that adjuvant chemotherapy adversely affects the cosmetic outcome of breast irradiation, but that this effect is not clinically significant unless CMF is administered concurrently with RT. Patients treated with either sequential CMF or doxorubicin-based CT had only a slight decrement in their cosmetic result compared to patients treated without CT. Breast cancer, Conservative
surgery and radiotherapy, Chemotherapy,
INTRODUaION
Cosmesis.
in the cosmetic outcome when CT is added. Further, the sequence of administration of CT and RT requires additional investigation into its effect on local control, distant failure, and complications, as well as on cosmesis. Previous reports from the Joint Center for Radiation Therapy (JCRT) have used a standard cosmetic evaluation of treated patients, in which the physician routinely scored the overall cosmetic result and the extent of breast edema, telangiectasia, and retraction. We have recently published studies of the late cosmetic outcome after RT (18) and factors that influence this outcome ( 16). In an earlier report with a smaller number of patients, we investigated the effect of concurrent versus sequential administration of CT and RT (11). In this paper, we have enlarged our previous study population and updated our results in order to answer three questions: a) Does CT influence the cosmetic result in patients treated with RT?; b) Is the influ-
In recent years, two major developments have occurred in the management of early stage breast cancer: the use of less extensive surgery followed by radiation therapy (RT) for local control and the administration of adjuvant chemotherapy (CT) or hormonal therapy to reduce the risk of distant me&stases. The results of studies using these approaches were presented in June 1990 at a Consensus Development Conference of the National Cancer Institute ( 15). The conclusions reached at this conference will likely result in increased use of both modalities. However, the precise effect of adjuvant chemotherapy on the cosmetic outcome of the breast after radiation therapy has not been fully determined. Contradictory results have been reported from retrospective series, with some finding significant differences ( 11, 18) but others finding no change ( 1, 2, 8) Reprint requests to: Anthony Abner, M.D., Joint Center for Radiation Therapy, 50 Binney St., Boston, MA 02115.
Accepted for publication 331
25 January 199 1
332
I. J. Radiation Oncology 0 Biology 0 Physics
ence of CT related to the timing (i.e., sequential versus concurrent) of CT and RT?; and c) What is the effect of doxorubicin (Adriamycin*)- containing regimens compared to CMF? METHODS
AND MATERIALS
One thousand six hundred twenty-four women with UICC-AJC clinical Stage I-II invasive breast carcinomas were treated at the JCRT from 1968-1985. This study excludes patients with a history of prior malignancy (other than non-melanoma skin cancers or carcinoma in situ of the cervix) and women who presented with simultaneous bilateral breast primaries. Of these 1624 patients, 390 received adjuvant chemotherapy. Patients were excluded from this study for the following reasons: 42 patients did not receive CMF or doxorubicin-based CT; 6 had local recurrence and 39 had distant failure within 24 months of completion of RT; and 33 patients had less than 24 months cosmetic follow-up at the JCRT. The study population for this analysis thus consists of 170 of these 390 women who had a minimum of 2 years of cosmetic followup at the JCRT without local or distant relapse during that time. All patients received either CMF- or doxorubicin-based chemotherapy, underwent complete gross excision of the tumor, and received a minimum of 60 Gy to the tumor bed. Follow-up was generally recorded at 6-month intervals, using a standardized scale to evaluate the overall appearance, breast edema, telangiectasia, retraction, and arm edema. The overall result was classified as “excellent” when the treated breast was virtually indistinguishable from the opposite breast, “good” when there were small but noticeable effects of RT, “fair” if there were significant variations, and “poor” if there were severe sequelae. Breast and arm edema, telangiectasia, and retraction were independently evaluated and assigned a score of O-3 corresponding to none, minimal, moderate, or severe degrees. These results were grouped into 12-month intervals from the time of completion of RT. If there was more than one evaluation in a given interval, the worse score was used. Evaluations within 6 months of the time-point were considered to occur at the midpoint of the interval. The first interval consisted of evaluations from 0 to 6 months after completion of RT. Cosmetic follow-up ranged from 24-134 months, with a median of 60 months. One hundred seven patients (63%) had follow-up greater than 4 years. Patients were censored at the time of local or distant failure since subsequent treatment may have affected the cosmetic results. Cosmetic results were followed to 96 months or until a subgroup had fewer than 10 patients within the given interval.
