•

Local Control of Breast Cancer With Tumorectomy Plus Radiotherapy Or Radiotherapy Alone 1

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Therapeutic Radiology

Nemetallah A. Ghossein, M.D., Patricia Stacey, R.T., Seymour Alpert, M.D., Phyllis J. Ager, M.D., and Vasudevasastri Krlshnaswamy, Ph.D. 58 cases of breast cancer treated primarily by radiotherapy were evaluated to determine the optimum dose for local control. Of 36 patients with T1 T2 lesions who had tumorectomy prior to radiotherapy, incomplete excision of tumor was demonstrated on microscopic examination in 18. The minimum tumor dose to the breast was 4,500 rads in 5 weeks. Treatment failed to control local tumor in only 2 (5 %) and metastases in 1. 26 (72 %) remained disease-free for 2 to 9 ye;:trs. Of the '22 patients with T3 + T4lesions, treatment failed to control both local tumor and metastases in 12 (54 %); in those who received 6,000 rads or less in 6 weeks, treatment failed to control any of these lesions. 4,500-5,500 rads controlled the tumor in 95 % of those with NO N1 disease, compared to only half of those with N2 N3 tumors.

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INDEX TERMS:

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Breast neoplasms, therapeutic radiology • Therapeutic radiology, postoper-

ative Radiology 121:455-459, November 1976

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ANY AUTHORS (1, 17, 18, 20) have shown that

Staging

M

local excision followed by radical radiotherapy gives similar results to radical surgery in patients with operable cancer of the breast. With increasing interest in conservative management of breast cancer, it is important to determine the tumor dose which will give the highest local control with the fewest complications in both early and advanced stages. Although several authors have studied the time-dose relationship and rate of cure of primary squamous-cell cancer (10, 14, 23) and recurrent carcinoma of the breast (7, 13), primary breast cancer has not received such clinical attention. The purpose of this study was to determine the optimal dose for local control of (a) early breast cancer treated by tumorectomy and radiotherapy and (b) locally advanced cancer treated by radiotherapy alone.

The staging used was similar to that of the American Joint Committee for Cancer Staging (6): T1 tumor 2 em or less in its greatest dimension T2 tumor more than 2 em but not more than 5 em in its greatest dimension T3 tumor more than 5 em in its greatest dimension T4 tumor of any size with direct extension to the chest wall or skin no palpable homolateral axillary nodes NO movable homolateral axillary nodes, considered N1 to contain growth homolateral axillary nodes fixed to one another N2 or to other structures homolateral supraclavicular or infraclavicular N3 nodes or edema of the arm.

= =

= =

= = =

=

MATERIAL AND METHODS

The records of 56 women and one man given radical radiotherapy for histoiogically proved carcinoma of the breast at the Albert Einstein College of Medicine from 1957 to 1973 were reviewed, The patients ranged from 23 to 92 years of age (mean age, 61 yr.). In one patient who was initially irradiated for a T3/N 1 carcinoma of the left breast, a T 1INO carcinoma of the opposite breast developed one year later and was believed to be a second primary; since she therefore received another course of radical radiotherapy, a total of 58 primary cancers were actually analyzed. The man, who refused radical surgery, had a T1/NO lesion. All patients who received at least 3,000 rads tumor dose to the area of the primary were included in this study, regardless of the extent of local disease.

Treatment Policy All patients were treated on a 60CO unit; 10-MeV electrons or 250-kV x rays were occasionally used to boost the dose to the primary site. The techniques used varied through the years; however, since 1965 the treatment has been standardized and is similar to that described by Fletcher and Montague (12). The patient was treated supine with her arm extended at a right angle on an arm rest and her head tilted 45° to the opposite side. The lateral tangential field was set to the midaxillary line. The medial tangential field was tilted 10° downward, extended 1 em across the midline, and received 3 to 2 loading in its favor to increase the dose to the internal mammary lymph nodes.

