End Results of Salvage Therapy After Failure of Breast-Conservation Surgery
End Results of Salvage Therapy After Failure of Breast-Conservation Surgery
Drs. Lannin and Haffty's comprehensive
and thoughtful review
of breast cancer recurrence
therapy details the risk factors for
local recurrence, factors predictive of
outcome at the time of a breast recurrence,
and prognosis after recurrence.
The complex interaction between
local and distant recurrence is also
explored; the authors argue that
locally recurrent disease is both a
marker of a more aggressive primary
cancer, as well as a potential source
for seeding distant sites. Strategies
for managing local recurrences are
also discussed. We are in agreement
with this excellent review and will
take this opportunity to expand on a
The strongest predictors of local recurrence
surgery are patient age, surgical margin,
and the use of systemic therapy.
The latter association has been convincingly
demonstrated with both chemotherapy
and hormonal therapy, and
may potentially influence our thoughts
on the adequacy of the surgical margin.
The National Surgical Adjuvant
Breast and Bowel Project B-06 trial
showed a reduced risk of local recurrence
in women with positive nodes
who received adjuvant systemic therapy
(melphalan [Alkeran] and fluorouracil
[5-FU]) in addition to radiation therapy (8.8% rate of local recurrence
at 20 years vs 14.3% for the entire cohort).
The reduction in local recurrence
with the addition of systemic therapy
applies at least as much to the adjuvant
use of tamoxifen and, more recently,
to aromatase inhibitors.
Randomized trials of tamoxifen vs
placebo in patients treated with breastconserving
therapy have demonstrated
a substantial reduction in local
recurrence with tamoxifen when combined
with radiation therapy.[2,3] In
the Arimidex, Tamoxifen Alone and
in Combination (ATAC) trial, the
local recurrence rate was at least as
low in patients treated with anastrozole
(Arimidex) as with tamoxifen. In
the National Cancer Institute of Canada
trial, which studied the utility
of an aromatase inhibitor following
5 years of tamoxifen, the addition of
letrozole (Femara) further reduced the
risk of local recurrence.
Whether the timing of the use of
tamoxifen in relation to radiation therapy
influences the risk of local recurrence
remains unknown. A recent
abstract by Pierce et al found no difference
in the risk of local recurrence
when radiation was given concurrently
or sequentially with radiation
There is also evidence that the risk
of local recurrence is potentially influenced
by the timing of adjuvant
chemotherapy. While several studies
have shown an increased risk of local
recurrence when radiation therapy is
delayed, this effect seems to be most
prominent in women with close
margins. In the updated results of a
randomized trial comparing chemotherapy
followed by radiation therapy
with immediate adjuvant irradiation
followed by chemotherapy, there
were no statistically significant differences
in the overall pattern of first
failures, with a median follow-up of
11.3 years. In the group with close
margins, however, the risk of local recurrence was 4% when radiation
was delivered promptly after surgery,
compared with 32% in the group that
received delayed radiation.
Overcoming Adverse Risk Factors
Some research has suggested that the addition of systemic therapy might overcome adverse risk factors for recurrent disease. Park et al reported a retrospective look at the risk of local recurrence in 533 patients. On multivariate analysis, only margin status and the use of systemic therapy predicted for local recurrence. The risk of recurrence at 8 years was 7% in women with close (< 1 mm) or negative margins, and this increased to 13% with focally positive margins. However, the risk in women with focally positive margins fell to 7% with the addition of systemic therapy. Assersohn also reported on a high-risk group of women with positive margins (defined as at the margin or within 1 mm). Local recurrence was 3% (2/70). Similarly, in a prospective trial of concurrent CMF chemotherapy (cyclophosphamide [Cytoxan, Neosar], methotrexate, 5-FU) and reduced-dose radiation therapy (3,960 cGy to the whole breast, 1,600 cGy lumpectomy site boost), crude rates of local recurrence were 4%, 6%, and 4% in patients with negative, close, and positive margins, respectively. Clearly, the more modern focus on anthracycline- based regimens makes concurrent integration with radiation therapy more problematic, resulting in the widespread use of a sequential approach. Galper et al reported on one of the largest series of women with recurrences in the breast following conservative surgery. In this study, 341 patients were followed for a median of 85 months after a local recurrence. The disease-free survival rate at 5 years was 65%, which is consistent with the prognosis reported in multiple trials summarized by Lannin and Haffty. On multivariate analysis, factors influencing the risk of distant recurrence, second nonbreast malignancies, or death included invasive histology of the recurrent disease, time to recurrence of less than 1 year, and age > 60 at diagnosis. As Lannin and Haffty also emphasize, surgery less extensive than a mastectomy is associated with a higher risk of subsequent recurrence. Galper et al found that no local therapy at the time of recurrence (vs mastectomy) and a second local excision (when compared with mastectomy) were associated with a higher risk of distant spread. Although there are small preliminary studies examining the role of partial breast irradiation following local recurrence in order to avoid mastectomy,[ 12,13] the data are far too premature for this strategy to become standard treatment. We agree that at the present time, the clear standard for treating breast recurrence following conservative surgery and radiation therapy is mastectomy. Despite the established increased risk of distant metastasis in patients with a local recurrence after breastconserving breastconserving therapy, we agree that there is little evidence firmly supporting the role of systemic therapy in such patients. Further study is required to more fully elucidate the role of systemic therapy in this situation.
2. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen- receptor-positive tumors. N Engl J Med 320:479-484, 1989
3. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20:4141-4149, 2002.
4. Baum M, Buzdar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002.
5. Goss, PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003.
6. Pierce LJ, Hutchins L, Green S, et al: Sequencing tamoxifen (TAM) and radiotherapy (RT) with breast conservation (BCT) in early stage breast cancer (abstract 39). Proc Am Soc Clin Oncol 22:10, 2003.
7. Bellon J, Come S, Gelman R, et al: Sequencing of chemotherapy with radiation therapy in early stage breast cancer: Updated results of a prospective randomized trial (abstract plenary 4). Int J Radiat Oncol Biol Phys 51(suppl 1):2-3, 2001.
8. Park CC, Mitsumori M, Nixon A, et al: Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breat cancer: Influence of margin status and systemic therapy on local recurrence. J Clin Oncol 18:1668-1675, 2000.
9. Assersohn L, Powles TJ, Ashley S, et al: Local relapse in primary breast cancer patients with unexcised positive surgical margins after lumpectomy, radiotherapy and chemoendocrine therapy. Ann Oncol 10:1451- 1455, 1999.
10. Bellon J, Come S, Gelman R: Concurrent CMF and reduced dose radiation in patients with early stage breast cancer (abstract 94). Int J Radiat Oncol Biol Phys 54(suppl 1):57, 2002.
11. Galper S, Blood E, Gelman R: Prognosis following local recurrence after conservative surgery and radiation for early-stage breast cancer (abstract 92). Int J Radiat Oncol Biol Phys 54(suppl 1):56, 2002.
12. Resch A, Fellner C, Mock U, et al: Locally recurrent breast cancer: Pulse dose brachytherapy for repeat irradiation following lumpectomy—a second chance to preserve the breast. Radiology 225:713-718, 2002.
13. Yoden E, Hiratsuka J, Imajo Y, et al: Interstitial brachytherapy for recurrent breast cancer using a high dose rate Ir-192 remote afterloading system: A report of two cases. Breast Cancer 7:252-255, 2000.