- Email: [email protected]
The effect of adjuvant chemotherapy on cosmesis and complications in patients with breast cancer treated by definitive irradiation
Bid.
036&3016/83/$3.00 + .OO Copyright 0 1983 Pergamon Press Ltd.
ht. 1. Radiation Oncology Phys.. Vol. 9. pp. 1625-1630 Prinkd in the U.S.A. All rights reserved.
??Original Contribution THE EFFE:CT OF ADJUVANT CHEMOTHERAPY ON COSMESIS AND COMPLICATIONS IN PATIENTS WITH BREAST CANCER TREATED BY DEFINITIVE IRRADIATION BARBARA F. DANOFF, JOHN H. GILICK,
M.D.,’ ROBERT L. GOODMAN, M.D.,’
M.D.,’ DANIEL
G.
HALLER’
AND THOMAS
F. PAJAK,
PH.D.~
Department of Radiation Therapy’ and Department of Medicine, Division of Hematology Oncology,’ University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104 and Department of Biostatistics,’ American
College of Radiology,
925 Chestnut Street, Philadelphia,
PA 19107
From1978 to 19811,46 patients received primary radiotherapy following excisional biopsy and axillary staging procedure for Stages I and II carcinoma of the breast. The patients were divided into 2 groups: 27 patients who received radiation and completed 12 cycles of adjuvant chemotherapy (CMF or CMFP) and 19 patients who received radiation alone. All patients received radiation to the breast and regional nodes (4600-5000 rad) and a boost to the site of the primary tumor (1500-2000 rad). Median follow-up from completion of radiation was 26 months in the non-adjuvant and 241months in the adjuvant group with a range of 12 to 49 months. Cosmesis was judged to be good to excellent in 89% (1’7/19) of the patients receiving radiation alone and 81% (22/27) of the patients receiving adjuvant chemotherapy. Fair to poor cosmesis in the adjuvant group was attributed primarily to increased fibrosis and reduction of breast size. The single complication for which there was an increased incidence in the adjuvant group was arm edema (22 vs. 0 % ). The incidence of arm edema was unrelated to T stage, type of axillary surgical procedure, number of positive nodes, addition of prednisone or sequencing of chemotherapy. Further efforts should be directed towards minimizing complications and maximizing cosmesis without sacrificing relapse-free survival in patients receiving primary radiotherapy and adjuvant chemotherapy for early breast cancer. Primary
radiotherapy,
Early breast cancer, Adjuvant chemotherapy,
INTRODUCTION
Cosmesis, Complications.
results and complications in patients receiving primary radiotherapy is not well known. This report presents the results of the University of Pennsylvania experience in patients treated with adjuvant chemotherapy and primary radiotherapy for ear!y breast cancer in terms of cosmesis and complications. .
The optimal treatment of early breast cancer (Stage I and II) continues to evolve as clinical experience with various treatment regimens accumulates. The conventional treatment has been the radical or modified radical mastectomy. Excisional biopsy and primary radiotherapy have been employed with increasing frequency. European and North American trials have produced local-regional control and survival rates comparable to those achieved by mastectomy.‘~2~6~7~‘o~~‘~‘“~2~23~2h Primary radiotherapy, therefore, represents an acceptable alternative to mastectomy for the treatment of early breast cancer. The obvious advantage of primary radiotherapy is preservation of the breast. Factors related to cosmetic outcome include the initial surgical procedure, radiotherapy technique and time/dose factors.t3 Current treatment regimens are directed towards maximizing cosmesis and minimizing complications without sacrificing localregional control. The addition of adjuvant chemotherapy has resulted in an improved relapse-free surviva13,4.8 for patients with histologically positive axillary nodes. However, the impact of adjuvant chemotherapy on cosmetic
METHODS
AND
MATERIALS
Between January, 1978 and January, I98 I, 27 patients received primary radiotherapy and completed 12 cycles of adjuvant chemotherapy for early breast cancer (Table I ). All patients underwent an excisional biopsy of the primary and an axillary staging procedure. Twelve patients had a limited axillary procedure with less than IO nodes removed and I5 had a level I or level I&II dissection (IO-37 nodes removed). Twelve patients had T, lesions and 15 had Tz lesions. Twenty-six patients had histologically positive axillary nodes. Sixteen patients were premenopausal and I I were post-menopausal. Chemotherapy consisted of I2 cycles of CMF or CMFP (cyclophosphamide 100 mg/m’ by mouth per day from the first to the 14th day, methotrexate 40 mg/m’
Presented at the Ameriwn Society of Therapeutic Radiologists Annual Meeting, Kissimee, Florida, October 25529, 1982.
Reprint requests to: B. F. Danotf, M.D. Accepted for publication I5 June 1983. 1625
1626
Radiation Oncology
Table
0 Biology
0 Physics
I. Patient Characteristics Adjuvant Control Group
Chemotherapy
CMF CF ->
CMFP
Total
No. patients Pre-menopausal Post-menopausal Path stage
19 I3 6
9 6 3
I8 IO 8
27 16 II
T,N, T&I TJ’J, Axillary procedure Limited Dissection Follow-up (mos.) Median Mean Range
I 14 4
5 I 3
7 0
I2 I
II
14
I2 I
5 4
7 II
I2 I5
17 21 12-41
24 24 12-49
intravenously
26 26 13-47
36 31 12-49
on the first and eighth
days,
5-fluorouracil
mg/m2 intravenously on the first and eighth days and prednisone 40 mg/m’ by mouth per day from the first day to the 14th day). Nine patients received chemotherapy (CMF) after the completion of radiation. Eighteen patients received comcomitant radiation and chemotherapy (CMFP). During radiation patients received two cycles of cyclophosphamide and 5-fluorouracil followed by IO cycles of CMFP upon completion of radiation. Chemotherapy in this group was initiated 2 to 3 weeks following axillary surgery concurrent with the start of irradiation. Details of the regimen are reported elsewhere.’ Chemotherapy injections were not given into the axillary node dissection arm. Radiation was directed to the breast and regional nodes in all patients. Prior to 1979, patients with histologically negative axillary nodes routinely received radiation to the regional nodes. The breast, internal mammary nodes and lower portion of the axilla were treated with opposed tangential fields. Both fields were treated per day with compensating wedge filters and no bolus. A total dose of 4600 to 5000 rad was delivered over a period of 4’/2 to 5 weeks at the rate of 200 rad per day. A separate anterior supraclavicular-apical axillary field was employed. This field was angled 12O to avoid divergence through the spinal cord and vertebral bodies. For this field, 4400 to 5000 rad was delivered over 4% to 5 weeks with a daily fraction of 200 rad. The external beam treatment was delivered on a 6 MeV linear accelerator. The region of the excisional biopsy was then irradiated with an additional 1500 to 2000 rad boost with either an iridium implant (24 patients), electron beam (2 patients) or external beam (1 patient) treatment. Of the patients undergoing an implant, 2 1 had a single plane implant. Median and mean follow-up was 24 months. All patients were followed for a minimum of I year following completion of radiation with a maximum follow-up of 49 months. Nineteen patients with Stages I and II breast cancer 600
