SAKK 23/82
ForGood-risk ILRR after mastectomy, post excision + RT, TAM-naive
TL;DR5-yr DFS 61% vs 40% with tamoxifen after excision + RT for good-risk post-mastectomy ILRR; OS unchanged (median 11.5 vs 11.2 yr, P=0.79).
For the RT reader, failure after excision plus 5000 cGy at 200 cGy/fx was mostly further local recurrence, and TAM mainly reduced that, not distant spread. Endocrine therapy works here as a local-control partner to chest wall RT. ILRR is also not always a metastatic marker: about 30% stayed relapse-free on local therapy alone.
In a postmenopausal woman with ER+ isolated chest wall or nodal recurrence after mastectomy, resected and irradiated, this supports adding endocrine therapy for DFS. It does not cover premenopausal pts, who gained no DFS, or pts who already had adjuvant TAM.
Even after excision plus 5000 cGy at 200 cGy/fx, further local recurrence was the dominant failure, and TAM mainly reduced it. The trial supports full-dose curative-intent RT for good-risk ILRR combined with endocrine therapy as a local-control partner, not a replacement.
The DFS gain from TAM was confined to postmenopausal women (5-yr 61% vs 33%, P=0.006) and did not translate into OS. Because pts with prior adjuvant TAM were excluded, the trial does not say which agent to use for today's endocrine-pretreated ER+ ILRR.
11 details
Phase III randomized, central telephone randomization at SAKK, stratified by menopausal status, adjuvant chemo and axillary nodes at diagnosis. 178 randomized, 11 ineligible (6%). Median f/u 11.6 yr for surviving pts.
Good-risk ILRR after mastectomy: first recurrence in the ipsilateral chest wall, shoulder, neck or upper arm, or in regional nodes. Eligibility required an ER+ recurrence, or ER unknown with DFI >12 mo and <4 nodules ≤3 cm. Pts with prior adjuvant TAM were excluded.
Every pt had radical excision, then 5000 cGy at 200 cGy/fx, 5 days a week, to the involved region. RT was fixed across arms, so the trial tests systemic therapy added to full local therapy.
Tamoxifen 20 mg/d orally until progression vs observation.
DFS favored TAM (log-rank P=0.053, Gehan-Wilcoxon P=0.008), with no OS difference (P=0.79). The benefit was confined to postmenopausal pts (5-yr DFS 61% vs 33%, P=0.006). In the multivariate model, TAM and DFI >12 mo predicted longer DFS.
| Endpoint | TAM | Observation | P |
|---|---|---|---|
| Median DFS | 6.5 yr | 2.7 yr | 0.053 log-rank; 0.008 Gehan-Wilcoxon |
| 5-yr DFS | 61% | 40% | n/a |
| Median OS | 11.5 yr | 11.2 yr | 0.79 |
| 5-yr OS | 73% | 79% | n/a |
| Subgroup | TAM | Observation | P |
|---|---|---|---|
| Premenopausal DFS | 60% | 60% | n/a |
| Postmenopausal DFS | 61% | 33% | 0.006 |
| Premenopausal OS | 67% | 90% | 0.175 |
| Postmenopausal OS | 75% | 75% | n/a |
No deaths from pulmonary embolism or endometrial cancer attributable to TAM in either menopausal group.
The authors describe this as the only randomized trial of systemic therapy for ILRR to reach its accrual goal. IBCSG Trial 27 was opened to test chemotherapy vs local treatment alone in LRR, a question this trial does not address.
The early-weighted test carries the DFS result while log-rank misses 0.05. The menopausal split rests on small subgroups. Receptor status was not determined in about a third of pts.
The DFS benefit has persisted since the first analysis, but OS is unchanged, possibly because there were few events and competing mortality in postmenopausal pts. The premenopausal OS deficit with TAM is unexplained and nonsignificant, so it reads as noise more than harm.
Mature phase III, but small, 1980s accrual, borderline log-rank DFS and no OS gain. Backs current endocrine therapy after resected ILRR without defining it for TAM-pretreated pts.
- Aromatase inhibitor benefit after ILRR in tamoxifen-pretreated pts
- Role of chemotherapy for poor-risk ILRR
- Optimal RT dose and volume after ILRR excision
📚 Sources · 📄 1 paper
The longer read
The trial's lasting value is less the tamoxifen result than what it shows about the natural history of isolated locoregional recurrence after mastectomy. The older view, set out in the paper's introduction, is that ILRR is mainly a marker of disseminated disease and that local treatment is palliative. Here, roughly 30% of good-risk pts in the observation arm stayed free of further local and distant relapse after excision and 5000 cGy, and close to 40% of the TAM arm had long-term disease control. That supports treating good-risk ILRR with curative intent and full-dose local therapy, rather than minimal surgery followed by systemic treatment alone.
For an RT reader, the pattern of failure is the informative part. In the authors' analysis, tamoxifen mainly reduced further local recurrence, and its effect on distant failure was not significant. So even after radical excision and 5000 cGy at 200 cGy/fx, a meaningful share of pts failed again in the field or nearby, and endocrine therapy acted largely as a local-control adjunct. This raises the question of whether that RT dose and target volume were enough, but the trial cannot answer it: RT was the same in both arms and the paper does not describe field design. Pairing the late distant-metastasis peak reported by Fortin et al. with the idea that ILRR can itself seed metastases strengthens the argument for eradicating the recurrence early and completely.
How much confidence the DFS result deserves depends on the statistics. The log-rank P was 0.053, and the stronger Gehan-Wilcoxon P of 0.008 gives more weight to early events. In practice, TAM delays relapse in the first years after ILRR, and the curves are less clearly separated later. That fits a disease-control effect better than a cure effect, and it agrees with the absent OS difference. The authors attribute the null OS to small numbers and competing non-cancer deaths in older pts. That is plausible but cannot be tested in a trial of this size.
The menopausal split should be read cautiously in both directions. The postmenopausal DFS gain (61% vs 33%, P=0.006) is large, but only about 35 premenopausal pts were enrolled. The premenopausal pattern of equal DFS and a numerically worse OS on TAM rests on very few events, and the authors' trophic-estrogen hypothesis is speculative. It is not a reason to withhold endocrine therapy from a premenopausal woman with ER+ ILRR.
The main limit on applying this today is the eligibility rule excluding prior adjuvant TAM. Most current pts with ER+ ILRR recur on or after adjuvant endocrine therapy, so the relevant question is a switch, for example to an aromatase inhibitor, which this trial did not test. The authors point to metastatic-setting data that aromatase inhibitors keep activity after TAM, but that is indirect. For poor-risk ILRR, the chemotherapy question went to IBCSG Trial 27. What would make this result wrong is if it does not transfer to receptor-defined modern pts: about a third of this cohort entered with receptor status undetermined, on volume and interval criteria alone.