* Adria Laboratories, Columbus, OH.
July 1991. Volume 21. Number 2
Table 1. Characteristics of concurrent CMF, sequential CT, and RT alone cohorts Concurrent CMF Sequential Number of patients Axillary node status Performed Node positive T Stage Tl T2 Machine energy 4MV 6-8 MV Treatment fields Breast tangents only Breast and medial SC Breast, medial SC, and axilla Dose to breast (Gy) Median Range Total dose to primary (GY) Median Range Boost technique Implants Mean no. seeds
50 50 (100%) 50 (100%)
118
RT alone 170
115 (97%) I IO (95%)
116 (68%) 5 (4%)
22 (44%) 28 (56%)
53 (45%) 65 (55%)
78 (45%) 92 (55%)
43 (86%) 7 (14%)
96 (81%) 22 (19%)
144 (85%) 26 (15%)
2 (4%) 23 (46%) 25 (50%)
24 (20%) 31 (26%) 63 (53%)
27 (16%) 33 (19%) I IO (65%)
46.0 46.0-50.0
46.0 42.0-5 I .8
46.0 37.8-50.0
67.6 60.7-72.0
66.0 60.0-83.7
66.7 60.0-78.8
43 (86%) 68. I
91 (77%) 76.9
134 (79%) 71.1
SC = supraclavicular.
External beam techniques at the JCRT have been described previously (19). Details of treatment fields are shown in Table 1. The medial supraclavicular and axillary fields were matched to the breast tangential fields using the “hanging block” or “corner block” technique (3). The majority of patients received 45 Gy to 50 Gy to the entire breast (range, 42.00 Gy-5 1.82 Gy). Most were treated on a 4 MV or 6 MV linear accelerator, but 14 patients with very large breasts were treated on an 8 MV accelerator to minimize dose inhomogeneities. Boost doses to the primary site were delivered with interstitial iridium- 192 implantation alone in 125 patients, and implantation combined with either photons or electrons in nine patients; electrons alone were used for the boost in 36 patients. No patient in this group received a boost with external photons alone. All patients in this study received either CMF- or doxorubicin-based chemotherapy (Table 2). Fifty-two patients received CT concurrently with RT, of whom 50 received CMF without modification; the 2 patients who had methotrexate ommitted during RT have been excluded from analysis in the concurrent group but are included in the overall CT group. Fourteen received all CT prior to RT (“CT- first”), whereas 61 had all RT before CT (“RT-
Cosmetic results after surgery0 Table 2. Chemotherapy CMF-based CMF CMFVP CMF-melphalan Doxorubicin-based CAMFP CAMF CA
A.
L. ABNER
333
ef u/.
found to be associated with a poorer cosmetic outcome: tumor size (Tl vs T2); boost technique (electrons versus interstitial implant); and external beam technique (three-field RT vs tangents only). Matching by the year of treatment was also used to minimize variations in technical factors. In a few cases, an exact match could not be made in the designated year, requiring a match from the preceeding year. Other factors, including breast size and volume of excision, were not considered in the match. Statistical comparisons were made using the chisquared test at 36 months. P values of 0.05 or less were considered to be significant.
previously
regimens
133 4 4 20 5 4
C = Cyclophosphamide; M = Methotrexate; F = Fluorouracil; V = Vincristine; P = Prednisone; A = Doxorubicin.