November
1983. Volume
9. Yumbcr
II
who underwent an excisional biopsy and axillary procedure during the same time period and received primary radiation without adjuvant chemotherapy served as a non-randomized “control” group (Table I). Twelve patients had a limited axillary procedure (less than IO nodes removed) and 7 had a level I or level l-11 dissection (IO-24 nodes removed). Eighteen patients had T, lesions and one had a T, lesion. Five patients had histologically positive axillary nodes. Thirteen patients were pre-menopausal and 6 were post-menopausal. Radiation was directed to the breast and regional nodes in all patients with the same three held technique described above for the adjuvant group. The boost treatment consisted of an iridium implant in I6 patients (I3 single plane), an electron beam boost in one patient and an orthovoltage boost in 2 patients. All patients were followed for a minimum of one year following completion of radiation. The median and mean follow-up was 26 months with a range of I3 to 47 months. Cosmesis was assessed by two of the authors (BD,RG) in terms of breast size, breast edema, retraction and elevation of the breast, fibrosis and induration (breast, axilla, matchline), skin changes (telangiectasia, hypopigmentation, hyperpigmentation) and tissue loss secondary to the biopsy procedure. These changes were graded as none, slight. moderate or severe. An overall cosmetic score was given at the time of last examination as follows: Excellent-treated breast almost identical to untreated breast Good-minimal difference between the treated and untreated breast Fairobvious difference between the treated and untreated breast but without major distortion Poor-major functional and esthetic sequelae in the treated breast At each follow-up visit the presence or absence of the following complications was recorded: necrosis, symptomatic pneumonitis, rib fracture, arm edema, pleural effusion, pericarditis and brachial plexus injury (arm weakness, paresthesias). RESULTS Table 2 presents the results of the overall cosmetic scores for the control group and the adjuvant chemotherapy group. Eighty-nine percent (17/19) of the control Table 2. Cosmetic results Stage I and II breast cancer Adjuvant
chemotherapy
Control
Cosmesis
group
Excellent Good Fair
II 6 2
Poor Total no. patients
19
CMF CF-> 4 2 3
9
CMFP
Total
13 3 I
I7 5 4
I
I
18
27
Effect
of adjuvant chemotherapy on cosmesis 0 B.
group were classified as having a good to excellent result compared to 8 1% (22/27) of the adjuvant group. (p = .38). Fair to poor cosmesis in the 5 patients receiving adjuvant chemotherapy was attributed primarily to a significant decrease in breast size (>I/3 reduction) and moderate to severe fibrosis and induration. The two patients in the control group with a fair result had a significant decrease in breast size with fibrosis. Four of the nine patients receiving CMF post-radiation were classified as having an excellent result compared to 13 of 18 patients in the group receiving concomitant chemotherapy. Table 3 compares the number of patients with a fair to poor cosmetic result versus the period of follow-up in months. The number of patients with a fair to poor result in the control group appears to peak at 2 to 3 years whereas the number in thl: adjuvant chemotherapy group appears to increase with time. Table 4 presents the complications occurring in the two groups of patients. There were no instances of brachial plexus injury in either group. A single patient in the adjuvant chemotherapy group had a rib fracture. Symptomatic pneumonitis occurred in a single patient in the control group. Fat necrosis of the axilla was noted in one patient receiving concoml.tant chemotherapy who underwent two limited axillary procedures. Mild to moderate arm edema occurred in 6 (22%) of the patients receiving adjuvant chemotherapy compared to none of the patients in the control group. Mild. arm edema was defined as that amount which resulted in less than a one to two inch difference in arm circumference and required no treatment. Moderate edema required therapeutic intervention with either diuretics, the Jobst intermittent pressure device or a sleeve. Two patients had mild edema and 4 patients had moderate edema. In all patients, the changes were permanent for the period of follow-up. In three patients the changes have been progressive. The edema appeared at intervals of 4 to 12 months following completion of radiation with a median time of 5 months. The incidence of arm edema was unrelated to the T staging, type of axillary procedure or number of positive nodes (Table 5). The addition of prednisone did not alter the incidence. Four of 18 patients receiving prednisone developed arm edema compared to 2 of 9 who did not. Patients receiving concomitant chemotherapy developed arm edema with the same frequency as those who received chemotherapy following completion of radiation (4/ 18 Table 3. Follow-up interval and cosmesis Control RT only
Adjuvant chemo & RT
Fair/poor Time interval (me.) 12-23 24-35 236 Total
Total eval
No. (%)
9 7 3
0 2 0
(29)
I9
2
(II)
Fair/poor Total eval.
No. (%)
15 5 7
1 (7) 1 (20) 3 (43)
27
5
(19)
1627
F. DANOFF et al.
Table 4. Complications adjuvant
following primary radiotherapy and chemotherapy Stage I and II breast cancer Adjuvant
Complication Arm edema Rib fracture Symptomatic pneumonitis Necrosis (axilla) Brachial plexis injury
chemotherapy
Control group
CMF
0 0
2 I
4 0
6 I
I 0
0 0
0 I
0 I
0
0
0
0
CF->CMFP
All Pts.
versus 2/9). Table 6 presents the incidence of various complications reported following primary radiotherapy without adjuvant chemotherapy for Stage I and 11 breast cancer. In comparison with the present series, it appears that the addition of chemotherapy is associated with an increased incidence of arm edema.
DISCUSSION Sufficient data now exist in terms of local control and survival to support the use of excisional biopsy and irradiation as an alternative to mastectomy for early in addition, multiple stud_ breast cancer. I.Z.h.7.11.1X.19.20,21.23 ies 3.4.8have demonstrated a relapse-free survival benefit for histologically node positive patients who receive adjuvant chemotherapy. The effectiveness of chemotherapy appears to be related to the ability to deliver ~85% of the planned dose4.24 and prompt initiation of treatment.” While the ability to deliver optimal doses of chemotherapy with radiotherapy has been previously questioned,14 Glick et a1.9 and Botnick et a1.j have demonstrated no significant dose reductions in patients receiving primary radiotherapy. However, the effect of adjuvant chemotherapy on cosmesis and complications requires further assessment. In the present study, overall cosmetic scores were not significantly altered by the addition of chemotherapy. Table 5. Incidence
of arm edema
No. pts. arm edema/Total
no. pts.
