RADIATION THERAPY ONCOLOGY GROUP     RTOG 95-17

A PHASE I/II TRIAL TO EVALUATE BRACHYTHERAPY AS THE SOLE METHOD OF RADIATION THERAPY FOR STAGE I AND II BREAST CARCINOMA

ELIGIBILITY: (see Section 3.0 for details)

- Invasive ductal, medullary, papillary, colloid (mucinous), tubular histologies

- Stages T1, T2, (lesions = 3 cm) N0, N1 (up to 3 metastatic axillary lymph nodes with no extracapsular nodal extension

[a minimum of 6 nodes in specimen], or a negative sentinal node is acceptable), M0

- Six surgical clips placed at time of tylectomy to delineate target volume.

- Unifocal breast cancer (single focus which can be encompassed by one tylectomy)

- Unilateral breast cancer; no synchronous or previous contralateral breast cancer

- Negative or close but negative microscopically-assessed surgical margins (see Section 10.6)

- No extensive intraductal component (see Section 3.2.16)

- No collagen vascular disease (see Section 3.2.7)

- No known unresected residual carcinoma; no diffuse suspicious microcalcifications

- No prior malignancy (< 5 years prior to enrollment in study) except non-melanoma skin cancer if continuously diseasefree

- Negative post-tylectomy mammogram if cancer presented with malignancy-associated microcalcifications

- Negative pregnancy test for women of child-bearing age

- Time interval from final definitive breast surgical procedure to brachytherapy loading is less than 6 weeks

 

Within the last ten years, breast conserving therapy has become a major treatment modality for Stage I and II breast

carcinoma. Seven studies, including NSABP B-061 and the Milan trial,2 have demonstrated in a prospective

randomized setting similar overall and distant disease-free survival for patients receiving breast conserving therapy,

compared with patients treated by conventional mastectomy. Breast conserving therapy in both NSABP B-06 and

the Milan study consisted of initial tumor excision with negative gross and histologic margins, axillary lymph node

dissection, and whole breast external beam radiation therapy. The major advantages of breast conserving therapy

are superior cosmetic outcome and the reduced emotional and psychological trauma afforded by this procedure

compared with conventional mastectomy. The principal disadvantage of breast conserving therapy (BCT) is its

more complex and prolonged treatment regimen requiring approximately 6 weeks of external beam radiation

therapy which poses problems for some patients such as the working woman, elderly patients, and those who live at

a significant distance from a treatment center. These factors, along with the patient's geographic location, result in

only a small fraction of the patients who currently meet eligibility criteria for BCT actually receiving it, despite its

cosmetic and probable psychological advantages. The logistical problems of BCT are primarily related to the

protracted course of external beam radiation therapy to the whole breast. While some investigators reported what

they believe to be acceptable local control rates in carefully selected patients treated by wide local excision without

radiation therapy, the criteria for patient selection are controversial and poorly defined and probably restrict the

access of many patients to breast conserving therapy. For instance, Crile at the Cleveland Clinic and Liljegren

et al.4 from the Uppsala-Orebro Breast Cancer Study Group treated patients with wide local excision and no

radiation therapy with breast recurrence rates of 10.9% and 18.4% respectively. Both studies were quite restrictive

in their criteria, treating only small tumors. These results are in sharp contrast to the tylectomy alone arm of the

NSABP B-06 randomized prospective trial, which included patients with invasive cancers up to 4 cm in size with

negative surgical margins, where the breast recurrence rate of 43% is considerably higher than the 10% breast

failure rate of the tylectomy and whole breast irradiation arm.1 At ten years, the local recurrence rates were 53%

and 12% respectively p < 0.001).5

Whole breast irradiation subsequent to tylectomy is postulated to reduce the breast recurrence rate through

eliminating residual foci of cancer remaining in the peri-tylectomy site and occult multicentric areas of in-situ or

infiltrating cancer in remote areas of the breast. Rosen et al. evaluated 203 mastectomy specimens and identified

multicentric areas of in-situ or invasive cancer in 26% of breasts with index cancers = 2 cm, and in 36% of breasts

with index cancers of 2.1 to 4 cm.6 Holland et al. evaluated 217 mastectomy specimens and noted residual foci of

cancer greater than 4 cm from the index cancer in 32% of patients with an extensive intraductal component (EIC)

and in 12% of patients without EIC.

