Restaging Patients with Locoregional Relapse: Is There Any Benefit?

The recent Annals of Surgical Oncology article entitled “Radiological Staging for Distant Metastasis in Patients with Loco-Regional Failure after Breast Cancer Surgery”¹ poses the important and practical question of whether it is necessary to restage breast cancer patients for possible synchronous distant metastasis at the time of the first locoregional relapse, and what possible implications this may have for local and systemic patient management.

The most important finding of this study is that one-third of breast cancer patients with locoregional recurrences were found to have distant metastasis at re-staging with PET and or CT scans. Even patients at low risk for metastasis at first diagnosis were found to have a 20-25% risk of distant metastasis at the time of locoregional relapse, supporting the postulated role of local relapses as independent prognostic factors for distant disease.²

The authors have disclosed a limitation of their study as it being retrospective; however, the data from the study were extracted from a prospectively maintained modern database with detailed biology and staging of the cancers, making the overall analysis more robust.

No clear guidelines exist at present regarding how to assess patients with locoregional recurrences. Current National Comprehensive Cancer Network (NCCN) guidelines recommend staging all patients with locoregional relapses, even if the recommendations are based on a low level of evidence consisting primarily of data from the National Cancer Institute database that show a 27% risk of distant metastases in patients with locoregional relapses.³ The NCCN recommendations were stronger for patients with lymph node metastasis or chest wall relapses after mastectomy, where the risk of distant metastasis was higher.

In the present study, where the number of locoregional relapses after conservation was relatively high (35%), the risk of distant metastasis after breast-conservation surgery was lower (23% vs 48% after mastectomy), but still consistent with the finding that the guidelines for restaging patients with locoregional relapses should be extended to all breast cancer patients.

The question that now arises is in what instances can patients benefit from a diagnosis of synchronous distant metastasis, thus justifying the restaging tests. The most obvious answer is in the instance of avoiding unnecessary surgery for stage IV breast cancer, in which the surgical and systemic treatments are merely palliative.

Surgical management of the local recurrence of breast cancer can often be complex, especially in the reconstruction phase of a pre-irradiated breast. The complication rate has been shown to increase 29.7% with implant reconstructions.⁴ The high complication rate of the implant base reconstruction procedure predisposes these patients for more complex reconstruction with free or pedunculated flaps, along with the possible morbidity, high cost, and unproven benefits of this procedure.⁵ In some patients, avoiding surgery is of significant importance, especially in cases involving local relapses after conservation surgery and radiation in which patients are candidates for mastectomy and complex reconstructions.

The possible benefit of a surgical procedure in stage IV restaging-detected patients may be extrapolated from the similar population of patients with de novo stage IV breast cancer in whom the debate regarding the role of surgery is still open. After the first publication of retrospective data^6-9 on large databases showing the benefit of surgery on both overall and disease-free survival when surgery was performed with curative intent, randomized clinical trials are now reporting controversial results. In a recently published article, the prospective phase III ABCSG-28 (POSYTIVE) trial could not demonstrate an overall survival benefit for surgical resection of the primary in breast cancer patients presenting with de novo stage IV disease. However, this trial was ended early because of poor accrual, raising questions regarding the power of its statistical analysis.¹⁰

One recent study of surgery on de-novo stage IV breast cancer patients of note is the MF07-01 trial sponsored by the Turkish Federation of Breast Diseases Societies.¹¹ In it, the last statistical analysis at a median follow-up of 40 months showed results that were different from the previous follow-up of 36 months in which no difference in survival was noted in the surgery versus no-surgery groups. The longer follow-up revealed a significant improvement in median overall survival of about 9 months. Five-year overall survival was 42% with surgery vs 25% with systemic therapy alone. The greatest benefit was observed in patients with estrogen receptor positive/HER2 negative disease, patients with solitary bone metastases, and patients younger than 55 years of age. Patients with multiple liver and/or pulmonary metastases had a significantly worse prognosis with initial surgery.¹¹

Other similar trials are in progress internationally, and may contribute to a better understanding of this controversial issue and how best to select patients in whom surgery may give the most benefit.

We are aware that the population of patients with local relapses and synchronous distant metastases is markedly different from the systematically untreated de novo stage IV breast cancer patient population in which systemic treatments may have much more effect with respect to patients already exposed to adjuvant treatments at the first diagnosis. If it is difficult to compare the two populations in terms of overall survival, some attempt may be made in the setting of the role of palliative surgery to avoid chest wall disease or bulky axillary disease with plexopathy, which adversely affect patient quality of life.

In the Turkish randomized study by Soran and colleagues, among the group of patients randomized for no surgery, the local progression and need for palliative surgery was higher and statistically significant, with 18% of patients in the no-surgery group requiring palliation surgery. What was not clear in this study was how many lost the window of opportunity for surgery because they developed unresectable chest wall or axillary lymph node disease. We may speculate that in the local relapse group and the distant metastasis group, the potential need for palliative surgery may be higher due to the resistance of the disease to previous treatments, but this consideration may also apply to the concomitant distant metastasis, making the prognosis of the patient severe, with shorter overall survival.

Another important consideration in this matter is the possible benefit of restaging in migrating the stage to stage IV from the systemic treatment viewpoint. The CALOR study¹² did not show any benefit in treating patients with locoregional estrogen receptor and progesterone receptor positive relapses with chemotherapy. In this contest, knowing that the patient with local ER positive local relapse has distant metastasis wouldn’t change the intent to cure systemic approach with the intent of palliate with hormonal therapy alone. We can then speculate that staging patients for local relapse may not alter the systemic treatment decision in all cancer subgroups.

A number of published articles suggest a possible overall survival benefit from earlier detection of asymptomatic distant metastases. Aggressive multimodality treatments, such as chemotherapy, hormonal therapy, surgery, and radiosurgery on local and distant metastasis may provide an overall survival benefit in patients.¹³ Unfortunately, however, these findings have a low level of evidence.

In 2010 a fascinating theory on “cancer cell self-seeding” was presented. A basic concept of metastasis is that cancer cells that leave the primary tumor can seed metastases in distant organs. But can this unidirectional process also be bi-directional? An elegant animal model study was able to show that circulating tumor cells can also colonize their tumors of origin, in a process that the authors called "tumor self-seeding." The self-seeding of breast cancer, colon cancer, and melanoma tumors in mice was preferentially mediated by aggressive circulating cancer cells, including those with bone, lung, or brain-metastatic tropism.¹⁴ Academically, we cannot exclude the possibility that this also occurred in some de novo stage IV breast cancer patients. In this situation, the cell clones of the local recurrence should be the same as those of distant metastases, making them sensitive or resistant to second-line systemic therapy, and similar in terms of progression and response.

In summary, this article by Guth and colleagues provides evidence that re-staging patients with locoregional relapses can reveal distant metastases in 25% of patients, with the main benefit being the avoidance of unnecessary surgery and, in some instances, complex surgery if reconstruction is involved. It is likely that an earlier diagnosis of distant metastasis may not have any role in modifying the survival of the patients, with minimal impact on the systemic treatment indicated. We cannot exclude a possible role for palliative surgery in improving patient quality of life, but this is a consideration that should be evaluated in the setting of personalized case management.