Adjuvant chemotherapy Control group T stage T, T* Axillary procedure Limited Dissection No. of positive nodes 0 l-3 >_4 r4
No.
(S)
O/l O/l8
2112 4115
(17) (27)
O/l2
3112 3115
(25) (20)
O/7 O/l4 O/4 O/l
O/l 4117 219
(24) (22)
Radiation Oncology
1628
Table 6. Primary
Complications Arm edema Rib fracture Symptomatic pneumonitis Necrosis Brachial plexus injury Pericarditis Pleural effusion
0 Biology 0 Physics
radiotherapy
November
Stage
Pierquin” 15
I 1
With a median follow-up of 24-26 months, further time may be required to assess cosmetic outcome more accurately. The optimum time for evaluation, however, is controversial. Harris et al.” noted no significant change in the average cosmetic score over a period of 1 to 4 years in 10 patients evaluated. Pierquin ef &.I9 suggested that cosmesis could be examined definitively at 3 years. The authors felt that radiation sequelae reached a maximum between 2 and 3 years following treatment and noted no difference in cosmetic results at 3 and 5 years. Spitalier,23 however, reported good to excellent results in y, of patients at 5 years but only ‘/3at 10 years, suggesting that the changes were progressive. The present data suggest that the 2 to 3 year period may be adequate in patients receiving radiation alone; however, a longer time is needed in those receiving adjuvant chemotherapy. The only significant increase in complications noted in the adjuvant chemotherapy group was the incidence of arm edema which was unrelated to the T stage, type of axillary procedure or number of positive nodes. As all patients were treated with a three field technique with uniform doses, this complication could not be related to radiation technique or dose. Weiss et ~1.~’ reported an increased incidence of venous thrombosis (5%) occurring during adjuvant chemotherapy in post-mastectomy patients. In 18% of patients, the venous thrombosis involved the arms. The authors felt that this complication was most likely related to a hypercoagulable state produced by CMF. The increased incidence of mild to moderate arm edema in the present series, therefore, may be directly related to the chemotherapy. The incidence of other complications is not significantly different from that reported in the literature for radiotherapy alone (Table 6). The selection and sequencing of chemotherapy agents may affect the cosmetic outcome and incidence of complications. CMFP was chosen in the present study because of its possible superiority over CMF in the treatment of patients with advanced breast cancer.25 The decision to omit methotrexate and prednisone during radiotherapy was based on empirical observations in Stage III patients in whom the local skin reaction appeared to be exacerbated with concurrent CMF. The addition of prednisone was associated with an increased frequency of excellent results in the concomitant group when compared to the group receiving CMF following radiotherapy. However,
1983. Volume 9, Number
II
I and II breast cancer complications (%)
Harris and Hellman” 5 5 2
Prosnitz
Bedwinek
et al. ”
et al. ‘I
et al. ’
1
2
6
2
I I
2 2
Chu
I
1 I I I
1
1
the incidence of arm edema was unaltered by the addition of prednisone or sequencing of chemotherapy. Botnick et CMF and a1.5 reported their results with concomitant radiotherapy for early breast cancer. Sixty-seven percent of the patients had a good to excellent cosmetic result compared to 92% in a control group. An increased incidence of acute skin reactions and symptomatic pneumonitis was associated with greater than two injections of methotrexate and 5-fluorouracil during the external beam treatment. The authors felt that the radiation sequelae persisted longer in patients receiving adjuvant chemotherapy but would eventually resolve. Lichter15 noted good to excellent cosmesis in 70% of the patients receiving sequential cyclophosphamide and adriamycin and primary radiotherapy for early breast cancer. An increased incidence of rib fractures was observed in the patients receiving adjuvant chemotherapy. Tables 7 and 8 summarize the data from the 3 institutions in terms of cosmesis and complications. The preliminary results would indicate that cosmesis is not adversely affected by the current adjuvant chemotherapy regimen (CMFP), but that there is an increased incidence of mild to moderate arm edema. The addition of prednisone to the CMF regimen following radiation and the omission of prednisone and methotrexate during radiation may be responsible for the apparent improved results in the present series when compared to others,5~‘s although it must be emphasized that the number of patients is small and the follow-up limited. Efforts must be directed towards decreasing the incidence of arm edema. Changes in the radiation technique which may help to reduce the incidence of arm edema would include elimination of the supraclavicular-apical axillary field in patients with positive nodes who will receive adjuvant
Table 7. Cosmesis in patients receiving adjuvant chemotherapy
and primary
Median follow-up
Penn JC($i+ NCI”
series)
radiotherapy
% good-excellent
(mos)
RT & chemo
RT alone
25 I3
81 (27)* 67 (40) 70 (16)
89 (19) 92 (37) 80 (24)
Effect of adjuvant
chemotherapy
Table 8. Complications in patients receiving adjuvant chemotherapy and primary radiotherapy (%) Penn (this series) Rib fracture RT RT & chemo Arm edema RT RT & chemo Symptomatic pneumonitis RT RT & chemo
JCRT’
NCI”
0 4
4 12
0 22
22 IO
5 0
0 8
Sarrazin et ~1.~~ noted no additional benefit in terms of local-regional control, 5 year survival or 5 year relapse-free survival in patients with positive axillary nodes when comparing those who had radiation to the chemotherapy.
on cosmesis 0 B. F. DANOFF et 41.
1629
regional nodes versus those who did not following a complete axillary node dissection. The current Milan protocol26 omits radiation to the regional nodes in patients with positive nodes who are undergoing primary radiotherapy and adjuvant chemotherapy. Information obtained from this study regarding local-regional control and relapse-free survival may provide additional support for irradiating only the breast in node positive patients. The omission of treatment to the regional nodes may result in a decreased incidence of arm edema and symptomatic pneumonitis as well as an increased hematologic tolerance to chemotherapy. As further experience is gained in the treatment of early breast cancer with primary radiotherapy and adjuvant chemotherapy, modifications in the treatment protocol may be necessary to maximize cosmesis and minimize complications but without sacrificing local-regional control and survival.
REFERENCES I
2.
3.
4.
5.
6.