1 From the Department of Radiology, Section of Radiotherapy (N.A.G., P.S., P.J.A., V.K.) and the Department of Surgery (S.A.), Albert Einstein College of Medicine, Yeshiva University, Bronx, N.Y. Accepted for publication in April 1976. Part of this work was performed during P.J.A.'s ACS fellowship year. sjh

455

456

NEMETALLAH A. GHOSSEIN AND OTHERS

November 1976

Table I: Stage of Primary and Nodal Involvement in 58 Cases of Breast Cancer Treated Conservatively HUMERAL HEAD SHielDED

\n;::~-

ICM OFMUSCLE EDGESHIELDED

SUPERIOR MARGIN CRICO-THYROID MEMBRANE

r

~

FiElD ANGLED IS' LATERAllY 2

nd

COSTAL CARTILLAGE

~

CONE DOWN FiElD

LATERAL TANGENTIAL TO MID AXILLARY LINE

T \

9)

MEDIAL TANGENTIAL lCM OVER MIDLINE

Fig. 1. Radiotherapy portals. The patient is treated supine with her arm extended at a right angle. The dose to the axilla is boosted via a posterior field.

The lower margin of the tangential fields was placed 1 em below the inframammary fold, while the upper margin bisected the second costal cartilage. If the separation between the tangential fields was more than 22 em, a separate internal mammary field was used. A breast plate was used to eliminate the penumbra and collimate the beam. The supraclavicular field abutted the upper margin of the tangential fields and extended superiorly to the level of the cricoid cartilage. Medially, it extended 1 em across the midline to include the medial margin of the sternocleidomastoid muscle. Laterally, it extended to the coracoid process. The head of the humerus was shielded with 5 em of lead. The field was angled 15° laterally. 1 em of the lateral edge of the pectoral muscle was shielded unless bulging of the axillary fat pad was present (Fig. 1). The breast received 5,000 rads tumor dose, calculated to the 90% isodose line when normalized to the maximum dose. An additional tumor dose of 1,000-3,000 rads was given to the area of the primary through significantly reduced fields. The supraclavicular field, which included the axilla, received 5,000 rads surface dose and the axilla was boosted posteriorly to receive a total tumor dose of 5,000 rads. In addition, 1,000-2,000 rads was delivered to clinically palpable nodes in the axilla and/or supraclavicular area through reduced fields. All fields were treated five times a week to a total of 1,000 rads. RESULTS

The stage of primary and nodal involvement is shown in TABLE.I. There were 36 early lesions (T1 + T2) and 22 advanced tumors (T3 + T4). More than half of the patients had clinical evidence of nodal involvement. Of the 36 pa-

Table II:

Stage

NO

Tl T2 T3 T4 Total

11 13 1 1 26 (45%)

N3

Total

9 (16%)

1 1 4 6 {10%}

15 (26%) 21 (36%) 8 (14%) ~ (24%) 58

2

2

~

17 (29%)

tients with early disease, all of whom had excisional biopsy of the primary tumor (tumorectomy) prior to irradiation, 18 (50 %) showed tumor involving the margin of surgical resection on microscopic examination. In 11 (30 % ) of these cases, mastectomy was medicaliy contraindicated. The remaining 25 were treated conservatively because the patients had refused mastectomy. With the exception of one patient who had local excision, all 22 patients with advanced cancer (T3 T4) had biopsy of the primary only .prior to radiotherapy. Sixteen patients (73 %) were considered surgically inoperable and 3 (14 % ) were medically inoperable. Patients who were free of local disease either in the breast or in the regional lymph nodes for at least two years, or who died of metastatic cancer or intercurrent disease but were free of local disease at the time of death, were considered to have local control of disease for the purpose of this study. Of the 7 patients with early cancer who died of intercurrent disease, 4 died 2-9 years after treatment, while 3 died within less than 2 years. Only one patient with advanced cancer died of intercurrent disease, one year after therapy. TABLE II shows the sites of failure according to the stage and nodal involvement. Of the 36 early lesions (T1 + T2), treatment failed to control the primary in 2 (5.5 %); initially the margin of resection showed microscopic tumor involvement in one case but not in the other. Subsequent radical mastectomy demonstrated persistent disease in the breast in one and the breast and axilla in the other. Distant metastases subsequently developed in both patients. Of the 22 advanced tumors (T3 + T4), treatment failed to control both the local tumor and metastases in 12 (54 %). Patients with local failure of advanced cancer had persistent disease in the breast alone or in the breast and regional lymph nodes. All 14 local failures occurred within 2 years after treatment (average, 16 ± 3 months). Analysis of control of nodal disease (TABLE 111) shows that treatment failed to control the disease in the axilla in only one patient