first”). Twenty-six had at least one cycle of CT prior to RT with additional CT following the completion of RT
(“sandwich” therapy). Seventeen patients had an interstitial implant followed by some CT, then had external beam RT with additional CT following the completion of RT (“interval” therapy). Since external beam RT and CT were delivered with similar timing relative to each other in the sandwich and interval groups, they are considered together in subsequent analyses. No patient received doxorubicin concurrently with RT. To explore further the effect of chemotherapy, a casecontrol method was used. A one-to-one match of study patients with a cohort of patients who did not receive chemotherapy was made by matching for factors we have
RESULTS The overall cosmetic outcome for the 170 patients treated with CT and RT and the 170 matched-pair patients treated with RT alone is shown in Figure 1. At 36 months, cosmetic results in the patients receiving CT were classified as excellent in 47% of the patients, good in 36%, and fair/ poor in 17% compared to 7 l%, 19%, and 9%, respectively, for the matched pair control population. The difference in the percentage of patients judged as excellent between the CT and control groups was statistically significant (p < 0.0000 1). The primary effect of adjuvant CT appeared to be a shift of the results from excellent to good. There
RT
ALONE
p=A
EXCELLENT
b?$w
GOOD FAIR/POOR
RT
AND
CT
m
EXCELLENT
I]
GOOD
m
FAIR/POOR
MONTHS
Fig. 1. Overall cosmetic results over time for the RT alone group and for the RT and CT group. For each time point, the RT alone group is on the left and combined RT and CT on the right. Excellent and good scores are above the axis, while fair and poor scores are shown below.
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I. J. Radiation Oncology 0 Biology 0 Physics
July 1991, Volume 2 I, Number 2
90 80
-m-
-.-
0
12
24
36
48
60
72
84
RT RT
ALONE AND CT
(N1170) (Nx170)
96
MONTHS
Fig. 2. Percent of patients with breast edema over time for the RT alone group and the combined CT and RT group.
was also a trend toward more fair/poor results in the CT group but this did not reach statistical significance (p = 0.06). We examined the contributions of breast edema, retraction, and telangiectasia to the overall cosmetic outcome for the two groups. Breast edema was found to be greatest in both groups at the time of initial evaluation, and then decreased over the interval studied. Breast edema was more common in patients treated with RT and CT compared to RT alone (Fig. 2).At 36 months, 36% of the CT group had evidence of edema compared to 18% of the controls (p = 0.04). Breast retraction was found to increase with time for both groups, and was also more common in patients treated with both CT and RT (Fig. 3);at 36 months 7 1% of the CT patients had evidence of retraction compared to 49% of the controls (p = 0.000 1). Telangiectasia was not found to be affected by the addition of CT (data not shown). We then examined the effect of timing of CT by comparing patients who received concurrent CMF and RT with patients treated with sequential CT and RT. The patient characteristics of these two groups are shown in Table 1, demonstrating that treatment techniques were similar. Compared with controls, the proportion of excellent results decreased when CT was administered in either manner, but patients treated with concurrent CT and RT were less likely to have an excellent result than patients treated with sequential CT and RT (Fig. 4). At 36 months, 3 1% of patients treated with concurrent CT
had an excellent result compared to 54% for patients treated with sequential CT and 7 1% for the controls (p < 0.000 1, concurrent CMF versus control; p = 0.002, sequential versus control; p = 0.009,concurrent CMF versus sequential). Fair/poor results were somewhat more common in the concurrent group than the sequential group. At 36 months, 24% of the concurrent CMF group had a fair/poor result compared to 14% of the sequential group and 9% of the control group (p = 0.01, concurrent CMF versus control; p = 0.2,sequential versus control; p = 0.3, concurrent CMF versus sequential). The extent of breast edema was similar in the two groups, with 42% of the concurrent group and 34% of the sequential group demonstrating clinically significant edema. Retraction was noted in 76% of the patients treated with concurrent CMF and 68% of those who received sequential CT compared with 49% of the controls. The incidence of telangiectasia was increased only in the concurrent group (data not shown). Within the group treated with sequential CT and RT, we compared outcome in patients treated with all CT first, patients treated with all RT followed by CT, and the “sandwich/interval” group as defined above. The percentage of excellent scores was similar in all groups (data not shown); however, these comparisons were limited by the small numbers in the subgroups. We also examined the effect of different chemotherapeutic agents on the cosmetic outcome to determine if doxorubicin had a greater impact on the cosmetic result
335
Cosmetic results after surgery 0 A. L. ABNERd a/
%
60 -m-o-
50
RT RT
ALONE and CT
(N=l70) (N=170)
40
10
t
01
I I
I
12
0
I
24
36
48
60
72
84
96
MONTHS Fig. 3. Percent group.