Amalric, R., SantamarIa, F., Robert, F., Seigle, J., Altschuler, C., Kurtz, J.M., Spitalier, J.M., Brandore, H., Ayme, Y., Pallet, J.F., Burmeister, R., Abed, R.: Radiation therapy with or without primary limited surgery for operable breast cancer. A 20 year experience at the Marseilles Cancer Institute. Cancer 49: 30-34, 1982. Bedwinek, J.M., Perez, C.A., Kramer, S., Brady, L., Goodman, R., Grundy, G.: Irradiation as the primary management of stage I and II adsenocarcinoma of the breast. Cancer Clin. Trials 3: I l-18, 1980. Bonadonna, G., Brusamolino, E., Valagussa, P., BrugnatelIi, L., Rossi, A., Brambilla, C., DeLena, M., Tancini, G., Bajetta, E., Veronesi, U.: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Engl. J. Med. 294: 405-410, 1976. Bonadonna, Cl., Valagussa, P.: Dose response effect of adjuvant chemotherapy in breast cancer. N. Engl. J. Med. 304: IO-IS, 1981. Botnick, L.E., Come, S., Rose, C., Goldstein, M., Lange, R., Tishler, S., Schnipper, L: Primary breast irradiation and concomitant adjuvant chemotherapy (CMF). In Alternatives to Mastectomy, IHarris, J.R., Hellman, S., Silen, W. (Eds.), Philadelphia, PA, JB Lippincott Co. (In press) 1982. Calle, R.: Breast carcinoma-Local treatment place of conservative surgery and irradiation exclusively for early breast cancer. In Alternatives to Masfectomy, Harris, J.R., Hellman, S., Silen, W. (Eds.), Philadelphia, JB Lippincott Co. (In press) 1982.
I. Chu, A.M., Cope, O., Russo, R.. Wang, C.C., Schultz, M.D., Wang, C., Rodkey, G.: Treatment of early stage breast cancer by limited surgery and radical irradiation.
Int. J. Radial. Oncol. BIoI. Phys. 6: 25-30,
1980.
8. Fisher, B., Redmond, studies of the NSABP:
C., Wolmark, N.: Breast cancer An editorialized overview. In Adjuvant Therapy o/Cancer III. Salmon, S., Jones, S. (Eds.). New York, Grune & Stratton. 198 I, pp. 359-369.
9. Glick, J.H., Danoff, B.F., Haller, D.G., Weiler, C., Goodman, R.: Adjuvant chemotherapy in patients undergoing definitive irradiation for primary breast cancer: The University of Pennsylvania experience. In Alternatives to Mastectomy, Harris, J.R., IHellman, S., Silen, W. (Eds.), JB Lippincott Co. (In press) 1982.
IO. I I.
12.
13.
14.
IS.
Haagensen, C.D.: Treatment of curable cancer of the breast. Int. J. Radiat. Oncol. Biol. Phys. 2: 975-980. 1977. Harris, J.. Hellman, S.: Primary radiation therapy for early breast cancer: The experience at the Joint Center for Radiation Therapy. In Alfernatives to Mastectomy. Harris, J.R., Hellman, S., Silen, W.. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. Harris, J.R., Levene. M.B.. Hellman, S.: Results of treating stage I and II carcinoma of the breast with primary radiation therapy. Cancer Treat. Rep. 62: 985-991, 1978. 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: 257-26 I, 1979. Holland, J., Glidwell, 0.: Adverse effects of radiotherapy on adjuvant chemotherapy for carcinoma of the breast. Surg. Gyn. Obstet. 150: 8 17-82 I, 1980. Lichter, AS.: The National Cancer Institute experiencePrimary radiotherapy and adjuvant chemotherapy. In Alternafives to Mastectomy. Harris, J.R., Hellman, S.. Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982.
16. Montague, E.D., Schell, S.R., Ames, F.C., Romsdahl, M.M.: Conservative surgery and irradiation in clinically favorable breast cancer: The M.D. Anderson Experience. In Alternafives fo Mastectomy. Harris, J.R., Hellman. S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 17. Nissen-Meyer, R.: One short chemotherapy course in primary breast cancer: 12 year follow-up in series I of the Scandinavian Adjuvant Chemotherapy Study Group. In Adjuvant Therapy of the Cancer II. Salmon, S.. Jones, S. (Eds.). New York, Grune & Stratton. 1979. pp. 2077213. 18. Pierquin, B.: Conservative treatment for carcinoma of the breast-Experience of Creteil. IO years’ results. In AIfernarives to Masfectomy, Harris, J.R., Hellman, S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 19. Pierquin, B., Baillet, F., Wilson, J.F.: Radiation therapy in the management of primary breast cancer. Am. J. Roenfgeno/. 127: 645-648,
1976.
20. Pierquin, B., Owen, R.. Maylin. C., Otmezguine. Y.. Raynal. M., Mueller, W., Hannoun, S.: Radical radiation therapy of breast cancer. fnt. J. Radiat. Oncol. Biol. Phys. 6: 17-24,
1980.
1630
Radiation Oncology 0 Biology 0 Physics
21. Prosnitz, L. R., Weshler. Z., Goldenberg, IS.: Primary radiotherapy for breast carcinoma instead of mastectomy: The Yale experience. In Alternatives to Mastectom,v, Harris, J.R., Hellman, S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 22. Sarrazin, D., Le. M.., Fontaine, F., Arriagada, R.: Conservative treatment vs. mastectomy in T, or small Tz breast cancer: The experience of the Institute Gustave-Roussy. In AIternativrs to Mastectomy. Harris, J.R.. Hellman, S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 23. Spitalier. J.M.: A 20 year experience at the Marseilles Cancer Institute on conservative management for operable breast cancer. In Alternatives to Mastectomy. Harris, J.R., Hellman, S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 24. Tancini,
G., Bonadonna,
G., Marchini,
S.: Adjuvant
CMF
November
1983, Volume 9, Number
II
in breast cancer: Comparative 5 year results of I2 vs. 6 cycles (Abstr.). Proc. Am. Sec. C/in. One. I: 87. 1982. 25. Tormey, D.. Gelman. R., Band, P.R., Sears, M.. Rosenthal. S.N., DeWys. W., Perlia. C.. Riw, M.A.: Comparison of induction chemotherapies for metastatic breast cancer: An Eastern Cooperative Oncology Group Trial. Cancer 50: 1235-1244, 1982. U., Saccozzi, R., DelVecchio. M., Banti. A., 26. Veronesi, Clemente. C., DeLena. M.. Gallus. G., Greco, M., Luini. A., Maruloini, E., Muscolino, G.. Rilke. F., Salvadori. B., Zecchini, A., Zucali. R.: Comparing radical mastectomy with quadrantectomy, axillary dissection and radiotherapy in patients with small cancers of the breast. N. EngI. J. Med. 305: 6-l I, 1981. 27. Weiss, R.B.. Tormey, D.C., Holland. J.F., Weinberg, V.E.: Venous thrombosis during multimodal treatment of primary breast carcinoma. Cancer Treat. Rep. 65: 677-679.
