Data from Prospective Randomized Clinical Trials
In 1985, the National Surgical Adjuvant Breast and Bowel Project (NSABP) began protocol B-17, a prospective randomized study to evaluate the worth of postoperative radiation therapy after lumpectomy for patients with DCIS. The initial results, with an average follow-up of 43 months, were published in 1993.2 Additional details of the pathology were published in 1995.3
In 1997, the results were updated.4 For this analysis, 814 patients were eligible for evaluation, with a mean time in the study of 90 months (range, 67 to 130 months). All patients had been followed for more than 5 years, and 35% had been followed for more than 8 years. Thirty-eight percent of these patients had axillary dissections, all of which were negative. The total number of ipsilateral breast tumor recurrences was 151, and 70 (46.4%) recurrences were invasive. Most of the ipsilateral breast tumor recurrences were at or near the original lesion.
Analysis by treatment arm showed 104 ipsilateral breast tumor recurrences among 403 patients treated with lumpectomy only (25.8%) (Table 3). The cumulative rate of ipsilateral breast tumor recurrence at 8 years was only slightly higher, 26.8%. (For comparison, the cumulative ipsilateral breast tumor recurrence rate at 5 years reported in 1993 was 20.9%.2) Fifty-one ipsilateral breast tumor recurrences were noninvasive (13.4%) and 53 were invasive (13.4%).
Table Table 3. 1997 Update of National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-17
The rate of ipsilateral breast tumor recurrence was markedly reduced for patients who received radiation therapy in addition to lumpectomy. Only 47 ipsilateral breast tumor recurrences occurred in 411 patients treated with lumpectomy plus radiation therapy (11.4%). The cumulative ipsilateral breast tumor recurrence rate at 8 years was only slightly higher, 12.1%. (Again for comparison, the cumulative ipsilateral breast tumor recurrence rate at 5 years for patients treated with lumpectomy and radiation therapy as reported in 1993 was 10.4%.2) Thirty ipsilateral breast tumor recurrences were noninvasive (8.2%), and 17 were invasive (3.9%) (Table 3). The P values were significantly different when patients who received radiation therapy were compared with patients who did not.
The update confirmed the original conclusions of NSABP protocol B-17 that ipsilateral breast tumor recurrence of both invasive and noninvasive breast cancer is significantly reduced by postlumpectomy radiation therapy.
In the original analysis, margin status and the presence of comedonecrosis were independent predictors of ipsilateral breast tumor recurrence.
Other randomized trials that have been started in North America and Europe (Table 4) compare the results achieved using breast-conserving surgery alone with those of breast-conserving surgery plus radiation therapy. All of them (except the Swedish trial) require histologically “negative” margins as an entry criterion. (Attempts by national cooperative groups in Germany and Denmark to perform randomized trials comparing surgery alone with surgery and radiotherapy had to be abandoned because of poor accrual.) As yet, no data are available from these trials.
The results of conservative surgery and radiation for DCIS from retrospective series are presented in Table 5. The crude incidence of breast tumor recurrence ranges from 4% to 18%. Deaths caused by breast cancer have been reported in up to 4% of patients treated in studies with a median follow-up of 10 years or fewer.
The long-term results of conservative surgery and radiation for DCIS were reported by Solin et al.5,6 This collaborative study of 10 institutions in the United States and Europe analyzed outcome in 268 patients. Seventy-eight percent of the tumors were detected by mammography alone. The 10-year actuarial risk of breast recurrence was 16%, and the 10-year actuarial cause-specific survival was 97%.5 The 15-year actuarial breast recurrence was 19%, and the 15-year actuarial cause-specific survival was 96%. Median follow-up was 10.3 years.6
Table Table 4. National and International Prospective Trials of Conservative Surgery with or without Radiotherapy for Ductal Carcinoma in Situ
Table Table 5. Results of Conservative Surgery and Radiation for Clinically and Mammographically Detected Ductal Carcinoma in Situ
Various clinical, pathologic, and treatment-related factors have been assessed for their ability to identify patients with a substantial risk of recurrence in the treated breast. For these patients, mastectomy may be recommended. One factor that appears to be associated with a high risk of recurrence is the presence of residual malignant-appearing calcifications on a postbiopsy mammogram. Failure to remove these calcifications before radiation has resulted in a 100% recurrence rate in the few patients reported.7,8 DCIS presenting as a bloody nipple discharge was noted in earlier series to be associated with a higher risk of recurrence. In the collaborative study, however, no increased risk appeared to exist in this group of patients.6
The significance of young age (less than 40 years) is controversial. Three studies have observed an increased risk of breast tumor recurrence (approximately 25%) in young women who have DCIS treated with conservative surgery and radiation compared with older women (approximately 10%).9–11 However, four additional studies have found no correlation between young age and breast recurrence rates.6,8,12,13
A similar controversy exists regarding a positive family history of breast cancer. Two series7,12 have reported a higher breast tumor recurrence rate (approximately 40%) in women with a positive family history compared with those who do not have such a history (approximately 10%). However, a third series found no such association.10 The impact of young age and a positive family history of breast cancer on treatment options in women with DCIS requires further evaluation.