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N2 + N3

NO + Nl

Stage

D*

L + 0*

Tl + T2 T3 + T4 Total

36 22 58

1 2 3 (5%)

2 2 4 (7%)

= distant disease only; L + 0 = local

D* 3 3 (5%,)

L + 0* 10 10 (17%)

(breast and/or nodes) and distant disease. ± 3 rno.). 4 died 2 to 9 years after therapy; 3 died in less than 2 years.

t Fre~ of disease for 2 to 9 years (average, 36

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4 7 4

N2

Site of Local Failure and Distant. Metastases According to Stage and Nodal Involvement

No. of Cases

* D

Nl

Dead of Intercurrent Disease

7+

1 8 (14%)

NEDt 26/36 (72%) 4/22 (18%) 30/58 (52%)

457

LOCAL CONTROL OF BREAST CANCER

Vol. 121

Therapeutic Radiology

10,000 T1 + T2

9000

;n 8000 0 4: ~

T3+T4



e

e

1I81

(161

(Il

(101

(121

2600

7000

UJ II)

0 0

0

0

2400

a::

0 ::?i

~

5000

2200

0

0

I-

;n I-

4000~--.L....-_...J..-_...L.------l._...L.----l---J

30

40

50

60

70

UJ

z 1800

.•

I

....

l/)

Fig. 2. Time-dose scatter distribution for T3 + T4 lesions. Isoeffect line A was drawn by analyzing the highest 20 % of failures by the least-squares method. All of the lesions above the line (3/3) and half of the lesions between the two lines (7/14) were controlled. Only failures (0/5) are present below Line B. • = controls; 0 = failures.

#t'

.

..

0

---'-------1-------------- ----.---------

1600

o

o o

1400 1200 1000

Table III: Local Control of Nodal Disease According to Stage and NSD

CONTROL

NSD (rets)

NO

N1

N2

N3

1,600 Total

7/8 18/18 (100%)

3/3 8/9 5/5 16/17 (94%)

2/3 1/3 2/3 5/9

0/2 1/2 1/2 2/6

+

...

~ 0

80 90 100

OVERAll TREATMENT TIME (DAYS)

25/26 (96%)

----------------o-----"t)--2000

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with a T1 T2 lesion. Of the 43 patients with NO N1 cancer, treatment failed to control the disease in the axilla in only 2 (5 %), while 8 of the 15 N2 + N3 lesions (53 %) were uncontrolled. Time-dose scatter distribution on a log-log plot was analyzed for advanced tumors (Fig. 2); it was not possible to assess the T1 + T2 lesions, as there were only 2 local failures. The mean limiting slope of the isoeffect line was evaluated by analyzing approximately 20 % of the T3 T4 failures given the highest dose (Fig. 2). When the regression line was drawn using the least-squares method, the resulting isoeffect line was found to have a slope of 0.34, which is in close agreement with the value obtained by other authors for recurrent breast cancer (7) and squamous-cell cancer of the tonsillar fossa (23) and supraglottic region (14). The local control rate was analyzed as a function of the position of the isoeffect line. Line B was drawn parallel to the isoeffect line on the time-dose plot so that all failures would fall below it; for a 7-week treatment, this line represented a dose of 1,300 rads less than the isoeffect line. The data suggest that the control rate increases with the dose. The equations representing isoeffect lines A and B (time-dose relationship similar to the Strandqvist curve) are

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line A: D = 2,000 rads - TO. 34 line B: D = 1,650 rads- TO. 34 Analyses carried out according to the NSD formula (8) for T1 + T21esions(with and without microscopic involvement

