Van Nuys Experience Contradicts NSABP B-17 Findings

July 1, 1997
Michael D. Lagios, MD

,
Melvin J. Silverstein, MD

Oncology NEWS International, Oncology NEWS International Vol 6 No 7, Volume 6, Issue 7

In the May, 1997, issue of Oncology News International , the updated eight-year results of NSABP protocol B-17 were reported as presented by Dr. Bernard Fisher in Paris. B-17 randomized patients with ductal carcinoma in situ (DCIS) into two groups: One group received excision only, the other excision plus postoperative radiation therapy.

In the May, 1997, issue of Oncology News International , the updatedeight-year results of NSABP protocol B-17 were reported as presented byDr. Bernard Fisher in Paris. B-17 randomized patients with ductal carcinoma insitu (DCIS) into two groups: One group received excision only, the otherexcision plus postoperative radiation therapy.

The NSABP concluded that all subsets regardless of grade, size, or marginstatus were benefited by irradiation, and they recommended that all breastconservation patients with DCIS receive postoperative irradiation. However,although this was a prospective randomized trial, the pathologic featurescited by the author to reach these conclusions were analyzed retrospectively.[1]

Many of the significant prognostic features of DCIS that we have documentedin our own studies (size, margin width, nuclear grade)[2,3] were not tabulatedprospectively by the NSABP and were not available at the time of originalanalysis.[4] In fact, at the time of retrospective analysis, 27% of theentire B-17 study population was unavailable for pathologic evaluation.

In the original study, all tissue was not submitted and sequentiallyprocessed. There were no guidelines regarding size measurement, specimenradiography, or mammographic-pathologic correlation. Margins were definedas free (clear) when tumor was not transected. In other words, in somecases, only a few fat cells separated DCIS from the inked margin.

In 40% of cases, no tumor size was provided by the initial pathologist,and, therefore, size could not be determined prospectively nor accuratelyanalyzed retrospectively.

Possible differences in outcome (local recurrence) were also obscuredby the pathologic definitions, which created minimally divergent comparisongroups such as DCIS with one third or fewer of ducts exhibiting comedonecrosis versus one third or more, and which pooled nuclear grade (NG)I and II lesions with or without necrosis versus NG III DCIS.

Our database, including more than 440 conservatively treated DCIS patients[3,5-7],has led us to a diametrically opposite conclusion. Our DCIS cases werefully evaluated prospectively for grade, size, and margin status, and wehave defined those features to accentuate, not diminish, the differencesin the subgroups.

We found that irradiation provided no significant benefit in local controlfor low-grade DCIS (NG I with or without necrosis) and for all DCIS regardlessof grade if the margins were greater than 10 mm or the re-excision wasnegative for residual DCIS (see figures).

Irradiation did provide a mean 13% benefit reduction in local recurrencerate in subsets of DCIS characterized by narrower margins, larger size,and/or higher grade (Van Nuys Prognostic Index scores 5,6,7). [See reference3 for a description of the Van Nuys Prognostic Index.]

Like all other studies of irradiation for DCIS except B-17, half ofthe local recurrences were invasive regardless of radiation therapy. Longerfollow-up shows that the differences in recurrence rates between irradiatedand nonirradiated groups has begun to diminish, a feature suggested byprior studies of irradiation for DCIS. [8] Finally, in our patient population,invasive recurrences in the irradiated group were three times as largeas in the nonirradiated group (35 mm versus 11 mm).

For patients most at risk of recurrence, those with NG III DCIS withany comedo necrosis, size greater than 40 mm, and margins less than 1 mm(Van Nuys Prognostic Index scores 8,9), radiation therapy made a majorimpact, reducing local recurrences from 100% at four years to 60% at sixyears, but clearly this is a pyrrhic achievement unacceptable in clinicalpractice.

Ours was not a randomized trial, but our methods of patient selectionand clinical judgment are a more realistical reflection of actual clinicalpractice; moreover, we could not control the grade or the size of the DCIS,and patients frequently self-selected their mode of therapy regardlessof recommendations. Our study does not compare treatments but, rather,prognostic factors over which we have no control.

We conclude that the morphologic heterogeneity of DCIS reflects a similarbiologic heterogeneity and that therapies should be tailored to fit theactual risks of local recurrence. Although our methods must be validated,we have every expectation that they will be in programs now developingin other centers.

References:

1. Fisher ER, Costantino J, Fisher B, et al: Pathologic finding fromthe National Surgical Adjuvant Breast Project protocol B-17: Intraductalcarcinoma (duct carcinoma in situ). Cancer 75:1310-1319, 1995.

2. Lagios MD, Margolin FR, Westdahl PR, et al: Mammographically detectedduct carcinoma in situ: Frequency of local recurrence following tylectomyand prognostic effect of nuclear grade on local recurrence. Cancer 63:619-624,1989.

3. Silverstein MJ, Lagios MD, Craig PH, et al: A prognostic index forductal carcinoma in situ of the breast. Cancer 77:2267-2274, 1996.

4. Fisher B, Costantino J, Redmond C, et al: Lumpectomy compared withlumpectomy and radiation therapy for the treatment of intraductal breastcancer. N Engl J Med 328:1581-1586, 1993.

5. Silverstein MJ, Lagios MD, Waisman JR, et al: Outcome after localrecurrence for patients with ductal carcinoma in situ of the breast. ProcAm Soc Clin Oncol 16:129A, 1997.

6. Silverstein MJ, Lagios MD: Use of predictors of recurrence to plantherapy for DCIS of the breast. Oncology 11:393-410, 1997.

7. Lagios MD, Silverstein MJ: Ductal carcinoma in situ. The successof breast conservation therapy: A shared experience of two single institutionalnonrandomized prospective studies. Surg Oncol Clinics North Am 6:385-392,1997.

8. Solin L, Kurt J, Fourquet A, et al: Fifteen-year results of breast-conservingsurgery and definitive breast irradiation for the treatment of ductal carcinomain situ (intraductal carcinoma) of the breast. J Clin Oncol 14:754-763,1996.

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