Metastectomies: Local Approaches to Breast Cancer Metastases

Linda Brookes, MSc

Disclosures

April 28, 2016

Local Approaches in Low-Volume Metastatic Disease

In patients with metastatic breast cancer (MBC), realistic treatment goals are improvement in quality of life (QOL) and life prolongation. However, there is increasing evidence that patients with oligometastatic disease (OMBC) do better in terms of prognosis and survival than patients with multimetastatic disease. The upcoming third international consensus guidelines for advanced breast cancer (ABC3) define OMBC as low-volume metastatic disease with limited number and size of metastatic lesions (up to 5, and not necessarily in the same organ), potentially amenable to local treatment, with the aim of achieving complete remission.[1]

Speaking at the 2016 European Breast Cancer Conference, Elżbieta Senkus-Konefka, MD (Medical University of Gdańsk, Poland), described patients with OMBC as "those in whom we can modify the natural history of their disease and possibly offer the chance of cure."[2]

OMBC is sometimes considered as an intermediate biological state between localized and widely metastatic disease, she noted. However, evidence suggests that OMBC is biologically distinct from polymetastatic disease.[3,4] "It is important to remember that all data on treatment of OMBC come from retrospective series, with none from prospective randomized clinical trials," Dr Senkus-Konefka stressed. "So there is a big risk for selection bias, and no one has ever proven that this treatment does really affect the natural history of MBC. All this has to be taken into account before taking any clinical treatment decisions."

However, there is increasing use of individualized, multidisciplinary management of OMBC, with favorable results of aggressive local therapy reported for limited metastatic disease. "These patients appear to do better than those with polymetastatic disease," with one study showing significantly longer median overall survival (OS) (107.7 months vs 22 months, respectively) and 5-year survival of 59.6% vs 11.6%.[5]

Local Therapies for Visceral Metastases

"The dogma has been that there is little role for local therapy in visceral metastases in breast cancer, but the concept of 'oligomets' is changing that," noted Karen Gelmon, MD (BC Cancer Agency/BC Cancer Research Centre, University of British Columbia, Vancouver, Canada). "Metastectomies" are becoming increasingly common in other solid tumors, such as colorectal cancer, lung cancer, and sarcoma, she noted, and "we are trying to change the paradigm in breast cancer."

Liver metastases are usually associated with other sites of metastatic disease, and isolated liver involvement is rare (5%-10% of patients with MBC). "Outcomes in these patients seem to be in line with the overall results for MBC (OS, 20-26 months)," commented Dr Gelmon. The annual rate of hepatic resection for noncolorectal nonendocrine liver metastases has increased significantly since the 1980s.[6] Independent predictors of OS after liver resection in patients with MBC have been identified as a positive hepatectomy surgical margin[7,8] and a disease-free interval < 1 year between treatment of the primary tumor and diagnosis of hepatic metastasis.[8]

A study of 86 patients seen at one center found that those with estrogen receptor (ER)-positive primary tumors who had responded to therapy had improved OS after resection compared with those with ER-negative tumors,[9] which is typical for metastatic disease overall, Dr Gelmon noted. However, there appears to be no difference in OS between patients who undergo surgical resection and those who receive medical treatment.[10]

Nonsurgical alternatives for the management of oligometastatic hepatic disease include radiofrequency ablation (RFA), laser-induced thermotherapy, microwave ablation, transarterial chemoembolization, and radioembolization. Local recurrence after RFA seems to be associated with the size of the lesion, with success rates being much better for those < 3 cm (90%) than those > 5 cm (24%).[11,12]

 
A recurring theme in local control is that size makes a difference.
 

"A recurring theme in local control is that size makes a difference," Dr Gelmon stressed. In a retrospective review of primary and metastatic liver lesions treated with stereotactic body radiation therapy (SBRT) (62 patients) or RFA (127 patients), SBRT was more effective for the larger tumors; for tumors ≥ 2 cm, there was decreased freedom from local progression with RFA compared with SBRT (hazard ratio, 3.35; P=.025).[13] The latest published ABC guidelines, ABC2,[14] emphasize that because there are no randomized data supporting the effect on survival of local therapy for breast cancer liver metastases, every patient must be informed of this when discussing a local-therapy technique as a treatment option.

