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All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/64366; and 4) view/print certificate.
Release date: April 17, 2015; Expiration date: April 17, 2016
Learning Objectives
Upon completion of this activity, participants will be able to:
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Assess the merit of primary tumor resection for local control and survival in women presenting with de novo stage IV breast cancer
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Discuss the QOL hazards that relate to the primary tumor, regardless of whether or not PSLT is used
Approximately 5% of women with primary breast cancer in the United States and Western Europe present with de novo stage IV breast cancer.1 Although systemic therapy is clearly the primary treatment for women with overt metastases, retrospective data published over the past decade have suggested that primary tumor resection (and possibly radiotherapy) may improve survival when used in conjunction with effective systemic therapy. These data, along with the relative lack of morbidity of breast surgical procedures and the fact that patients with metastatic breast cancer are living longer with newer therapies,2 have led to some enthusiasm for the resection of asymptomatic primary tumors. However, the classical therapeutic approach for de novo stage IV breast cancer includes local therapy for the primary site only when required for palliation of symptoms. The evidence for resection of the intact primary tumor in women with metastases is discussed herein, with emphasis on the emergence of new prospective data that will likely drive reevaluation of this question.
Reasons to Question the Classical Paradigm
Retrospective analyses during the past 15 years, prompted by data on primary site local therapy (PSLT) in several organ sites, suggest that patients with stage IV breast cancer may gain a survival advantage with resection of the primary tumor. These studies include a randomized trial of patients with stage IV renal cell carcinoma that demonstrated a modest but significant survival advantage for the nephrectomy group.3 Improved survival with resection of primary disease with or without resection of distant disease has also been observed in patients with metastatic ovarian, colorectal, and gastric cancers. Based on retrospective data, these cancers are frequently managed with tumor debulking before chemotherapy,4–9 drawing on the theory that a smaller tumor burden increases the efficacy of chemotherapy.10 Theoretically, based on preclinical studies, a benefit from resection of the primary tumor in patients with overt metastases can be supported along several lines, ranging from its potential role as a source of tumor stem cells with enhanced metastatic potential,11,12 to the possibility that tumor-induced immunosuppression is facilitated by the intact primary tumor.13,14 Conversely, there has been a concern, based on laboratory data, that primary tumor resection may accelerate the growth of metastatic lesions, but this has not been demonstrated in humans. Although these laboratory data may suggest a biological basis for improved survival with resection of the primary tumor in the setting of metastatic disease, these specific hypotheses have not been validated in humans.
Retrospective Data on Primary Tumor Resection
Potential for Benefit
Several retrospective studies have examined the impact of surgical resection of the primary tumor on survival in the setting of metastatic breast cancer.15–29 These studies have come from single institutions and large databases from the United States, Europe, and Asia.27 The type of local therapy has largely been surgery alone (evaluated in 18 studies), although a few authors have been able to evaluate surgery plus radiotherapy.30–32 The survival outcomes in these retrospective analyses have been the subject of several reviews and meta-analyses.33–36 A recent meta-analysis by Petrelli and Barni34 including 15 retrospective case series found that surgery of the primary tumor was independently associated with longer survival (hazard ratio [HR], 0.69; P<.00001). The survival benefit was independent of age, tumor burden, type of surgery, margin status, site of metastases, hormone receptor status, and HER2 status. Use of systemic therapy and radiotherapy were significantly associated with survival. The potential biases of these retrospective data, which have been discussed previously,37 are presented in depth in the following section.
Potential Biases
Surgical Timing: The timing of surgery in relation to the diagnosis of metastases and use of systemic therapy has not always been specified in the published retrospective literature, although several authors have attempted to address it,21,29,38,39 with varying conclusions. This is a source of bias in that women who are diagnosed with metastases only after they have undergone surgery for the primary tumor most likely have asymptomatic (and therefore lower-volume) metastases. In contrast, those who present with symptomatic metastases are likely to have a higher burden of distant disease. A review of the available literature showed that a substantial fraction of women had T1–2 tumors, raising the possibility that these women were operated on with the assumption of nonmetastatic disease, diagnosed with metastases postoperatively, and then classified as having stage IV disease during the abstraction process by local tumor registrars.
Other sources of bias exist in the retrospective data and the meta-analyses based on that data, although all studies have attempted to control for these using multivariate regression. Women who received surgery tended to be younger,16,17,19,20,23–26,29 have smaller tumors,16,18–20,22,24,27 have fewer comorbidities,24,26,28 have a lower burden of metastatic disease,16–18,21,24,26,28,29 be less likely to have visceral metastases,16,18,24,25,28 and be likely to have better access to care.18,20 In addition to these known biases that were adjusted for statistically, there was likely a variable number of unknown biases. These consistent biases raise real questions as to whether the increased survival of women undergoing PSLT illustrates a cause-and-effect relationship, or simply means that doctors are good at selecting patients who are likely to survive longer. Physicians should therefore exercise appropriate caution in applying these data to their therapeutic strategies, because the value of PSLT clearly remains to be proven.