of patients
with breast retraction
over time for the RT alone group and the combined
-•RT ALONE -*SEQUENTIAL .-----A------ CONCURRENT
CT CMF
RT and CT
(N=170) (N=118) (N-50)
‘..
01
0
I 1
12
24
L I
36
L ,
48
60
72
84
96
MONTHS Fig. 4. Percent of patients with an excellent cosmetic score over time for the RT alone group, the RT and CT (sequential) group, and the RT and CT (concurrent CMF) group.
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1. J. Radiation Oncology 0 Biology 0 Physics
than CMF. Since all patients who received doxorubicin were treated with sequential CT and RT, the comparison was limited to those patients who received sequential CMF-based regimens and RT. The two groups differed in two important respects: 66% of the doxorubicin group received an interstitial implant compared to 82% of the sequential CMF group, while a three-field external beam RT technique was used in 84% of the sequential CMF patients compared with 66% of those who received doxorubicin CT. Other factors, including machine energy, varied between these groups, limiting interpretation of these results. Figure 5 shows the proportion of acceptable (good plus excellent) results for the two groups. There was no statistically significant difference. Similarly, no differences in breast edema, telangiectasia, or retraction were identified for the two chemotherapeutic regimens. DISCUSSION The results of this study confirm and expand our previous reports of the effect of CT on the cosmetic results following breast-conserving surgery and RT. These may be summarized as follows: a) breast cosmesis is adversely affected by CT; b) concurrent external beam RT and CT using unmodified CMF are more likely than sequential CT and RT to be associated with a fair or poor result and less likely to be associated with an excellent one; and c) the effects of sequential administration of RT and doxorubicin are similar to those of sequential administration
% E X C E L
July 1991, Volume 21, Number 2
of RT and CMF, and the majority of patients treated with sequential CT have an excellent/good cosmetic result. Several factors have been shown to influence the cosmetic result after conservative surgery and RT for early stage breast cancer. Tumor size (6, 9), breast size (6, 17) extent of resection ( 16), external beam radiation technique (12, 14) and boost type (I 6) have all been shown in retrospective studies to contribute to the subsequent texture and appearance of the breast. However, considerable controversy exists regarding the effect of adjuvant CT on the cosmetic outcome. Previous reports from the JCRT (11) have demonstrated that adjuvant chemotherapy is less likely to be associated with an excellent cosmetic result. This effect was reported by Gore et al. (11) to be most significant when CT and RT were administered concurrently. This finding was not corroborated by investigators at the University of Pennsylvania (8) in a group of 27 patients who received CMF or CMFP chemotherapy who were compared to a control group of 19 patients who received no adjuvant treatment. Of note, the chemotherapy was modified to delete methotrexate during RT, based on the empiric observation that concurrent use of methotrexate and prednisone with RT caused an increased skin reaction. There was no significant difference in the number of excellent and good results between the patients who received this chemotherapy regimen and those who had no adjuvant therapy. A study conducted at the National Cancer Institute (1) demonstrated no effect on the cosmetic effects from sequential administration of doxoru-
!!ip=&
70--
60--
;
50--
N T t
40--
:
30--
-.-.-
OOXORU6ICIN SEQUENTIAL
CMF
(N=29) (N=93)
0 o
20-r 10 i 01
0
I
1
12
24
36
40
MONTHS Fig. 5. Percent of patients with an excellent or good cosmetic score for patients CMF and patients treated with sequential RT and doxorubicin-based regimens.