Reported data for surgery of lung metastases in MBC are available only for highly selected patients, Dr Gelmon pointed out. In a highly selected population, it may be possible to achieve long survival, and "probably in breast cancer, we need to be more creative and follow the lead from other solid tumors," she suggested. "Most series give systemic therapy beforehand and only resect those who are responding, and currently only after a very individualized and personal discussion," she noted. SBRT represents an alternative, competitive option in patients who decline surgical treatment or who are unsuitable for surgery. Patients who may be suitable for SBRT may be those with a disease-free interval > 12 months, small lesions, a limited number of metastases, good physical status, and limited or no other disease.[15]

Local Therapies for Brain Metastases

Overall survival after brain metastasis, although limited in the general population of cancer patients, is better in patients with breast cancer. Most breast cancer patients with central nervous system metastases die of systemic disease, explained Prof Martin J. van den Bent, MD (Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands).

Historical trials, which were randomized but underpowered, have shown the benefit of effective, local treatment of brain metastases in cancer in general. A trial of radiation therapy showed that addition of neurosurgery increased OS by 5 months in patients with a single-brain metastasis and stable extracranial cancer.[16] This and other studies paved the way for more intensive local treatments in patients with cancer and a single brain metastasis.

Intensified local management is indicated in a subset of patients with relatively favorable prognosis, Prof van den Bent noted, but personal factors must be taken into consideration. "The rule of thumb is that more intensive local treatment of brain metastases is warranted in patients with more than 6-12 months of anticipated survival. This is a broad range, and personally I would like to see it more in the area of 12 months rather than in the area of 6 months," commented Prof van den Bent.

 
The decision for local vs systemic treatment should be made on clinical grounds.
 

Mainstays of local treatment for brain metastases are surgery, SBRT, and whole-brain radiation therapy (WBRT); hyperthermia and RFA are not well established, noted Prof van den Bent. However, "I would like to stress that systemic treatments may work locally," he added. "Many series show improved outcome in patients managed with systemic chemotherapy. The decision for local vs systemic treatment should be made on clinical grounds": the need for systemic treatment (systemic progression), the likelihood of systemic response, and clinical signs and symptoms of brain metastases. In the case of upfront chemotherapy, there should be separate and close monitoring of brain metastases. He emphasized the importance of having a neurologist on the team when systemic treatment is selected.

"There has been a lot of discussion in oncology about whether a local treatment, such as resection or stereotactic radiosurgery (SRS), should be followed by WBRT," said Prof van den Bent. "It is clear from a number of studies that with WBRT, you increase both local control and outfield control, so you have fewer occurrences inside the brain. But there is a price to pay in terms of long-term toxicity, including cognitive decline (in immediate recall, memory, and verbal fluency) and induction of leukoencephalopathy," he cautioned.[17]

"Nowadays, we give a local SRS boost after incomplete resection to improve local control, and we do not follow up routinely with WBRT. WBRT should be withheld after both SRS and confirmed complete resection. Especially in patients with a good prognosis, I think it is clear to avoid WBRT for as long as possible," he stated.

SRS has certain advantages over surgery, Prof van den Bent acknowledged. SRS is noninvasive, can be used for deep-seated lesions and lesions in eloquent areas of the brain, allows treatment of multiple (3-4) lesions, and can be repeated.

Surgery, on the other hand, provides immediate relief of the mass effect resulting from edema, allows treatment of larger lesions, and provides histologic proof that metastasis as actually present. The downsides of surgery are that it is invasive and there are risks for complications and tumor spill, Prof van den Bent pointed out. "The problems with SRS are that the efficacy depends on the size of the lesion (less local control at a diameter > 3 cm), edema may worsen clinical signs and symptoms, and there is risk for radiation necrosis."

Tumor size, SRS dose, and previous WBRT are significant factors for local control. But data suggest that with more than four lesions, SRS may still provide effective disease control. Some trials show that SRS is as effective in local control of metastases of ≥ 10 lesions as it is for < 10 lesions (median survival, 4 months with ≥ 10 lesions)[18] Whether this approach would prove practical or cost-effective, however, remains questionable, said Prof van den Bent.

Data comparing surgery with SRS are limited. Class II evidence suggests that larger lesions (3 cm) or those causing significant mass effect (1-cm midline shift) may have better outcomes with surgical resection,[19] Prof van den Bent noted. "The difference between SRS and surgery is that with a single lesion, surgery may induce tumor spill. Whether that qualifies for immediate WBRT, I would say not; I think it is safe to wait and see whether that happens."

Surgery of the Primary Tumor

According to the upcoming ABC3 guidelines,[1] removal of the primary tumor in patients with de novo stage IV breast cancer has not been associated with prolongation of survival, "with the possible exception of the subset of patients with bone-only disease." However, it may be considered in selected patients, particularly to improve QOL. The guidelines add that surgery may be valuable only if performed with the same attention to detail (eg, complete removal of the disease) as in patients with early-stage disease.