Despite the discovery of remote foci of cancer in 26% to 36% of patients in the above studies, the relationship of

these foci to local control rates after breast conservation treatment is debatable. Sixty-five to 100% of breast

recurrences reported after tylectomy and radiation therapy have been found in the same quadrant as the initial

tumor, with an histology similar to the primary tumor, and probably representing residual viable cancer in the peritylectomy

site not controlled by radiation therapy. Since breast recurrence rates after conservative surgery

with negative surgical margins and whole breast irradiation have been approximately 10%, and since 65 to 100%

of these local recurrences are in the immediate vicinity of the tylectomy site, it appears that only 0 to 3.5% of

patients treated with tylectomy and radiation therapy relapse in remote areas of the breast. This 3.5% recurrence

rate is far below the anticipated rate of remote recurrence predicted by the Rosen/Holland data on multicentricity. Is

this absence of the expected number of remote breast recurrences due to the whole breast radiation therapy

employed in these series or to the biological insignificance of occult cancer foci in remote quadrants of the breast?

To address this question, one must examine studies of breast conservation patients treated with surgery only and

evaluate the number of remote recurrences. Fisher evaluated 110 patients with breast recurrence, initially treated by

tylectomy without radiation therapy, and found that all relapses were in the immediate vicinity of the tylectomy

site.8 Crile evaluated 32 patients with breast recurrence initially treated with segmental mastectomy alone; in 84%

of these patients the recurrence was in the immediate vicinity of the segmental mastectomy scar. Liljegren et al.

also evaluated 43 patients who recurred in the breast after wide local excision only and in 84%, the recurrence was

in the immediate vicinity of the tylectomy site, defined as the surgical scar and the skin directly over the surgical

field.4 From these data, one can infer that radiation therapy following tylectomy has as its maximal effect the

reduction of breast cancer recurrence at or very near the tylectomy site.

If the above observations are valid and breast irradiation following tylectomy exerts its maximal effect in

eradicating occult disease remaining in the immediate vicinity of the tylectomy site, can radiation therapy be

directed only to the tissue surrounding the excision cavity of the breast, using brachytherapy alone? If so, the entire

course of radiation therapy could be delivered over a 3 to 7 day period immediately following tylectomy and/or

axillary dissection, thus markedly reducing treatment time. Brachytherapy also inherently provides a higher central

dose to the volume most at risk for recurrence. In addition, there may be biological advantages to low dose rate

continuous radiation over a short time interval.11 Cosmetic outcome after the use of a brachytherapy boost after

external whole breast radiotherapy is comparable or slightly inferior to electron beam boost radiation therapy.

The complication rate after standard implants is < 2%.

The Ochsner Experience:

Reducing the duration of treatment time from 6 weeks to 4 days and confining irradiation to the tissue at greatest

risk for tumor recurrence were the objectives of a prospective phase I/II trial designed to evaluate cosmesis,

complications, and local tumor control following wide-volume double-plane iridium-192 breast implants.15 Since

patients were assigned to receive low dose rate (LDR) or high dose rate (HDR) brachytherapy alternating in blocks

of 10 patients, a comparison of these two methods with the same end points was undertaken.

Fifty-one women with 52 breast cancers were entered into the trial. Eligibility criteria included intraductal or

invasive carcinomas less than or equal to 4 cm in size, 0 to 3 positive axillary nodes, and negative inked

microscopic surgical margins. A double-plane implant was placed under direct visualization of the excision cavity

or with ultrasound guidance, and the catheters extended 2 cm beyond the cavity in all peripheral dimensions. LDR

patients received 45 Gy in 3.5 to 6 days, while HDR patients received 32 Gy in 8 fractions over 4 days. The

prescription isodose curve for the first 17 patients was selected by the physicians as the curve best covering the

target volume. Thereafter, the ICRU dosimetry guidelines which establish the gradient between the mean central

dose rate and the peripheral or reference dose rate at 15% were consistently used. Cosmesis was strictly evaluated

by a three person panel from photos taken every 6 months according to established criteria which is described in

Section 11.3.1. Median follow-up is 50 months (range = 30 - 62 months) as of March 1997.