treated
with sequential
RT and
Cosmetic results after surgery 0 A. L.
bicin and cyclophosphamide when compared to patients treated with RT alone. However, the overall cosmetic results in both groups in this study were worse than those seen in other series. The optimal method of combining chemotherapy and radiation therapy remains uncertain. Chemotherapy appears to have little effect on the risk of local failure following breast-conserving surgery when RT is not used (lo), but may improve local control in patients who do receive RT. Results from the NSABP B-06 trial appear to demonstrate an additive or synergistic effect of radiation therapy and chemotherapy in reducing the rate of local failure (lo), but patients in this study who received CT were node-positive, whereas those who did not were nodenegative, which may bias the conclusions reached. Randomized studies of node-negative patients comparing RT alone to RT and CT or tamoxifen after breast-conserving surgery have been conducted by the NSABP, but meaningful results on local control will not be available for several years. We would like to stress that the cosmetic result is only one factor in determining the optimum sequencing of RT and CT. Of more importance, local and distant control may be affected by a lengthy delay in beginning either RT or CT. Ultimately, the sequence that provides the best likelihood of survival will likely be favored. There are concerns that giving all CT prior to RT delays the start of RT by at least several months. A study by Clarke et al. (5) has shown that, in patients who did not receive CT, an interval of 7 weeks or more between surgery and radiation therapy increased the risk of failure in the breast,
337
ABNER rt a/.
although this was not significant on multivariate analysis. There are perhaps even greater concerns regarding delays in starting chemotherapy. Buzdar et al. (4), however, found no effect of a period of 18 weeks between excision and systemic treatment. An opposite finding was reached by Dalton et al. (7) in a study of patients having 1-3 positive nodes. Lara et al. (13) found a greater risk of distant failure in patients who completed RT before beginning CT; however, the interval was not stated. Until further data become available, the influence of timing of CT and RT will remain controversial. This study confirms our previous findings that both sequential and concurrent administration of CT result in fewer excellent cosmetic results after RT. This effect was most prominent in the group that received concurrent treatment with unmodified CMF. Among those patients who received sequential RT and CT, there was no significant difference in cosmesis between those who received all RT first, all CT first, or sandwich therapy. Although the percentage of excellent results was decreased in all groups, 83% of the women treated with CT and RT were found to have an excellent or good result. Given the widespread use of combined CT and RT and the paucity of information regarding sequencing of these modalities, further study, especially using randomized clinical trials, will be required to determine the optimal sequence of administration. Our institution has initiated one such trial comparing chemotherapy (using four cycles of CAMFP given over a 12-week period) either before or after radiation not be available
therapy.
Definitive
for several
results
of this trial will
years.
REFERENCES I. Bader, J. L.; Lippman, M. E.; Swain, S. Cosmetic evaluation (CE) following lumpectomy and radiation (XRT) for early breast cancer (BC) is similar with and without adjuvant adriamycin/cytoxan (AC) (Abstract). Proc. Am. Sot. Clin. Oncol. 6:62; 1987. 2. Borger, J. H.; Keijser, A. H. Conservative breast cancer treatment: analysis of cosmetic results and the role of concomitant adjuvant chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 13:1173-1177; 1987. 3. Buck, B. A.; Siddon, R. L.; Svensson, G. K. A beam alignment device for matching fields. Int. J. Radiat. Oncol. Biol. Phys. Il:1039-1043; 1985. 4. Buzdar. A. U.; Smith, T. L.; Powell, K. C.; Blumenschein, G. R.; Gehan, E. A. Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res. Treat. 2: 163-169; 1982. 5. Clarke, D. H.; Lee, M. G.; Sarrazin, D.; Lacombe, M. J.; Fontaine, F.; Travagli, J. P.; May-Levin, F.; Contesso, G.; Arriagada, R. Analysis of local-regional relapses in patients with early breast cancer treated with excision and radiotherapy: experience of the Institut Gustave-Roussy. Int. J. Radiol. Oncol. Biol. Phys. 11:137-145; 1985. 6. Clarke, D.; Martinez, A.; Cox, R. S. Analysis of cosmetic results and complications in patients with Stage I and II breast cancer treated by biopsy and irradiation. Int. J. Radiat. Oncol. Biol. Phys. 9: 1807-l 8 13; 1983.
