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Neurosurgery:
doi: 10.1227/NEU.0000000000000148
Research-Human-Clinical Studies

Predicting Tumor Control After Resection Bed Radiosurgery of Brain Metastases

Luther, Neal MD*; Kondziolka, Douglas MD*,‡; Kano, Hideyuki MD, PhD*; Mousavi, Seyed H. MD*; Engh, Johnathan A. MD*; Niranjan, Ajay MCh, MBA*; Flickinger, John C. MD§; Lunsford, L. Dade MD*,§

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*Department of Neurological Surgery and

§Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Department of Neurosurgery, New York University Langone Medical Center, New York, New York

Correspondence: Hideyuki Kano, MD, PhD, Research Assistant Professor of Neurological Surgery, University of Pittsburgh, Ste B-400, UPMC Presbyterian, 200 Lothrop St, Pittsburgh, PA 15213. E-mail kanoh@upmc.edu

Received March 20, 2013

Accepted August 27, 2013

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Abstract

BACKGROUND: Stereotactic radiosurgery (SRS) to the resection bed of a brain metastasis is an important treatment option.

OBJECTIVE: To identify factors associated with tumor progression after SRS of the resection bed of a brain metastasis and to evaluate patterns of failure for patients who eventually had tumor progression.

METHODS: We performed a retrospective analysis of 120 patients who underwent tumor bed radiosurgery after an initial gross total resection. The mean imaging follow-up time was 55 weeks. The median margin dose was 16 Gy. Forty-seven patients (39.2%) underwent whole-brain radiation therapy before or shortly after SRS.

RESULTS: Local tumor control was achieved in 103 patients (85.8%). Progression-free survival was 96% at 6 months, 87% at 12 months, and 74% at 24 months. Recurrence most commonly occurred deep in the cavity (65%) outside the planned treatment volume (PTV) margin (53%). PTV, cavity diameter, and a margin dose < 16 Gy significantly correlated with local failure. For patients with PTVs ≥ 8.0 cm3, local progression-free survival declined to 93% at 6 months, 83% at 12 months, and 65% at 24 months. Development or progression of distant metastases occurred in 40% of patients. Whole-brain radiation therapy was not associated with improved local control.

CONCLUSION: Resection bed SRS for brain metastases provided excellent local control. The cavity PTV is predictive of tumor control. Because failure usually occurs outside the PTV, inclusion of a judicious 2- to 3-mm margin beyond the area of postoperative enhancement may be prudent.

ABBREVIATIONS: ARE, adverse radiation effect

PTV, planned treatment volume

SRS, stereotactic radiosurgery

WBRT, whole-brain radiation therapy

Stereotactic radiosurgery (SRS) has a growing role in the management of brain metastases. Evidence of the efficacy of SRS as the primary intervention for brain metastases is convincing.1-9 The need for frequent visits when undergoing fractionated external beam radiation therapy is avoided, as are neurocognitive sequelae associated with whole-brain radiation therapy (WBRT).7,10,11 Gross total resection of symptomatic larger volume tumors remains the best option in patients eligible for craniotomy and removal. Historically, retrospective and randomized, prospective, controlled studies have shown local tumor control in 70% to 90% of patients who underwent WBRT12-16 after initial resection. Increasing evidence indicates that tumor bed SRS provides equal or superior local tumor control without the late toxicity of WBRT and that distant failure can be managed by repeat SRS.17-22

We sought to define both local and distant local tumor control rates and patterns of failure in an expanded series of patients who underwent tumor bed SRS with or without additional WBRT.

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MATERIALS AND METHODS

We performed a retrospective analysis of 2026 brain metastasis patients who underwent Gamma Knife SRS at the University of Pittsburgh Medical Center between 2002 and 2012. This review of patient data was approved by the Institutional Review Board. Gamma Knife procedures were performed as we have described in prior publications.4 SRS treatment was performed so that the planned treatment volume (PTV) included any remaining enhancing and non-contrast-enhancing borders of the resection cavity (Figure 1). All patients received a single 40-mg dose of intravenous methylprednisolone at the conclusion of the SRS procedure.