Arguments pro and con. Peter Dubsky, MD (Medical University of Vienna, Austria), admitted that the retrospective data available are "very likely to have overestimated the effects of surgery on OS." However, "there is no evidence of a detrimental effect on OS, and the good news is that we have excellent results concerning morbidity in stage IV disease and there is good local control." Other treatments currently in use have been shown to improve QOL, without evidence that they improve OS, "yet they are very expensive," Dr Dubsky noted.

"Surgery is cheap, has low morbidity, and improves local control, and that is why I think it should be part of multimodality treatment of de novo stage IV disease," he declared. Retrospective analyses indicate that patients with de novo stage IV disease have a better prognosis than those who have relapse after adjuvant treatment, Dr Dubsky noted.[20] This group may represent a selected entity (about 5% of all breast cancer diagnoses) that may require differential treatment, including surgery of the primary tumor.

"The primacy of systemic therapy must be respected," Dr Dubsky stressed, but opinions differ as to whether patients should undergo surgery. "Many people have suggested following systemic therapy with surgery, with or without radiation therapy if patients respond. Others have suggested that women who have surgery of the primary should have systemic therapy, followed by more surgery of metastasis in technically resectable disease." Although this issue is difficult to address in retrospective analyses, Dr Dubsky noted, various studies plus a meta-analysis[21] have concluded that there is probably about 40% risk reduction in terms of OS in women who have surgery. However, Dr Dubsky questioned this conclusion.

"We cannot say that we have truly compared apples with apples, or even apples with pears; we have simply chosen patients with a better prognosis"—typically healthier and younger women with smaller local tumor burden and fewer metastatic sites, and whether we do surgery or not has no effect, he said. He noted that a matched-pair analysis showed when women who had surgery were accurately matched to women who responded and did not have surgery, the advantage of surgery diminished or even disappeared.[22]

Evidence from clinical trials. Two large randomized trials have compared surgery with no surgery in women with de novo MBC. In a trial of over 700 women carried out in India, patients who responded to chemotherapy randomly assigned to receive either surgery or no surgery.[23] At first sight, commented Dr Dubsky, this appeared to be a very symptomatic cohort with a high disease burden that was not representative of patients in highly developed countries. There was no improvement in OS with surgery, "but very good local control and very low morbidity in the surgical arm," he noted. In a QOL analysis,[24] "unsurprisingly," patients who had surgery had a quick decline in their European Organisation for Research and Treatment of Cancer breast cancer-specific QOL (BR23) score, but then experienced a gradual increase in their BR23 score over the time of their median survival (18-24 months).

"This is good news; however, there was no significant difference in general health-related QOL," Dr Dubsky added. A different population of almost 300 patients was enrolled in the second trial, done in Turkey, with almost one half of them having bone-only metastasis.[25] Early follow-up after a median of 21 months showed a nonsignificant improvement in OS with surgery vs no surgery (35% vs 31%, respectively). The study revealed some interesting hypothesis-generating subgroups, Dr Dubsky commented. Surgery in the group of patients who had solitary bone–only metastasis had statistically significant survival benefit compared with no surgery, and with patients who had multiple-bone metastasis either with or without surgery. Dr Dubsky added that an update on this study is scheduled to be presented at the 2016 American Society of Clinical Oncology annual meeting.

Other prospective clinical trials are currently evaluating the value of surgery, the best candidates, and the best timing in MBC patients, Dr Dubsky noted. JCOG1017 in Japan is comparing systemic therapy plus surgery vs systemic therapy alone and is due to close in 2016.[26] However, other trials have experienced recruitment problems—these include ECOG-E2108 (early surgery vs standard palliative therapy) in the United States and Canada[27]; POSYTIVE (Primary Operation in SYnchronous meTastasized InVasivE Breast Cancer) in Austria[28]; and SUBMIT (Systemic Therapy With or Without Upfront Surgery in Metastatic Breast Cancer) in The Netherlands, which was terminated as a result.[29]

"Finding patients with oligometastatic disease that is technically resectable is an extremely small cohort, and it will be extremely hard to get a prospective randomized trial with the type of care that these patients need," Dr Dubsky commented. "I don't think we will have very good randomized data on this, but I think we can improve on ensuring that the data we get from patients who do receive surgery are at least prospective and that we have registries on this."

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