1981.
036&3016/83/$3.00 + .OO Copyright 0 1983 Pergamon Press Ltd.
ht. 1. Radiation Oncology Phys.. Vol. 9. pp. 1625-1630 Prinkd in the U.S.A. All rights reserved.
??Original Contribution THE EFFE:CT OF ADJUVANT CHEMOTHERAPY ON COSMESIS AND COMPLICATIONS IN PATIENTS WITH BREAST CANCER TREATED BY DEFINITIVE IRRADIATION BARBARA F. DANOFF, JOHN H. GILICK,
M.D.,’ ROBERT L. GOODMAN, M.D.,’
M.D.,’ DANIEL
G.
HALLER’
AND THOMAS
F. PAJAK,
PH.D.~
Department of Radiation Therapy’ and Department of Medicine, Division of Hematology Oncology,’ University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104 and Department of Biostatistics,’ American
College of Radiology,
925 Chestnut Street, Philadelphia,
PA 19107
From1978 to 19811,46 patients received primary radiotherapy following excisional biopsy and axillary staging procedure for Stages I and II carcinoma of the breast. The patients were divided into 2 groups: 27 patients who received radiation and completed 12 cycles of adjuvant chemotherapy (CMF or CMFP) and 19 patients who received radiation alone. All patients received radiation to the breast and regional nodes (4600-5000 rad) and a boost to the site of the primary tumor (1500-2000 rad). Median follow-up from completion of radiation was 26 months in the non-adjuvant and 241months in the adjuvant group with a range of 12 to 49 months. Cosmesis was judged to be good to excellent in 89% (1’7/19) of the patients receiving radiation alone and 81% (22/27) of the patients receiving adjuvant chemotherapy. Fair to poor cosmesis in the adjuvant group was attributed primarily to increased fibrosis and reduction of breast size. The single complication for which there was an increased incidence in the adjuvant group was arm edema (22 vs. 0 % ). The incidence of arm edema was unrelated to T stage, type of axillary surgical procedure, number of positive nodes, addition of prednisone or sequencing of chemotherapy. Further efforts should be directed towards minimizing complications and maximizing cosmesis without sacrificing relapse-free survival in patients receiving primary radiotherapy and adjuvant chemotherapy for early breast cancer. Primary
radiotherapy,
Early breast cancer, Adjuvant chemotherapy,
INTRODUCTION
Cosmesis, Complications.
results and complications in patients receiving primary radiotherapy is not well known. This report presents the results of the University of Pennsylvania experience in patients treated with adjuvant chemotherapy and primary radiotherapy for ear!y breast cancer in terms of cosmesis and complications. .
The optimal treatment of early breast cancer (Stage I and II) continues to evolve as clinical experience with various treatment regimens accumulates. The conventional treatment has been the radical or modified radical mastectomy. Excisional biopsy and primary radiotherapy have been employed with increasing frequency. European and North American trials have produced local-regional control and survival rates comparable to those achieved by mastectomy.‘~2~6~7~‘o~~‘~‘“~2~23~2h Primary radiotherapy, therefore, represents an acceptable alternative to mastectomy for the treatment of early breast cancer. The obvious advantage of primary radiotherapy is preservation of the breast. Factors related to cosmetic outcome include the initial surgical procedure, radiotherapy technique and time/dose factors.t3 Current treatment regimens are directed towards maximizing cosmesis and minimizing complications without sacrificing localregional control. The addition of adjuvant chemotherapy has resulted in an improved relapse-free surviva13,4.8 for patients with histologically positive axillary nodes. However, the impact of adjuvant chemotherapy on cosmetic
METHODS
AND
MATERIALS
Between January, 1978 and January, I98 I, 27 patients received primary radiotherapy and completed 12 cycles of adjuvant chemotherapy for early breast cancer (Table I ). All patients underwent an excisional biopsy of the primary and an axillary staging procedure. Twelve patients had a limited axillary procedure with less than IO nodes removed and I5 had a level I or level I&II dissection (IO-37 nodes removed). Twelve patients had T, lesions and 15 had Tz lesions. Twenty-six patients had histologically positive axillary nodes. Sixteen patients were premenopausal and I I were post-menopausal. Chemotherapy consisted of I2 cycles of CMF or CMFP (cyclophosphamide 100 mg/m’ by mouth per day from the first to the 14th day, methotrexate 40 mg/m’
Presented at the Ameriwn Society of Therapeutic Radiologists Annual Meeting, Kissimee, Florida, October 25529, 1982.
Reprint requests to: B. F. Danotf, M.D. Accepted for publication I5 June 1983. 1625
1626
Radiation Oncology
Table
0 Biology
0 Physics
I. Patient Characteristics Adjuvant Control Group
Chemotherapy
CMF CF ->
CMFP
Total
No. patients Pre-menopausal Post-menopausal Path stage
19 I3 6
9 6 3
I8 IO 8
27 16 II
T,N, T&I TJ’J, Axillary procedure Limited Dissection Follow-up (mos.) Median Mean Range
I 14 4
5 I 3
7 0
I2 I
II
14
I2 I
5 4
7 II
I2 I5
17 21 12-41
24 24 12-49
intravenously
26 26 13-47
36 31 12-49
on the first and eighth
days,
5-fluorouracil
mg/m2 intravenously on the first and eighth days and prednisone 40 mg/m’ by mouth per day from the first day to the 14th day). Nine patients received chemotherapy (CMF) after the completion of radiation. Eighteen patients received comcomitant radiation and chemotherapy (CMFP). During radiation patients received two cycles of cyclophosphamide and 5-fluorouracil followed by IO cycles of CMFP upon completion of radiation. Chemotherapy in this group was initiated 2 to 3 weeks following axillary surgery concurrent with the start of irradiation. Details of the regimen are reported elsewhere.’ Chemotherapy injections were not given into the axillary node dissection arm. Radiation was directed to the breast and regional nodes in all patients. Prior to 1979, patients with histologically negative axillary nodes routinely received radiation to the regional nodes. The breast, internal mammary nodes and lower portion of the axilla were treated with opposed tangential fields. Both fields were treated per day with compensating wedge filters and no bolus. A total dose of 4600 to 5000 rad was delivered over a period of 4’/2 to 5 weeks at the rate of 200 rad per day. A separate anterior supraclavicular-apical axillary field was employed. This field was angled 12O to avoid divergence through the spinal cord and vertebral bodies. For this field, 4400 to 5000 rad was delivered over 4% to 5 weeks with a daily fraction of 200 rad. The external beam treatment was delivered on a 6 MeV linear accelerator. The region of the excisional biopsy was then irradiated with an additional 1500 to 2000 rad boost with either an iridium implant (24 patients), electron beam (2 patients) or external beam (1 patient) treatment. Of the patients undergoing an implant, 2 1 had a single plane implant. Median and mean follow-up was 24 months. All patients were followed for a minimum of I year following completion of radiation with a maximum follow-up of 49 months. Nineteen patients with Stages I and II breast cancer 600