CONTROL

FAILURE

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FAILURE

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Fig. 3. Control and failure of T1 T2 and T3 T4 lesions according to the NSD. E9 = microscopic involvement of the line of excision uninvolved. line of surgical excision;

e=

Table IV: Local Control of Primary Disease According to Stage and NSD NSD,* (rets)

T1 + T2

T3 + T4

>2,100

1/1 23/25 (92%) 10/10 (100%)

3/4 (75%) 6/12 (50%) 1/6 (17%)

2,100

~ NSD > ~ 1,750

1,750

* Treatment was given at a rate of 200 rads/five fractions/ seven days. Table V: None

Complications of Radiotherapy Minimal

Moderate

Severe

3/40(7.5%) 3/40(7.5%) 1/40(2.5%) 33/40 (82.5%) Lung 4/40(10%) 1/40(2.5%) 35/40 (87.5%) 1/40(2.5%) Shoulder 39/40 (97.5%) Breast

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of the margin of resection) and T3 T41esions are represented in Figure 3. NSD values corresponding to isoeffeet lines A and B were found to be 2,100 and 1,750 rets, respectively. These values differ from the intercepts of the isoeffect line, since the NSD in this study applied to normal tissues whereas the time-dose relationship applies to tumor NSD. The control rate is shown as a function of NSD in TABLE IV. This analysis suggests an increase in local control for T3 T4 lesions as NSD values increase. Microscopic involvement of the margin of resection did not appear to affect local control of T1 + T2 lesions.

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Morbidity Thirty-two patients with early lesions and 8 with advanced cancer were examined for evidence of radiation complications two years or more after treatment (TABLE

458

NEMETALLAH

A.

GHOSSEIN AND OTHERS

November 1976

Fig. 4. Grading of cosmetic results following radiotherapy. A. None: carcinoma of the right breast. The breast is normal in appearance except for the tumorectomy scar. B. Minimal: there is radiation telangiectasia involving less than one-third of the breast. The breast is not distorted. C. Moderate: carcinoma of the lower outer quadrant. Healing of the wound following tumorectomy was delayed because irradiation was begun too early. The deformity is due to localized fibrosis. D. Severe: fibrosis involving the entire breast.

V). Cosmetic results and radiation complications were graded as follows: Breast None: no change in the appearance of the breast attributable to radiotherapy (Fig. 4, A) Minimal: radiation skin changes and/or fibrosis involving less than %of the circumference of the breast, with no significant distortion of its shape (Fig. 4, B) Moderate: radiation skin changes and/or fibrosis involving more than Y3 but less than %of the circumference of the breast, or moderate distortion of its shape (Fig. 4, C) Severe: marked skin changes and/or fibrosis, or marked distortion of the breast (Fig. 4, D). Lung None: no significant findings on the chest radiograph Minimal: radiographic changes attributable to irradiation, but no symptoms Moderate: symptoms present Severe: patient's activity restricted by more than 50 % compared to before treatment. Shoulder Joint None: no limitation of shoulder movement Minimal: minimal restriction of movement compared to the opposite side Moderate: limitation of movement by more than

30° Severe: "frozen" shoulder. Only one patient had severe and unacceptable radiation changes of the breast; 3 had moderate changes and 3 had minimal changes. The 4 patients with severe or moderate radiation changes had received 7,000-8,000 rads tumor dose with no significant reduction in field size after delivery of the first 5,000 rads. Only one patient exhibited symp-

tomatic pulmonary fibrosis, and one had minimal restriction of shoulder movement. There was no incidence of radiation necrosis of bone. DISCUSSION