Potential for Harm: Surgical procedures carry inherent risk. There is the possibility of hematoma, infection, and poor healing of the surgical site, particularly if combined with axillary surgery or postmastectomy reconstruction. There is a 16% risk of lymphedema for those undergoing axillary dissection,40 which is roughly doubled by the addition of radiation following axillary dissection.41 In the metastatic setting, this may only add to a patient’s suffering in the last few months or years of life. Complications from surgery may delay systemic treatment, which is the primary therapeutic modality in patients with metastatic disease. This delay may adversely affect control of distant disease in some patients. If mastectomy is performed, questions about breast reconstruction arise, which increases the risk of surgical complication rates and may further delay adjuvant chemotherapy42; other data suggest that delays in systemic therapy can negatively affect survival. Lohrisch et al43 found a decrease in survival in patients who started chemotherapy more than 12 weeks after surgery in patients with early-stage breast cancer, although whether this is true for metastatic breast cancer is less certain. Finally, women with metastatic disease offered primary site surgery are inquiring about (and anecdotally receiving) contralateral prophylactic mastectomy, a clearly inappropriate intervention for this patient population. However, the fact that patients consider it indicates the need for definitive, unbiased information to guide treatment plans for a patient population that is highly motivated to pursue any and all options with a possibility of benefit.
Apart from the risks and quality of life (QOL) hazards of locoregional therapy for breast cancer, it is also important to remember that this patient population is often stretched to the limit in terms of out-of-pocket expenses for imaging and therapy, even when insurance plans are generous. Locoregional therapy adds considerably to this burden, which must be considered when arriving at a management plan for this vulnerable population.
QOL Considerations
There are QOL hazards that relate to the primary tumor, regardless of whether PSLT is used or not. If the intact primary tumor progresses, the QOL impact of uncontrolled chest wall disease can be disastrous for a minority of women.23,44 However, for most women with intact primaries and distant disease that is responsive to systemic therapy, the primary tumor will remain controlled and asymptomatic with medical therapy.23 If all women are subjected to PSLT, however, they will all experience the QOL risks of surgery and potentially radiotherapy, including those who would not have developed uncontrolled local disease during the remainder of their lives. The analysis of the QOL impact therefore must be very thoughtful, weighing the possibility of uncontrolled local disease in a minority of women against the potentially unnecessary costs of PSLT in all women.
Clinical Trials
The initial wave of retrospective data suggesting a survival advantage associated with primary tumor resection, the recognition of consistent biases observed in the published retrospective analyses, and the potential for harm from surgical and radiotherapy interventions led to the launch of 7 randomized trials in as many countries (Table 1). Of these, 4 are ongoing (JCOG1017; ClinicalTrials.gov identifiers: NCT01242800, NCT01906112, and
Randomized Clinical Trials Addressing Impact of Local Therapy for the Primary Tumor
Trials Requiring Induction Systemic Therapy
The rationale for initial systemic therapy is based on the notion that PSLT can provide survival value only if disease at distant sites is responsive to systemic therapy. This approach has been adopted by 4 trials (Table 1). The first trial to open was in India, at the Tata Memorial Centre in Mumbai, in 2005 (ClinicalTrials.gov identifier: NCT00193778); the trial enrolled 350 patients with de novo metastatic breast cancer and an expected survival of 1 year. As reported at SABCS, induction therapy consisted of anthracyclines with or without taxanes, followed by randomization to surgery with or without radiotherapy (when indicated) versus no locoregional therapy.47 Use of induction endocrine therapy was rare. Primary outcomes were overall survival and progression-free survival. Secondary outcomes were not reported at SABCS. Overall survival was 20.5% in the nonsurgical group and 19.2% in the surgical group at 5 years (HR, 1.04; 95% CI, 0.80–1.34). However, local progression-free survival was significantly better in the surgical group (80% at 5 years vs 20% in the nonsurgical group; P<.001). No significant differences in survival were seen in planned subset analyses (menopausal status, visceral vs bony metastases, >3 vs 1–3 metastatic sites, and hormone receptor/HER2 status).
Three trials with a similar design are ongoing. In Japan, JCOG 1017 seeks to enroll 410 patients with newly diagnosed metastatic breast cancer to compare the efficacy of primary tumor resection plus systemic therapy versus systemic therapy alone. After 3 months of systemic therapy, women who show no disease progression are randomized to undergo surgery or continue systemic therapy; radiotherapy is not required. The primary outcome is overall survival. Secondary outcomes are local recurrence rate, local control rate, and effect on distant metastasis after resection of the primary site.48 More than 250 patients have been accrued to date.
In the United States and Canada, the ECOG EA2108 trial (ClinicalTrials.gov identifier: NCT01242800) seeks to recruit 368 patients with metastatic breast cancer (revised from 880 patients because of slow accrual). All patients receive induction systemic therapy at the discretion of the treating physician, which may consist of endocrine, cytotoxic, or biologic regimens appropriate to the patient’s age and tumor type. Patients without progression of disease after 16 to 32 weeks of treatment are randomized to either locoregional therapy, including surgery and radiotherapy (to mirror standards of treatment for patients with nonmetastatic disease) or to the continuation of systemic therapy. Therapy for the primary site may be provided for palliation, later in the course of disease, for women who are randomized to the systemic therapy–alone arm. The primary outcome is survival; secondary outcomes are local progression-free survival and QOL, and biological samples are being banked for correlative studies. As of November 2014, 273 patients have been accrued and the trial is projected to close by mid-2015.