November
1983. Volume
9. Yumbcr
II
who underwent an excisional biopsy and axillary procedure during the same time period and received primary radiation without adjuvant chemotherapy served as a non-randomized “control” group (Table I). Twelve patients had a limited axillary procedure (less than IO nodes removed) and 7 had a level I or level l-11 dissection (IO-24 nodes removed). Eighteen patients had T, lesions and one had a T, lesion. Five patients had histologically positive axillary nodes. Thirteen patients were pre-menopausal and 6 were post-menopausal. Radiation was directed to the breast and regional nodes in all patients with the same three held technique described above for the adjuvant group. The boost treatment consisted of an iridium implant in I6 patients (I3 single plane), an electron beam boost in one patient and an orthovoltage boost in 2 patients. All patients were followed for a minimum of one year following completion of radiation. The median and mean follow-up was 26 months with a range of I3 to 47 months. Cosmesis was assessed by two of the authors (BD,RG) in terms of breast size, breast edema, retraction and elevation of the breast, fibrosis and induration (breast, axilla, matchline), skin changes (telangiectasia, hypopigmentation, hyperpigmentation) and tissue loss secondary to the biopsy procedure. These changes were graded as none, slight. moderate or severe. An overall cosmetic score was given at the time of last examination as follows: Excellent-treated breast almost identical to untreated breast Good-minimal difference between the treated and untreated breast Fairobvious difference between the treated and untreated breast but without major distortion Poor-major functional and esthetic sequelae in the treated breast At each follow-up visit the presence or absence of the following complications was recorded: necrosis, symptomatic pneumonitis, rib fracture, arm edema, pleural effusion, pericarditis and brachial plexus injury (arm weakness, paresthesias). RESULTS Table 2 presents the results of the overall cosmetic scores for the control group and the adjuvant chemotherapy group. Eighty-nine percent (17/19) of the control Table 2. Cosmetic results Stage I and II breast cancer Adjuvant
chemotherapy
Control
Cosmesis
group
Excellent Good Fair
II 6 2
Poor Total no. patients
19
CMF CF-> 4 2 3
9
CMFP
Total
13 3 I
I7 5 4
I
I
18
27
Effect
of adjuvant chemotherapy on cosmesis 0 B.
group were classified as having a good to excellent result compared to 8 1% (22/27) of the adjuvant group. (p = .38). Fair to poor cosmesis in the 5 patients receiving adjuvant chemotherapy was attributed primarily to a significant decrease in breast size (>I/3 reduction) and moderate to severe fibrosis and induration. The two patients in the control group with a fair result had a significant decrease in breast size with fibrosis. Four of the nine patients receiving CMF post-radiation were classified as having an excellent result compared to 13 of 18 patients in the group receiving concomitant chemotherapy. Table 3 compares the number of patients with a fair to poor cosmetic result versus the period of follow-up in months. The number of patients with a fair to poor result in the control group appears to peak at 2 to 3 years whereas the number in thl: adjuvant chemotherapy group appears to increase with time. Table 4 presents the complications occurring in the two groups of patients. There were no instances of brachial plexus injury in either group. A single patient in the adjuvant chemotherapy group had a rib fracture. Symptomatic pneumonitis occurred in a single patient in the control group. Fat necrosis of the axilla was noted in one patient receiving concoml.tant chemotherapy who underwent two limited axillary procedures. Mild to moderate arm edema occurred in 6 (22%) of the patients receiving adjuvant chemotherapy compared to none of the patients in the control group. Mild. arm edema was defined as that amount which resulted in less than a one to two inch difference in arm circumference and required no treatment. Moderate edema required therapeutic intervention with either diuretics, the Jobst intermittent pressure device or a sleeve. Two patients had mild edema and 4 patients had moderate edema. In all patients, the changes were permanent for the period of follow-up. In three patients the changes have been progressive. The edema appeared at intervals of 4 to 12 months following completion of radiation with a median time of 5 months. The incidence of arm edema was unrelated to the T staging, type of axillary procedure or number of positive nodes (Table 5). The addition of prednisone did not alter the incidence. Four of 18 patients receiving prednisone developed arm edema compared to 2 of 9 who did not. Patients receiving concomitant chemotherapy developed arm edema with the same frequency as those who received chemotherapy following completion of radiation (4/ 18 Table 3. Follow-up interval and cosmesis Control RT only
Adjuvant chemo & RT
Fair/poor Time interval (me.) 12-23 24-35 236 Total
Total eval
No. (%)
9 7 3
0 2 0
(29)
I9
2
(II)
Fair/poor Total eval.
No. (%)
15 5 7
1 (7) 1 (20) 3 (43)
27
5
(19)
1627
F. DANOFF et al.
Table 4. Complications adjuvant
following primary radiotherapy and chemotherapy Stage I and II breast cancer Adjuvant
Complication Arm edema Rib fracture Symptomatic pneumonitis Necrosis (axilla) Brachial plexis injury
chemotherapy
Control group
CMF
0 0
2 I
4 0
6 I
I 0
0 0
0 I
0 I
0
0
0
0
CF->CMFP
All Pts.
versus 2/9). Table 6 presents the incidence of various complications reported following primary radiotherapy without adjuvant chemotherapy for Stage I and 11 breast cancer. In comparison with the present series, it appears that the addition of chemotherapy is associated with an increased incidence of arm edema.
DISCUSSION Sufficient data now exist in terms of local control and survival to support the use of excisional biopsy and irradiation as an alternative to mastectomy for early in addition, multiple stud_ breast cancer. I.Z.h.7.11.1X.19.20,21.23 ies 3.4.8have demonstrated a relapse-free survival benefit for histologically node positive patients who receive adjuvant chemotherapy. The effectiveness of chemotherapy appears to be related to the ability to deliver ~85% of the planned dose4.24 and prompt initiation of treatment.” While the ability to deliver optimal doses of chemotherapy with radiotherapy has been previously questioned,14 Glick et a1.9 and Botnick et a1.j have demonstrated no significant dose reductions in patients receiving primary radiotherapy. However, the effect of adjuvant chemotherapy on cosmesis and complications requires further assessment. In the present study, overall cosmetic scores were not significantly altered by the addition of chemotherapy. Table 5. Incidence
of arm edema
No. pts. arm edema/Total
no. pts.