Figure 1
Figure 1
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We identified 139 patients who had undergone prior craniotomy and gross total resection of a brain metastasis followed by Gamma Knife SRS to the operative cavity, of whom 19 were excluded because follow-up imaging was not available. Of 120 patients included in the final analysis, 73 (61%) were female. The mean age at the time of the procedure was 58 years. A total of 71 patients had multiple metastases at time of SRS. The most common primary tumor pathologies were non-small-cell lung cancer (n = 48), breast cancer (n = 25), and melanoma (n = 19). After the SRS procedure, patients were followed up with serial magnetic resonance imaging at intervals of 10 to 14 weeks. The mean and median imaging follow-up intervals after SRS were 55 and 32 weeks, respectively. The median margin dose was 16 Gy. Further dose planning data are given in Table 1. Forty-seven patients (39%) also received WBRT, 28 before and 19 after tumor bed SRS. Patients without imaging performed at least 1 month after SRS were excluded from the analysis.

Table 1
Table 1
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Univariate and multivariate analyses were performed to determine factors associated with local and distant tumor progression. We evaluated patient age, histological type, cerebellar vs cerebral lobar location, treatment volume, maximum treatment diameter, margin dose, margin isodose, maximum dose, addition of WBRT, and multiple vs solitary metastases. For patients with breast cancer, estrogen, progesterone, and epidermal growth factor (Her2neu) receptor status was evaluated. Progression rates were evaluated by Kaplan-Meier analysis. All statistical analyses were performed with SPSS version 19.0 (SPSS Inc, Chicago, Illinois). For patients in whom delayed local tumor progression was observed, the site of progression was characterized as either superficial (proximal to the pial surface) or deep, as well as either inside or outside the original marginal isodose field targeted. Adverse radiation effects (AREs) were defined as the development of new neurological symptoms or signs in the absence of tumor hemorrhage or enlargement.

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RESULTS

Tumor Bed Control

Local resection bed tumor control was achieved in 103 of 120 patients (85.8%) in this series. In the 17 patients who developed local progression, time to progression was a median of 33 weeks after the procedure. Tumor progression was observed at the deep margin of the cavity in 11 patients (65%), was detected at the superficial or pial surface in 2 patients (12%), and was noted at both superficial and deep margins in 4 patients (24%). Progression occurred within the PTV in 6 patients (35%), was outside the margin in 9 (53%), and was both inside and outside the PTV in 2 patients (12%). Salvage WBRT was used in 4 patients because of local tumor progression. AREs were seen in 4 patients (3%). SRS planning details for patients who developed AREs are shown in Table 2. All 4 patients who experienced AREs at the site of SRS also had undergone prior WBRT.

Table 2
Table 2
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The progression-free survival for this series is shown in Figure 2. Progression-free survival for tumors with treatment volumes < 8.0 cm3 was 98% at 6 months, 91% at 12 months, and 86% at 24 months. For patients with PTVs ≥ 8.0 cm3, local progression-free survival declined to 93% at 6 months, 83% at 12 months, and 65% at 24 months (P < .05).

Figure 2
Figure 2
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A summary of the univariate analyses of factors that impacted the risk of local tumor progression is presented in Table 3. PTV, maximum resection cavity diameter, and margin dose <16 Gy individually correlated with a greater likelihood of tumor progression. Multivariate analysis found that increasing PTV (continuous) correlated with a higher chance of progression (P < .001). Receptor status was available in 14 of 33 patients (42.4%) with primary breast or gynecological malignancies, 2 of whom were “triple negative” for expression. Her2neu expression status did not correlate with outcomes in these patients.

Table 3
Table 3
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Distant Tumor Progression and Its Management

Distant progression or development of new metastases outside the tumor bed was confirmed in 48 patients (60% distant control rate) at a median 31 weeks after SRS. Thirty-seven patients underwent a repeat Gamma Knife procedure for distant metastases, and 8 patients underwent WBRT for distant progression. Distant development of new metastases was significantly associated with multiple vs single metastases at the time of SRS (P = .002) but did not correlate with any other analyzed variable.