There have been 3 grade 3 complications (5.8% overall, 3.8 % LDR, 7.7% HDR). Two HDR patients experienced

severe fat necrosis, one requiring a mastectomy and the other a quadrantectomy with flap coverage. One LDR

patient developed an abscess from an infected seroma at 4 months which was incised and drained. There were 2

grade 2 complications: both symptomatic fat necroses not requiring surgery. Cosmesis was excellent in 44%, good

in 28%, fair in 19%, and poor in 9% of the patients. The rate of good/excellent cosmesis was 78% in LDR, 67% in

HDR (p=0.39). Fat necrosis developed in 5 of 10 patients receiving chemotherapy as compared to 5 of 42 patients

without chemotherapy (p=0.008), and in 8 of 46 (17%) with acceptable dosimetry versus 2 of 5 patients (40%) with

unacceptable dosimetry, defined as a dose gradient greater than 30%. With four year median follow-up period there

have been no local breast tumor recurrences. Refinements in dosimetry and increasing the number of HDR

fractions to 10 (5 days) may improve the cosmesis and decrease the complications. At the Ochsner Clinic, LDR

brachytherapy including hospitalization, offers a reduction of 23% in Medicare allowable fee collections when

compared to a standard 6 week course of external beam irradiation.

The Guy's Hospital and Christie Hospital Trials

Two trials from Great Britain investigated the use of small field irradiation in breast cancer. The Guy's Hospital

trial included patients with lesions up to 4 cm in size, grossly excised margins which were not evaluated, complete

axillary dissection, and 55 Gy in 5 1/2 days low dose rate (LDR) brachytherapy.16 There were 2 isolated local

regional recurrences (7.5%) and 2 with distant metastases (7.5%). Cosmetic results were 96% Excellent/Good

according to patients and 80% judged by the physicians. Complications included 4 wound infections, 3 skin

necroses, 7 temporary erythema, 2 frozen shoulders, and 1 patient with claustrophobia.

Important differences between the Guy's trial and this RTOG study include: requiring inked microscopic margin

assessment, large volume implants, (typically 17 catheters compared to a median of 9 wires in the Guy's trial), a

total prescribed dose 10 Gy lower in RTOG, the use of free-hand technique rather than templates, and the exclusion

of patients with an extensive intraductal component (EIC) and lobular histologies. Stricter patient selection criteria

and broader volume implants in the RTOG study may result in a lower breast recurrence rate, and the lower total

dose may reduce the complication rate and improve cosmesis.

The Christie Hospital and Holt Radium Institute randomized 708 patients with lesions 4 cm or less in diameter and

without an axillary dissection to receive either: (1) quadrant irradiation, typically 10 MeV electron beam to an

average field of 6 x 8 cm, 42.50 Gy in 8 fractions; or (2) tangential whole breast 4 MV photon beams to 40 Gy in

15 fractions. The primary tumor was completely excised in only 80% of the cases. The actuarial 5 year breast

recurrence-free rates were 94% in the wide field arm and 87% in the local field. Lobular carcinomas in the local

field arm had a 20% recurrence rate. Axillary recurrences occured in 14% of the locally treated patients and 4% in

the wide field treatment arm. Ten patients in the local field and 2 in the wide field group had fat necrosis.17 These

results are difficult to extrapolate to this RTOG study, because of the differences in patient selection and surgical

technique, as well as the inherent physical differences in electrons and brachytherapy. Most critical are the smaller

treatment volumes and the probable underdosing of the deeper tissues with 10 MeV electron beams which fall off

steeply at a depth of 2.5 cm.

Patient selection criteria in this RTOG breast brachytherapy protocol has been chosen to minimize the risk of

multicentricity and a remote breast recurrence. The key factors are the exclusion of patients with microscopic

extension of tumor cells to the inked surgical margins, lobular histologies, tumors larger than 3 cm, and patients

having an extensive intraductal component. Patients with involvement of 4 or more axillary lymph nodes have a

significant risk for supraclavicular or infraclavicular nodal relapse. Most radiation oncologists treat such patients to

these nodal sites with 5 weeks of external beam radiation therapy. These patients would lose the logistical

advantage of a 3 to 7 day breast treatment regimen. Even with these strict selection criteria, approximately 71,000

women per year in the United States would be candidates for this protocol.

The radiobiological similarity between the proposed 10 fraction 5 day HDR treatment schedule and the 45 Gy 4 1/2

day LDR treatment has been calculated for both tumor control and late normal tissue effects by two independent

scientists, based on the linear quadratic model

Eligibility Criteria (2/14/00)

3.1.1 AJC stage I or II (T1N0, T2N0, T1N1, T2N1) histologically confirmed invasive carcinoma of the breast

with a lesion = 3 cm, treated with tylectomy and axillary dissection (see Section 8.0) . Tumor size is

determined by the pathologist (Section 10.3). Use clinical size only if the pathologic size is

indeterminate.

