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Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomized controlled trial

Fisher B, ... Oishi RH
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2001

Reviewers: John Han-Chih Chang, MD
Source: Lancet 1999 Jun 12; Volume 353: pages 1993 - 2000

Background

We have shown previously that lumpectomy with radiation therapy was more effective than lumpectomy alone for the treatment of ductal carcinoma in situ (DCIS). We did a double-blind randomized controlled trial to find out whether lumpectomy, radiation therapy, and tamoxifen were of more benefit than lumpectomy and radiation therapy alone for DCIS.

Methods

1804 women with DCIS, including those whose resected sample margins were involved with tumor, were randomly assigned lumpectomy, radiation therapy (50 Gy), and placebo (n = 902), or lumpectomy, radiation therapy, and tamoxifen (20 mg daily for 5 years, n = 902). Median follow-up was 74 months (range 57 - 93). We compared annual event rates and cumulative probability of invasive or non- invasive ipsilateral and contralateral tumors over 5 years.

Findings

Women in the tamoxifen group had fewer breast-cancer events at 5 years than did those on placebo (8.2 versus 13.4%, p = 0.0009). The cumulative incidence of all invasive breast-cancer events in the tamoxifen group was 4.1% at 5 years: 2.1% in the ipsilateral breast, 1.8% in the contralateral breast, and 0.2% at regional or distant sites. The risk of ipsilateral-breast cancer was lower in the tamoxifen group even when sample margins contained tumor and when DCIS was associated with comedonecrosis.

Interpretation

The combination of lumpectomy, radiation therapy, and tamoxifen was effective in the prevention of invasive cancer.

Background / Discussion / Critique

DCIS has become an ever-increasing problem. Fortunately this means that breast cancers are being "caught" at an earlier stage, when they are believed to be more curable. The standard of care has historically been mastectomy for DCIS. Lumpectomy and radiation therapy (RT) has now replaced mastectomy in those women desiring breast conservation with very comparable results. Some have advocated performing lumpectomy alone in very selected good prognosis patients. However, one large US trial (National Surgical Adjuvant Breast and Bowel Project B-17) has demonstrated a very significant improvement of local intraductal and invasive cancer recurrence rates with lumpectomy and RT over lumpectomy alone in all subsets of DCIS patients (local recurrence rate decrease from 27 to 12%). A number of European trials are ongoing attempting to confirm the efficacy of RT. Despite the efficacy of breast conservation therapy with RT, data supports a local recurrence of nearly 20% at 15 years. Nearly all (85 - 90%) of these can be salvaged with mastectomy, but there remains a need to improve on local control rates.

The focus of this NSABP trial was to evaluate if the addition of tamoxifen could improve on the local recurrence rates in patients receiving lumpectomy and RT. Tamoxifen is a nonsteroidal anti-estrogen that binds the estrogen receptors on cells and competitively inhibits estrogen binding. This causes a blockade of the cell cycle transit at G1, possibly leading to apoptosis. The beneficial effects of tamoxifen have been found to be preservation of bone mineral density in postmenopausal women and improvement of the lipid profile. The possible toxicities are deep venous thrombosis (1.7% tam versus 0.4% placebo), ocular degeneration and ovarian cysts. Endometrial cancer incidence is increased by 3 to 8 times the normal frequency. In a prior NSABP and other prospective studies for invasive breast cancer patients, there was improvement in outcome with the addition of tamoxifen in women who were estrogen receptor positive.

This current trial enrolled DCIS patients who could have fairly extensive tumors and even positive margins. Tamoxifen appeared to significantly lower total breast cancer events as indicated above. The breakdown is as indicated in the table below:

	Placebo	Tamoxifen	P value
All Breast Cancer	13.4%	8.2%	0.0009
Invasive	7.2%	4.1%	0.004
Non-Invasive	6.2%	4.2%	0.08
Ipsilateral Invasive	2.3%	1.8%	0.03
Ipsilateral Non-Invasive	5.1%	3.9%	0.43
Contralateral Invasive	2.3%	1.8%	0.22
Contralateral Non-Invasive	1.1%	0.2%	0.02
Endometrial Cancer	2/1000	7/1000	0.20

The results seem consistent with prior trials and retrospective data in regards to the control arm of lumpectomy and RT without tamoxifen. The reduction in invasive recurrences along with the contralateral non-invasive recurrence rates are the major factors in tamoxifen's benefit. The rate of endometrial cancer wasincreased but not significantly. The benefit seems to outweigh the increased risk. There was an increase in the grade 1 - 2 toxicities (hot flashes, menstrual disorders, fluid retention and vaginal discharge), but not in the overall severe (grade 3 or 4) complications (5.4% in the tamoxifen arm versus 4.3% in placebo arm). There was increased deep venous thrombosis incidence (1% in the tamoxifen arm versus 0.2% in the placebo arm). Overall survival at 5 years was 97% for all patients and was not significantly different in the two arms.

Overall, this trial has seemed to answer the question of whether tamoxifen is beneficial in prevention of recurrence. However, since most recurrences can occur in the first 6 years (and even further out), whether tamoxifen truly decreases recurrences may not be answered until a few years from now. What the article did a poor job addressing was whether there was a subgroup of patients that would not require tamoxifen. It states that even patients with comedo necrosis and positive margins benefited, but did not fully discuss whether they went through enough analysis to determine what patients may not benefit -- since tamoxifen is not an altogether benign drug.

In conclusion, tamoxifen has been proven to be of benefit in chemoprevention and invasive breast cancer (both pre- and postmenopausal). It now has found a new avenue for its application, but oncologists should not to be too caviler as survival is not improved with tamoxifen. The same could be stated about RT added to lumpectomy, albeit the amount of benefit is greater. Should we subject patients to additional risks for local control and breast conservation benefits only? Careful counseling must be instituted in each individual patient.