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DISCUSSION

The Role of SRS After Brain Metastasis Resection

SRS has become an important primary or adjuvant management strategy in patients with brain metastases.17,19,22-27 Clinical practice guidelines published in 2010 presented Class I evidence that surgical resection followed by WBRT is superior in terms of local tumor control to surgical resection alone. However, no clear recommendation could be made with regard to the efficacy of surgery followed by SRS vs surgery followed by WBRT.28,29 Our results add significant Class III evidence to preexisting Class II evidence that SRS to the resection cavity produces rates of local tumor control comparable to those of WBRT after resection of a metastatic tumor, suggesting that a Level 3 recommendation can now be made that resection plus SRS has an efficacy similar to that of surgery followed by WBRT.

Surgical removal of a brain metastasis must be followed by adjuvant radiation therapy or by SRS to significantly reduce the risk of tumor recurrence. The increased risk of diffuse white matter injury and deleterious neurocognitive side effects has prompted reevaluation of the role of WBRT in such patients, especially those with projected long-term survival. Such undesirable side effects may be reduced and tumor control enhanced by the substitution of resection cavity SRS.10,30 A growing number of studies support that similar rates of tumor control may be achieved with SRS in this setting.19-22,31,32 The present retrospective study provides additional data that further confirm the role of SRS. The treated tumor control rate was 86% 1 year after SRS.

Our data confirm the outcomes of prior studies. Robbins et al33 reported a local control rate of 81% in 85 patients, of whom one-third had initial subtotal resection of their brain metastasis. Jensen et al17 reported 112 patients who had a local control rate of 80% 1 year after SRS. They found that a preoperative tumor diameter of > 3.0 cm was associated with poorer outcomes. Other radiation delivery techniques such as multisession radiosurgery or hypofractionation do not seem to result in improved tumor control rates.34,35

Because of the larger patient experience in the present study, we were able to assess various clinical parameters that affect the local tumor rate. Our experience confirms the results reported in an SRS meta-analysis of 14 studies (614 patients): The residual cavity volume is the factor most predictive of local control.36 Larger tumor cavity volumes often lead to a reduction in dose delivered to the PTV to reduce AREs. In this prior meta-analysis, mean “crude” local control was achieved in 83% (control at 1 year in 78%). Unlike the present series, these studies did not evaluate the role of prior or concomitant WBRT in local tumor control, and in many cases, WBRT was the criterion for exclusion.17,20,31,36

We also found that lower margin doses were associated with reduced local tumor control rates. Treatment volume and margin dose are difficult variables to assay independently because larger tumor or cavity volumes are most commonly treated with lower marginal doses. Maximum cavity diameter, a cruder measurement that can be performed on postsurgical magnetic resonance imaging before the decision to proceed with resection bed SRS, also showed that a simple analysis with respect to cavity dimensions can be predictive. A margin isodose < 16 Gy was also associated with local recurrence, which is not surprising given that lower margin doses typically correlate with larger treatment volumes. Maximum dose (which in this setting is delivered into the center of the empty cavity) did not correlate with outcomes.

The finding that progression most commonly occurred in deep locations just outside the PTV may help future dose planning in additional patients. We generally include within the PTV all areas of the cavity, including any postoperative enhancement. These findings suggest that an increased margin including normal-appearing brain may be used judiciously. This analysis did not test how much margin is optimal, but 2- to 3-mm extension into normal brain beyond the cavity PTV may be reasonable.

Of interest, we did not find that tumor histology correlated with local tumor control, even in the 19 patients with melanoma. Similarly, progression-free survival rates did not vary, regardless of whether the treated tumor was in the cerebral hemispheres or the cerebellum.