3.1.2 Surgical clips in place delineating the margins of the tylectomy cavity.

3.1.3 Signed study-specific informed consent for participation in the study (Appendix I).

3.1.4 Negative, or close but negative, inked histologic margins of tylectomy or reexcision specimen to be

confirmed prior to introducing the radiation sources. Margins generally are positive if there is invasive

or noninvasive tumor at the inked resection margin, close but negative if the tumor is within 2 mm of

the inked margin and negative if the tumor is at least 2 mm away from the inked edge.

3.1.5 Negative post-tylectomy or post-reexcision mammography if cancer presented with malignancyassociated

microcalcifications; no remaining suspicious microcalcifications in the breast before

brachytherapy. If the catheters are placed at the time of reexcision, the criteria may not be feasible but a

post brachytherapy mammogram should be obtained as soon as is practical and the results recorded on

the data form.

3.1.6 Less than four positive axillary nodes with no extracapsular extension, and at least 6 axillary lymph

nodes sampled, or a negative sentinal node.

3.1.7 Invasive ductal, medullary, papillary, colloid (mucinous), or tubular histologies.

3.1.8 Tamoxifen therapy is allowed. Chemotherapy planned for = 2 weeks after removal of brachytherapy

catheters is permitted.

3.2 Ineligibility Criteria

3.2.1 Patients with distant metastases.

3.2.2 Patients with invasive or in-situ lobular carcinoma or pure ductal carcinoma in-situ or nonepithelial

breast malignancies such as sarcoma or lymphoma.

3.2.3 Patients with proven multicentric carcinoma (tumors in different quadrants of the breast, or tumors

separated by at least 4 cm) with other clinically or radiographically suspicious areas in the ipsilateral

breast unless confirmed to be negative for malignancy by biopsy.

3.2.4 Patients who are pregnant or lactating.

3.2.5 Patients with more than 3 histologically confirmed positive axillary nodes in the ipsilateral axilla.

Palpable or radiographically suspicious contralateral axillary, supraclavicular, infraclavicular, or internal

mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.

3.2.6 Prior non-hormonal therapy for the present breast cancer, including radiation therapy or chemotherapy.

3.2.7 Patients with collagen vascular diseases, specifically systemic lupus erythematosis, scleroderma, or

dermatomyositis with a CPK level above normal or with an active skin rash.

3.2.8 Patients with coexisting medical conditions in whom life expectancy is < 2 years.

3.2.9 Patients with psychiatric or addictive disorders which would preclude obtaining informed consent or

tolerating confinement of several days duration for brachytherapy (low dose rate) or completing the full

series of brachytherapy treatments on an outpatient basis (high dose rate).

3.2.10 Patients with Paget's disease of the nipple.

3.2.11 Patients with skin involvement, regardless of tumor size.

3.2.12 Patients with a breast unsatisfactory for brachytherapy. For example, if there is little breast tissue

remaining between the skin and pectoralis muscle after surgery, placement of catheters is technically

problematic.

3.2.13 Patients with tylectomies so extensive that the cosmetic result is fair or poor prior to brachytherapy.

3.2.14 Patients whose tylectomy cavity is not delineated by surgical clips.

3.2.15 Surgical margins which cannot be microscopically assessed or are positive at pathological evaluation.

3.2.16 Extensive intraductal carcinoma by the Harvard definition, i.e. 1) more than 25% of the tumor is DCIS

and there is DCIS in adjacent breast tissue, or 2) an intraductal carcinoma with microinvasion.

3.2.17 Any previously treated contralateral breast carcinoma or synchronous bilateral breast carcinoma.

3.2.18 Other malignancy, except non-melanoma skin cancer, < 5 years prior to participation in this study; the

disease free interval from any prior carcinoma must be continuous.

3.2.19 Time between final definitive breast procedure to radioactive source loading of the brachytherapy

catheters is greater than 6 weeks.

3.2.20 Patients with diffuse (>1 quadrant or >5 cm in diameter) suspicious microcalcifications.

3.2.21 Patients with suspicious microcalcifications remaining on the post-tylectomy mammogram.