Adjuvant chemotherapy Control group T stage T, T* Axillary procedure Limited Dissection No. of positive nodes 0 l-3 >_4 r4
No.
(S)
O/l O/l8
2112 4115
(17) (27)
O/l2
3112 3115
(25) (20)
O/7 O/l4 O/4 O/l
O/l 4117 219
(24) (22)
Radiation Oncology
1628
Table 6. Primary
Complications Arm edema Rib fracture Symptomatic pneumonitis Necrosis Brachial plexus injury Pericarditis Pleural effusion
0 Biology 0 Physics
radiotherapy
November
Stage
Pierquin” 15
I 1
With a median follow-up of 24-26 months, further time may be required to assess cosmetic outcome more accurately. The optimum time for evaluation, however, is controversial. Harris et al.” noted no significant change in the average cosmetic score over a period of 1 to 4 years in 10 patients evaluated. Pierquin ef &.I9 suggested that cosmesis could be examined definitively at 3 years. The authors felt that radiation sequelae reached a maximum between 2 and 3 years following treatment and noted no difference in cosmetic results at 3 and 5 years. Spitalier,23 however, reported good to excellent results in y, of patients at 5 years but only ‘/3at 10 years, suggesting that the changes were progressive. The present data suggest that the 2 to 3 year period may be adequate in patients receiving radiation alone; however, a longer time is needed in those receiving adjuvant chemotherapy. The only significant increase in complications noted in the adjuvant chemotherapy group was the incidence of arm edema which was unrelated to the T stage, type of axillary procedure or number of positive nodes. As all patients were treated with a three field technique with uniform doses, this complication could not be related to radiation technique or dose. Weiss et ~1.~’ reported an increased incidence of venous thrombosis (5%) occurring during adjuvant chemotherapy in post-mastectomy patients. In 18% of patients, the venous thrombosis involved the arms. The authors felt that this complication was most likely related to a hypercoagulable state produced by CMF. The increased incidence of mild to moderate arm edema in the present series, therefore, may be directly related to the chemotherapy. The incidence of other complications is not significantly different from that reported in the literature for radiotherapy alone (Table 6). The selection and sequencing of chemotherapy agents may affect the cosmetic outcome and incidence of complications. CMFP was chosen in the present study because of its possible superiority over CMF in the treatment of patients with advanced breast cancer.25 The decision to omit methotrexate and prednisone during radiotherapy was based on empirical observations in Stage III patients in whom the local skin reaction appeared to be exacerbated with concurrent CMF. The addition of prednisone was associated with an increased frequency of excellent results in the concomitant group when compared to the group receiving CMF following radiotherapy. However,
1983. Volume 9, Number
II
I and II breast cancer complications (%)
Harris and Hellman” 5 5 2
Prosnitz
Bedwinek
et al. ”
et al. ‘I
et al. ’
1
2
6
2
I I
2 2
Chu
I
1 I I I
1
1
the incidence of arm edema was unaltered by the addition of prednisone or sequencing of chemotherapy. Botnick et CMF and a1.5 reported their results with concomitant radiotherapy for early breast cancer. Sixty-seven percent of the patients had a good to excellent cosmetic result compared to 92% in a control group. An increased incidence of acute skin reactions and symptomatic pneumonitis was associated with greater than two injections of methotrexate and 5-fluorouracil during the external beam treatment. The authors felt that the radiation sequelae persisted longer in patients receiving adjuvant chemotherapy but would eventually resolve. Lichter15 noted good to excellent cosmesis in 70% of the patients receiving sequential cyclophosphamide and adriamycin and primary radiotherapy for early breast cancer. An increased incidence of rib fractures was observed in the patients receiving adjuvant chemotherapy. Tables 7 and 8 summarize the data from the 3 institutions in terms of cosmesis and complications. The preliminary results would indicate that cosmesis is not adversely affected by the current adjuvant chemotherapy regimen (CMFP), but that there is an increased incidence of mild to moderate arm edema. The addition of prednisone to the CMF regimen following radiation and the omission of prednisone and methotrexate during radiation may be responsible for the apparent improved results in the present series when compared to others,5~‘s although it must be emphasized that the number of patients is small and the follow-up limited. Efforts must be directed towards decreasing the incidence of arm edema. Changes in the radiation technique which may help to reduce the incidence of arm edema would include elimination of the supraclavicular-apical axillary field in patients with positive nodes who will receive adjuvant
Table 7. Cosmesis in patients receiving adjuvant chemotherapy
and primary
Median follow-up
Penn JC($i+ NCI”
series)
radiotherapy
% good-excellent
(mos)
RT & chemo
RT alone
25 I3
81 (27)* 67 (40) 70 (16)
89 (19) 92 (37) 80 (24)
Effect of adjuvant
chemotherapy
Table 8. Complications in patients receiving adjuvant chemotherapy and primary radiotherapy (%) Penn (this series) Rib fracture RT RT & chemo Arm edema RT RT & chemo Symptomatic pneumonitis RT RT & chemo
JCRT’
NCI”
0 4
4 12
0 22
22 IO
5 0
0 8
Sarrazin et ~1.~~ noted no additional benefit in terms of local-regional control, 5 year survival or 5 year relapse-free survival in patients with positive axillary nodes when comparing those who had radiation to the chemotherapy.
on cosmesis 0 B. F. DANOFF et 41.
1629
regional nodes versus those who did not following a complete axillary node dissection. The current Milan protocol26 omits radiation to the regional nodes in patients with positive nodes who are undergoing primary radiotherapy and adjuvant chemotherapy. Information obtained from this study regarding local-regional control and relapse-free survival may provide additional support for irradiating only the breast in node positive patients. The omission of treatment to the regional nodes may result in a decreased incidence of arm edema and symptomatic pneumonitis as well as an increased hematologic tolerance to chemotherapy. As further experience is gained in the treatment of early breast cancer with primary radiotherapy and adjuvant chemotherapy, modifications in the treatment protocol may be necessary to maximize cosmesis and minimize complications but without sacrificing local-regional control and survival.
REFERENCES I
2.
3.
4.
5.
6.