Our results show that the local control rate of early lesions (T1 T2) following excisional biopsy and radiotherapy is almost 95 % if at least 4,500 rads in 5 weeks is delivered to the breast and regional lymph nodes. Although this is comparable to other published series (4, 19), it is at variance with the findings of Farrow et al. (9), who stated that more than 50 % of their patients treated by tumorectomy and radiotherapy exhibited local recurrence. One explanation for this difference may be the fact that more than 30 % of their patients had a tumor dose of less than 5,000 rads and several of them were given orthovoltage therapy. Microscopic involvement of the margin of resection in T1 + T2 cancer does not appear to adversely affect the local recurrence rate, since half of our patients with early lesions had residual microscopic disease following excision of the mass and all but one lesion were controlled. This suggests that wide excision of the mass, which may be cosmetically unacceptable, is unnecessary. Rosen et al. (22) reported a high incidence of residual cancer following simulated partial mastectomy performed on breast specimens obtained following radical mastectomy. Because the partial excision did not remove all of the tumor, it was concluded that local control may not be achieved by anything less than total mastectomy. The purpose of radiotherapy following tumorectomy is eradication of subclinical disease, whether at the margin of resection or multifocally within the breast. Fletcher has shown that moderate radiation doses in the range of 4,500 rads in 5 weeks can eliminate 90 % of occult disease or more in the regional lymph nodes and chest wall (11). Our study shows that the same dose can eliminate minimal

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Vol. 121

459

LOCAL CONTROL OF BREAST CANCER

disease within the breast in a comparable percentage of cases. Bataini et al. (3) have shown that when the primary tumor is not excised and the breast is treated solely by irradiation, a much higher dose (on the order of 8,500 rads in 7 weeks, or 2,250 rets) is required to control the primary lesion. It is possible that some lesions we now consider controlled may recur, since the average follow-up period is only 3 years. However, all of the local failures in this series occurred within 2 years. This is in agreement with previous studies, which demonstrated that 75% of local recurrences develop within 2 years after radical radiotherapy (12) and 3 years after surgery (21). Advanced disease was controlled locally in only half of our patients, which is similar to the rate reported by Chu et al. (5). This is less than half the number reported by Montague (16); however, she gave 7,500-9,000 rads in 9-10 weeks, a significantly higher dose than that used for most of the patients in this series. Although a dose-response curve could not be demonstrated for early lesions, since only 2 patients exhibited local failure, we were able to construct one for advanced tumors. In our series, 3 lesions were controlled with doses of at least 7,500 rads in 7 weeks. All patients showed failure if the dose was :5 6,000 rads in 7 weeks. Other authors (2, 15) have shown poor local control of advanced breast tumors with doses of 4,000-5,500 rads. In patients with T3 lesions (larger than 5 em in diameter), Calle et al. (4) found that tumor doses on the order of 8,000-9,000 rads are needed to achieve a control rate of approximately 50 %; no tumor was controlled with 7,000 rads or less. Almost 95 % of the tumors with no or minimal clinical N1) were controlled with doses nodal involvement (NO ranging from 4,500 rads in 5 weeks to 5,500 rads in 6 weeks. Only half of those with massive nodal involvement (N2 + N3) were controlled, since most were not given more than 5,500 rads in 6 weeks. Our results agree with previous studies which showed that higher doses (on the order of 6,000-7,000 rads in 6-7 weeks) were needed to control axillary involvement in Stage III disease (11). Since the purpose of radiotherapeutic management of breast cancer, particularly the early stages, is to obtain maximum local control with minimum radiation changes, analysis of the cosmetic results and radiation complications is important. Only one patient exhibited severe and unacceptable radiation changes of the breast. Three had moderate radiation changes which were cosmetically acceptable, and only one had symptomatic pulmonary fibrosis. These results indicate that radical doses may be delivered to the breast and regional lymph nodes when well-planned fields and careful techniques are used. The fields should be markedly reduced after delivery of 5,000 rads tumor dose to include only the area of the primary and any persistent adenopathy.

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ACKNOWLEDGMENTS: We are grateful to Gilbert H. Fletcher, M.D., for reviewing the manuscript and for his constructive suggestions and criticisms. We also wish to thank Gershon Efron, M.D., Ralph Ger, M.D.,

Therapeutic Radiology

and Herbert Volk, M.D., for referring patients to us for this study, and Phyllis Pompadur for her secretarial assistance.