The contribution of various pathologic factors (histologic subtype, nuclear grade, necrosis) to the risk of breast recurrence in patients treated with conservative surgery and radiation is controversial.
It was suggested initially that high-grade or comedo DCIS was associated with a higher rate of breast tumor recurrence.5,14 However, in the collaborative study, the 10-year actuarial breast recurrence rate was 18% for tumors with the combination of both comedo pattern and a high nuclear grade versus 15% for DCIS in which these factors were absent (P = 0.15).6 The median interval to recurrence for comedo DCIS was 3.1 years versus 6.5 years for non-comedo DCIS. Therefore, series with shorter follow-up tend to underestimate the number of recurrences in low-grade or non-comedo DCIS, and recurrences in high-grade or comedo DCIS predominate. The influence of necrosis on breast recurrence rates remains to be determined.
Silverstein and colleagues15 have designed the Van Nuys Prognostic Index. This is a quantitative algorithm that uses tumor size, margin width, and a pathologic classification based on nuclear grade and comedo-type necrosis to predict the likelihood of local recurrence with breast-conservation treatment for patients with DCIS. Scores range from a low of 3 (best prognosis) to a high of 9 (worst prognosis). Their results suggest that patients who score 3 or 4 generally have small, well-excised, low-grade lesions that can be treated successfully with excision alone. The Van Nuys Prognostic Index must be confirmed by others before it is accepted for widespread use.
Most breast tumor recurrences in patients undergoing conservative surgery and radiation for DCIS occur near the primary tumor, and approximately 50% are invasive cancers.6–8,12,14,16–20 Invasive recurrences appear at later intervals (5 years) than do noninvasive recurrences (4 years) and may occur in a separate quadrant.9,17 Nearly all patients who develop a noninvasive recurrence are salvaged with mastectomy, and approximately 75% of those with an invasive recurrence are salvaged.7,8,12,16,18–21
Over the last 10 years, the method of detection of DCIS has changed significantly. Approximately 85% of all DCIS is now detected solely as a mammographic finding, which is most often characterized by the presence of microcalcifications. Earlier reports of conservative surgery and radiation for DCIS do not accurately reflect outcome for mammographically detected DCIS because many included clinically evident DCIS (palpable mass or bloody nipple discharge), and detailed mammographic and pathologic correlation was frequently lacking. Unfortunately, the results of these earlier series were compared with those of conservative surgery alone for mammographically detected DCIS and often claimed to be equal.
Table Table 6. Results of Conservative Surgery and Radiation for Ductal Carcinoma in Situ Detected by Mammography
The results of conservative surgery and radiation for mammographically detected DCIS are shown in Table 6. The 10-year actuarial breast tumor recurrence rate ranges from 6% to 23%, with a 10-year cause-specific survival of 96% to 100%. The variation in the results reported reflects differences in patient selection, the extent of surgical resection, and the degree of mammographic and pathologic correlation.
Increasing evidence exists that wide surgical excision8 and negative margins of resection diminish the risk of breast tumor recurrence in patients with mammographically detected DCIS treated with conservative surgery and radiation.8,9,22 In the collaborative study (which had a median follow-up of 9.3 years), the crude breast tumor recurrence rate was 29% for patients with close or positive margins compared with 7% for those with negative margins.9
Two series have reported the results of conservative surgery and radiation for mammographically detected DCIS in patients who would meet Lagios' criteria for observation (presence of calcifications only, size less than 2.5 cm, negative margins, and negative postbiopsy mammogram).9,10 Breast tumor has not recurred in the 37 patients reported to date (median follow-up 4.9 and 9.3 years, respectively). Lagios reported a 17% breast tumor recurrence rate in 78 such patients with a follow-up of 10.3 years.23