Amalric, R., SantamarIa, F., Robert, F., Seigle, J., Altschuler, C., Kurtz, J.M., Spitalier, J.M., Brandore, H., Ayme, Y., Pallet, J.F., Burmeister, R., Abed, R.: Radiation therapy with or without primary limited surgery for operable breast cancer. A 20 year experience at the Marseilles Cancer Institute. Cancer 49: 30-34, 1982. Bedwinek, J.M., Perez, C.A., Kramer, S., Brady, L., Goodman, R., Grundy, G.: Irradiation as the primary management of stage I and II adsenocarcinoma of the breast. Cancer Clin. Trials 3: I l-18, 1980. Bonadonna, G., Brusamolino, E., Valagussa, P., BrugnatelIi, L., Rossi, A., Brambilla, C., DeLena, M., Tancini, G., Bajetta, E., Veronesi, U.: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Engl. J. Med. 294: 405-410, 1976. Bonadonna, Cl., Valagussa, P.: Dose response effect of adjuvant chemotherapy in breast cancer. N. Engl. J. Med. 304: IO-IS, 1981. Botnick, L.E., Come, S., Rose, C., Goldstein, M., Lange, R., Tishler, S., Schnipper, L: Primary breast irradiation and concomitant adjuvant chemotherapy (CMF). In Alternatives to Mastectomy, IHarris, J.R., Hellman, S., Silen, W. (Eds.), Philadelphia, PA, JB Lippincott Co. (In press) 1982. Calle, R.: Breast carcinoma-Local treatment place of conservative surgery and irradiation exclusively for early breast cancer. In Alternatives to Masfectomy, Harris, J.R., Hellman, S., Silen, W. (Eds.), Philadelphia, JB Lippincott Co. (In press) 1982.
I. Chu, A.M., Cope, O., Russo, R.. Wang, C.C., Schultz, M.D., Wang, C., Rodkey, G.: Treatment of early stage breast cancer by limited surgery and radical irradiation.
Int. J. Radial. Oncol. BIoI. Phys. 6: 25-30,
1980.
8. Fisher, B., Redmond, studies of the NSABP:
C., Wolmark, N.: Breast cancer An editorialized overview. In Adjuvant Therapy o/Cancer III. Salmon, S., Jones, S. (Eds.). New York, Grune & Stratton. 198 I, pp. 359-369.
9. Glick, J.H., Danoff, B.F., Haller, D.G., Weiler, C., Goodman, R.: Adjuvant chemotherapy in patients undergoing definitive irradiation for primary breast cancer: The University of Pennsylvania experience. In Alternatives to Mastectomy, Harris, J.R., IHellman, S., Silen, W. (Eds.), JB Lippincott Co. (In press) 1982.
IO. I I.
12.
13.
14.
IS.
Haagensen, C.D.: Treatment of curable cancer of the breast. Int. J. Radiat. Oncol. Biol. Phys. 2: 975-980. 1977. Harris, J.. Hellman, S.: Primary radiation therapy for early breast cancer: The experience at the Joint Center for Radiation Therapy. In Alfernatives to Mastectomy. Harris, J.R., Hellman, S., Silen, W.. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. Harris, J.R., Levene. M.B.. Hellman, S.: Results of treating stage I and II carcinoma of the breast with primary radiation therapy. Cancer Treat. Rep. 62: 985-991, 1978. 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: 257-26 I, 1979. Holland, J., Glidwell, 0.: Adverse effects of radiotherapy on adjuvant chemotherapy for carcinoma of the breast. Surg. Gyn. Obstet. 150: 8 17-82 I, 1980. Lichter, AS.: The National Cancer Institute experiencePrimary radiotherapy and adjuvant chemotherapy. In Alternafives to Mastectomy. Harris, J.R., Hellman, S.. Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982.
16. Montague, E.D., Schell, S.R., Ames, F.C., Romsdahl, M.M.: Conservative surgery and irradiation in clinically favorable breast cancer: The M.D. Anderson Experience. In Alternafives fo Mastectomy. Harris, J.R., Hellman. S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 17. Nissen-Meyer, R.: One short chemotherapy course in primary breast cancer: 12 year follow-up in series I of the Scandinavian Adjuvant Chemotherapy Study Group. In Adjuvant Therapy of the Cancer II. Salmon, S.. Jones, S. (Eds.). New York, Grune & Stratton. 1979. pp. 2077213. 18. Pierquin, B.: Conservative treatment for carcinoma of the breast-Experience of Creteil. IO years’ results. In AIfernarives to Masfectomy, Harris, J.R., Hellman, S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 19. Pierquin, B., Baillet, F., Wilson, J.F.: Radiation therapy in the management of primary breast cancer. Am. J. Roenfgeno/. 127: 645-648,
1976.
20. Pierquin, B., Owen, R.. Maylin. C., Otmezguine. Y.. Raynal. M., Mueller, W., Hannoun, S.: Radical radiation therapy of breast cancer. fnt. J. Radiat. Oncol. Biol. Phys. 6: 17-24,
1980.
1630
Radiation Oncology 0 Biology 0 Physics
21. Prosnitz, L. R., Weshler. Z., Goldenberg, IS.: Primary radiotherapy for breast carcinoma instead of mastectomy: The Yale experience. In Alternatives to Mastectom,v, Harris, J.R., Hellman, S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 22. Sarrazin, D., Le. M.., Fontaine, F., Arriagada, R.: Conservative treatment vs. mastectomy in T, or small Tz breast cancer: The experience of the Institute Gustave-Roussy. In AIternativrs to Mastectomy. Harris, J.R.. Hellman, S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 23. Spitalier. J.M.: A 20 year experience at the Marseilles Cancer Institute on conservative management for operable breast cancer. In Alternatives to Mastectomy. Harris, J.R., Hellman, S., Silen, W. (Eds.). Philadelphia, JB Lippincott Co. (In press) 1982. 24. Tancini,
G., Bonadonna,
G., Marchini,
S.: Adjuvant
CMF
November
1983, Volume 9, Number
II
in breast cancer: Comparative 5 year results of I2 vs. 6 cycles (Abstr.). Proc. Am. Sec. C/in. One. I: 87. 1982. 25. Tormey, D.. Gelman. R., Band, P.R., Sears, M.. Rosenthal. S.N., DeWys. W., Perlia. C.. Riw, M.A.: Comparison of induction chemotherapies for metastatic breast cancer: An Eastern Cooperative Oncology Group Trial. Cancer 50: 1235-1244, 1982. U., Saccozzi, R., DelVecchio. M., Banti. A., 26. Veronesi, Clemente. C., DeLena. M.. Gallus. G., Greco, M., Luini. A., Maruloini, E., Muscolino, G.. Rilke. F., Salvadori. B., Zecchini, A., Zucali. R.: Comparing radical mastectomy with quadrantectomy, axillary dissection and radiotherapy in patients with small cancers of the breast. N. EngI. J. Med. 305: 6-l I, 1981. 27. Weiss, R.B.. Tormey, D.C., Holland. J.F., Weinberg, V.E.: Venous thrombosis during multimodal treatment of primary breast carcinoma. Cancer Treat. Rep. 65: 677-679.
1981.