7. Dalton, W. S.; Brooks, R. J.; Jones, S. E. Breast cancer adjuvant therapy trials at the Arizona Cancer Center using Adriamycin and cyclophosphamide. In: Salmon, S. E., ed. Adjuvant therapy of cancer V. Orlando: Grune & Stratton: 1987:263-269. 8. Danoff, B. F.; Goodman, R. L.; Glick, J. H.; Haller, D. G.; Pajak, T. F. The effect of adjuvant chemotherapy on cosmesis and complications in patients with breast cancer treated by definitive irradiation. Int. J. Radiat. Oncol. Biol. Phys. 9:1625-1630; 1983. 9. Dewar, J. A.; Benhamou, S.; Benhamou, E. Cosmetic results following lumpectomy, axillary dissection and radiotherapy for small breast cancers. Radiother. Oncol. 12:273-280; 1988. 10. Fisher, B.; Bauer, M.; Margolese, R.; Poisson, R.: Pilch, Y .; Redmond, C.; Fisher, E.; Wolmark, N.; Deutsch, M.; Montague, E. Five year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N. Eng. J. Med. 312:665-673; 1985. Il. Gore, S. M.; Come, S. E.; Griem, K.; Harris, J. R. Influence of sequencing of chemotherapy and radiation therapy in node-negative breast cancer patients treated with conservative surgery and radiation therapy. In: Salmon, S. E., ed. Adjuvant therapy of cancer V. Orlando, Grune & Stratton; 1987:365-373.
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12. Harris, J. R.; Levene, M. B.; Svensson, G.; Hellman, S. Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int. J. Radiat. Oncol. Biol. Phys. 5:257-261; 1979. 13. Lara, P.; Soler, M.; Asenio, C. Combined postoperative radiotherapy and chemotherapy in poor prognosis breast cancer patients: comparison of three different schedules (Abstract). Proc. 5th Europ. Conf. Clin. Oncol. P-0940, London, 1989. 14. van Limbergen, E.; Rijnders, A.; van der Schueren, E.; Lerut, T.; Christiaens, R. Cosmetic evaluation of breast conserving treatment for mammary cancer 2: a quantitative analysis of the influence of radiation dose, fractionation schedules, and surgical treatment techniques on cosmetic results. Radiother. Oncol. 16:253-267; 1989. 15. National Institutes of Health Consensus Development Conference Statement: treatment of early-stage breast cancer. JAMA 265:39 l-395; 199 1.
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16. Olivotto, I.; Rose, M. A.; Osteen, R. T.; Love, S.; Cady, B.: Silver, B.; Recht, A.; Harris, J. R. Late cosmetic outcome after conservative surgery and radiation therapy: analysis of causes of cosmetic failure. Int. J. Radiat. Oncol. Biol. Phys. 17:747-753; 1989. 17. Ray, G.; Fish, V. J. Biopsy and definitive radiation therapy in stage I and II adenocarcinoma of the female breast: analysis of cosmesis and the role of electron beam supplementation. Int. J. Radiat. Oncol. Biol. Phys. 9:813-819; 1983. 18. Rose, M. A.; Olivotto, I.; Cady, B.; Koufman, C.; Osteen, R.; Silver, B.; Recht, A.; Harris, J. R. Conservative surgery and radiation therapy for early breast cancer. Long-term cosmetic results. Arch. Surg. 124: 153- 157; 1989. 19. Siddon, R. L.; Buck, B. A.; Harris, J. R.; Svensson, G. K. Three-field technique for breast irradiation using tangential fields corner blocks. Int. J. Radiat. Oncol. Biol. Phys. 6: 689-694; 1980.