Prior resection bed SRS studies have not undertaken a specific analysis of patients who underwent prior or concomitant WBRT.17,20,31,36 We have purposefully included these patients to determine whether inclusion of WBRT is predictive of increased progression-free survival. Patients with progressive or symptomatic metastases may require surgical resection after WBRT. Alternatively, patients undergo WBRT for oligometastatic disease after resection of a dominant solitary symptomatic tumor. In this setting, cavity SRS may be viewed more as a “boost.” We found that tumor local control was not improved in patients who underwent WBRT either before or after SRS. All patients who suffered AREs also had history of prior WBRT. Four patients underwent salvage WBRT after progression at the primary site, but these patients were considered not to have undergone WBRT in our analysis (because their study end point had already been met). Our results add to mounting evidence that WBRT is not required for patients with resected brain metastases if SRS to the tumor bed is used instead. WBRT can be used as salvage treatment in patients who develop brain oligometastatic disease.12,15,30

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CONCLUSION

SRS to the resection bed of a brain metastasis is an effective strategy. The size of the resection cavity, whether measured by diameter or treatment volume required to encompass to region of postoperative enhancement, is predictive of likelihood for success. Progression after resection and SRS is most commonly detected deep in the resection bed and beyond the target isodose line. The addition of WBRT to this regimen does not appear to improve therapeutic efficacy.

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Disclosures

Drs Lunsford and Kondziolka are consultants for AB Elekta and Dr Lunsford is a stockholder. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

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COMMENTS

This is a retrospective review of 120 patients who underwent resection of brain metastases followed by stereotactic radiosurgery to the resection cavity. Over the last decade, a paradigm shift away from the dogmatic use of whole-brain irradiation (WBRT) for any scenario of intracranial metastasis has taken place. The awareness of the solely palliative character of WBRT and, especially, concerns about neurocognitive toxicity associated with this treatment have led to a search for reasonable alternatives. The focus of the present report is the assessment of efficacy of this treatment approach in terms of local and distant control of the metastatic disease. This report contributes additional data to a growing treatment trend of substituting whole-brain irradiation with focused radiation after resection of cerebral metastases and might also reflect a de facto increase in the implementation of this treatment strategy. The data presented by the authors, similar to previously published reports on stereotactic radiosurgery to the metastasis resection cavity, are, however, retrospective in nature and hence lack the power for a valid comparison between the 2 approaches. The authors discuss technical issues, in particular regarding target definition/delineation, and patterns of treatment failure. What is still missing is a randomized trial comparing WBRT with stereotactic radiosurgery to the resection cavity. Such study must include neurocognitive and health-related quality-of-life end points in addition to tumor control rate and survival. It is likely that postoperative WBRT will still be a valid treatment option in the context of novel radiation strategies that may minimize neurocognitive toxicity using sophisticated treatment planning (eg, hippocampal sparing) or chemical prophylaxis (such as memantine).

Andrew A. Kanner Zvi Ram

Tel Aviv, Israel

The authors have retrospectively analyzed patients who underwent surgical resection of metastatic tumors followed by stereotactic radio surgery. They demonstrate excellent local control during a reasonable follow-up period. As has been demonstrated in a number of prior reports, distant tumor development is still one of the pitfalls of this treatment approach. Nevertheless, this article provides important information about tumor bed radiosurgery failure patterns and constructive ideas for improving local control.

Randy Jensen

Salt Lake City, Utah

Although retrospective in nature, this is a well-designed and well-written study that concisely analyzes a large number of patients treated with surgical resection followed by stereotactic radiosurgery (SRS). The methods are sound and the conclusions are clear, make sense, and are useful. Their literature discussion is reasonable.

In the recent American Association of Neurological Surgeons/Congress of Neurological Surgeons metastatic brain tumor guideline publication,1 the paradigm of SRS to the surgical resection bed is addressed. At that time, only 1 Class 2 retrospective cohort study looked at surgery plus XRT vs surgery plus SRS. As a result of inadequate evidence, this paradigm was relegated to the “key issues for further investigation” section, and no guideline recommendations for this treatment paradigm were possible. The current large-patient-number Class 3 study, being strongly congruent in conclusion with the Serizawa et al 2000 study, would suggest that a Level 3 recommendation for surgery plus SRS to the resection bed being equivalent to surgery plus WBRT in local control outcome without the cognitive risk of WBRT would be in order for the next multidisciplinary metastatic brain tumor guideline update.

Mark E. Linskey

Orange, California

1. Linskey ME, Andrews D, Asher A, et al.. The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncology. 2010;96(1):45–68. Cited Here...

Keywords:

Brain metastasis; Cavity; Gamma Knife; Radiosurgery; Resection

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