Trials Requiring Randomization to Locoregional Therapy Before Systemic Therapy
The inclusion of all patients with stage IV disease in a randomization that occurs before systemic therapy, with the surgical group receiving upfront primary site therapy, is argued by some to be a purer test of the potential benefit of PSLT in the metastatic setting. However, this means that PSLT is provided to some patients who may not respond to systemic therapy at distant sites. The first trial with this design was opened by the Turkish Federation of Breast Diseases Societies (ClinicalTrials.gov identifier: NCT00557986) and has completed accrual, with early data reported at SABCS 2013. The design included randomization to surgery before systemic therapy or systemic therapy alone,49 with radiotherapy to the primary site in cases of breast conservation. A total of 278 evaluable women were recruited. The primary outcome was overall survival, with secondary outcomes related to progression-free survival, QOL measures, and morbidity related to locoregional therapy. The trial was reported at SABCS 2013, with a median follow-up of 18 months, and 31% of the population having died.46 No significant survival advantage was observed at the time of reporting, with a median survival of 42 versus 46 months, favoring surgery (HR, 0.76; 95% CI, 0.49–1.16; P=.20). Multiple unplanned subset analyses revealed only the possibility of an advantage with surgery for women with isolated bony metastases (33 women in the PSLT arm, 20 in the control arm; HR, 0.23; P=.02). The number of local recurrences was insufficient for analysis.
The SUBMIT trial in The Netherlands (ClinicalTrials.gov identifier: NCT01392586) was similarly structured, but closed after accrual of 10 patients.52 The POSYTIVE trial in Austria (ClinicalTrials.gov identifier: NCT01015625) has a roughly similar design, and aims to recruit 254 patients with de novo metastatic breast cancer and randomly assign them to receive either PSLT (lumpectomy or mastectomy plus axillary surgery with or without radiotherapy) or no local therapy. Primary outcomes are median survival, and secondary outcomes are time to distant progression and time to local progression.
Synthesis of Current Information and Implications for Patient Care
Although the retrospective data suggest that locoregional therapy may provide a survival advantage in women with metastatic breast cancer and an intact primary, this is not confirmed by 2 unpublished randomized trials (ClinicalTrials.gov identifiers: NCT00193778 [India] and NCT00557986 [Turkey]). The biases of the retrospective data include the use of surgery in younger women with smaller tumors, single sites of metastasis, and less visceral disease. The publication of data from the Tata Memorial and Turkish Federation trials will provide information on patients treated in a prospective randomized fashion, along with QOL data. These and ongoing trials will allow for the role of surgery alone or surgery plus radiotherapy to be evaluated, and will allow solid conclusions to be reached regarding the role of locoregional therapy, how extensive it should be, and its timing in stage IV breast cancer. Until additional unbiased data are available, surgery and/or radiotherapy should not be routinely recommended for patients with stage IV breast cancer with an intact primary tumor. In particular, there is no basis for recommending surgery to women with distant disease if (1) the distant disease is not well controlled and survival will likely not be long enough for the primary site to become a problem; or (2) both local and distant sites are well controlled, in which case the primary site is likely to remain well controlled for the patient’s lifespan. The only possible exception to these general rules may be the patient with well-controlled or ablated oligometastatic distant disease, who would be rendered stage IV NED (no evidence of disease) through resection of the primary tumor, although this is also based on highly selected series. For the patient whose distant disease is controlled but the primary site is progressing, surgery provides a reasonable approach, although whether radiotherapy following surgery is of benefit is unproven; its use may be justified if the risk of early local recurrence and uncontrolled chest wall disease is high. Locoregional therapy for the primary tumor should be offered to patients only with full disclosure of the lack of evidence of a survival benefit. If a clinical trial is available, and the patient is willing to consider it, that is clearly the most rational choice. If PSLT is chosen despite the considerations, breast conservation surgery (if feasible) is clearly the least harmful option, and the odds of successful breast conservation can be maximized by the use of effective systemic therapy preoperatively. The evidence supporting the use of postoperative radiotherapy is weak, at best, and cannot be recommended at this time. Primary radiotherapy can be considered with the same caveats as surgical resection, particularly if the surgical procedure required would be mastectomy.
CE AUTHORS
Deborah J. Moonan, RN, BSN, Director, Continuing Education, has disclosed that she has no relevant financial relationships.
Ann Gianola, MA, Manager, Continuing Education Accreditation & Program Operations, has disclosed that she has no relevant financial relationships.
Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships.
Rashmi Kumar, PhD, Senior Manager, Clinical Content, has disclosed that she has no relevant financial relationships.
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