REFERENCES 1. Atkins H, Hayward JL, Klugman OJ, et al: Treatment of early breast cancer: a report after ten years of a clinical trial. Br Med J 2: 423-429,20 May 1972 2. Atkins HL, Horrigan WD: Treatment of locally advanced carcinoma ot the breast with roentgen therapy and simple mastectomy. Am J Roentgenol 85:860-864, May 1961 3. Bataini JP, Ennuyer A, Dhermain P: Radiotherapie exclusive du cancer du sein. Bull Cancer (Paris) 59:13'5-160, Apr-Jun 1972 4. Calle R, Fletcher GH,PierquinB: Les bases de Ia radioth9rapie curative des epitheliomas mammaires. J Radiol Electrol 54:929-938, Dec 1973 5. Chu FCH, Nisce L, Baker AS, et al: Electron-beam therapy of cancer of the breast. Radiology 89:216-223, Aug 1967 6. Clinical Staging System for Carcinoma of the Breast (revision). Chicago, American Joint Committee on Cancer Staging and EndResults Reporting, 1973, p 14 7. Cohen L: Radiotherapy in breast cancer. I. The dose-time relationship: theoretical considerations. Br J Radiol 25:636-642, Dec 1952 8. Ellis F: The relationship of biological effect to dose-timefractionation factors in radiotherapy. [In] Ebert M, Howard A, eel: Current Topics in Radiation Research. Amsterdam, North-Holland; New York, Wiley, 1968, Vol 4, Chapt 7, pp 357-397 9. Farrow JH, Fracchia AA, Robbins GF, et al: Simple excision or biopsy plus radiation therapy as the primary treatment for potentially curable cancer of the breast. Cancer 28: 1195-1201, Nov 1971 10. Fletcher GH: Clinical dose-response curves of human malignant epithelial tumours. Br J RadioI48:1-12, Jan 1973 11. Fletcher GH: Local results of irradiation in the primary management of localized breast cancer. Cancer 29:545-551, Mar 1972 12. Fletcher GH, Montague ED: Radical irradiation of advanced breast cancer. Am J RoentgenoI93:573-584, Mar 1965 13. Friedman M, Pearlman AW: Time-dose relationship in irradiation of recurrent cancer of the breast. Iso-effect curve and tumor lethal dose. Am J RoentgenoI73:986-998, Jun 1955 14. Ghossein NA, Bataini JP, Ennuyer A, et al: Local control and site of failure in radically irradiated supraglottic laryngeal cancer. Radiology 112:187-192, Jul1974 15. Griscom NT, Wang CC: Radiationtherapy of inoperable breast carcinoma. Radiology 79:18-23, Jul 1962 16. Montague ED: Radiation therapy for locally advanced carcinoma of the breast. [In] Breast Cancer: Early and Late. Chicago, Year Book, 1970,pp 191-198 17. Mustakallio S: Conservative treatment of breast carcinoma-review of 25 years follow up. Clin Radiol 23: 110-116, Jan 1972 18. Peters MV: Wedge resection and irradiation. An effective treatment in early breast cancer. JAMA 200:144-145, 10 Apr 1967 19. Peters MV: The role of local excision and radiation in early breast cancer. [In] Breast Cancer: Early and Late. Chicago, Year Book, 1970, pp 171-189 20. Rissanen PM: A comparison of conservative and radical surgery combined with radiotherapy in the treatment of stage I carcinoma of the breast. Br J Radial 42:423-426, Jun 1969 21. Romsdahl MM, Sears ME,Eckles NE: Posttreatmentevaluation of breast cancer. [In] Breast Cancer: Early and Late. Chicago, Year Book, 1970, pp 291-299 22. Rosen PP,Fracchia AA, UrbanJA, et al: "Residual" mammary carcinoma following simulated partial mastectomy. Cancer 35:739747, Mar 1975 23. Shukovsky W, Fletcher GH: Time-dose and tumor volume relationships in the irradiation of squamous cell carcinoma of the tonsillar fossa. Radiology 107:621-626, Jun 1973 Department of Radiotherapy Albert Einstein College of Medicine 1825 Eastchester Rd. Bronx, N.Y. 10461