Neuro-Oncology 15(5):589 – 594, 2013. doi:10.1093/neuonc/nos328 Advance Access publication March 3, 2013

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Involved field radiation therapy after surgical resection of solitary brain metastases—mature results Eileen P. Connolly, Maya Mathew, Moses Tam, Josephine Vera King, Saroj D. Kunnakkat, Erik C. Parker, John G. Golfinos, Michael L. Gruber, and Ashwatha Narayana Departments of Radiation Oncology (E.P.C., M.M., M.T., J.V.K., S.D.K., A.N.), Neuro-Oncology (M.L.G.), and Neurosurgery, New York University Langone Medical Center, New York, New York (E.C.P., J.G.G.)

Background. Whole brain radiation therapy (WBRT) reduces local recurrence in patients after surgical resection of brain metastases without improving overall survival. Involved field radiation therapy (IFRT) has been used at our center to avoid delayed neurotoxicity associated with WBRT in well-selected patients with surgically resected single brain metastases. The purpose of this study was to evaluate the long-term outcomes of these patients. Methods. Thirty-three consecutive patients with single brain metastases from a known primary tumor were treated with gross total resection followed by IFRT between 2006 and 2011. The postoperative surgical bed was treated to 40.05 Gy in 15 fractions of 2.67 Gy with conformal radiation therapy. Patients received serial MRIs and neurological exams in follow-up. Surgery, WBRT, or stereotactic radiosurgery was performed as salvage treatment when necessary. Results. The median follow-up was 16 months (range: 2 –65 months). Local control, distant brain recurrencefree survival, and overall survival at 12 and 24 months were 90.3% and 85.8%, 60.7% and 51.4%, and 65.6% and 61.5%, respectively. Overall, 5 (15%) patients developed recurrence at the resection cavity, and 13 (39%) patients experienced recurrence at a new intracranial site. Two patients received WBRT, 8 stereotactic radiosurgery, 2 surgery, and 2 both chemotherapy and IFRT as salvage. Four patients died from CNS disease progression.

Received June 19, 2012; accepted December 4, 2012. Corresponding Author: Ashwatha Narayana, MD, Professor, Department of Radiation Oncology, New York University Langone Medical Center, 550 1st Avenue, New York, NY 11016 ([email protected]).

Conclusion. For patients with newly diagnosed single brain metastases treated with surgical resection, postoperative IFRT to the resection cavity achieves reasonable rates of local control and is an excellent alternative to WBRT. Keywords: involved field radiation therapy, surgical resection, whole brain radiation therapy, brain metastasis.

B

rain metastases are the most common tumors of the central nervous system (CNS), with 30% of cancer patients eventually developing these lesions and an estimated 200 000 cases diagnosed annually in the United States.1,2 Treatment options include medical management, surgical resection, whole brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS). In patients with single brain metastasis, surgical resection followed by WBRT has been shown to improve overall survival and quality of life compared with WBRT alone.3 However, no additional improvement in overall survival or functional independence was seen in these patients when surgical resection alone was compared with resection followed by WBRT.4,5 The benefits of postoperative WBRT include a reduction in the rate of recurrence at the site of resection as well as in other areas of the brain, based on a prospective trial.3 However, WBRT remains controversial because it is associated with potential late effects, including leukoencephalopathy, memory loss, and dementia.6,7 Given that patients with a single brain metastasis can have long-term survival exceeding 1 –2 years, concerns for these late toxicities have led investigators to explore localized postoperative radiation therapy such as brachytherapy8,9 and SRS,10 – 14 with WBRT reserved for salvage. Focal treatment delivered as involved field radiation therapy (IFRT) has been offered to select patients at our center following surgical resection of a single brain

# The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Connolly et al.: Involved field radiation therapy in brain metastases

metastasis as an alternative to WBRT. The purpose of this retrospective review was to analyze the long-term outcomes of this patient population in terms of local control, distant brain failure, and overall survival.

Materials and Methods Institutional review board approval was obtained for this retrospective analysis. The study population consisted of 33 consecutive patients with a single brain metastasis treated with gross total resection followed by IFRT to the postoperative cavity between 2006 and 2011 at New York University Langone Medical Center. Patients were selected for surgery at our institution if they had a lesion ≥2 cm, presence of edema, neurological symptoms, or a lesion located in a functionally critical region such as the motor cortex. In addition, patients with a primary tumor type of melanoma were more likely to receive surgery than those with other metastatic primary tumors. Patients found to have histology of small cell lung carcinoma (SCLC) were specifically excluded from treatment with IFRT postoperatively, given that a higher rate of distant brain recurrence was expected in these patients. Patients with SCLC received standard whole brain irradiation. All patients underwent preoperative gadolinium-enhanced MRI of the brain, and surgical resection was performed for either relief of mass effect or histological confirmation of metastatic disease. Postoperative MRI of the brain was performed within 48 h of surgery to assess the extent of resection. IFRT was typically delivered 3 –7 weeks after surgery. Treatment, for all patients, consisted of IFRT to the postoperative cavity with a 1-cm planning target volume using 3-dimensional conformal or intensity-modulated radiation therapy to a total dose of 40.05 Gy in 15 daily fractions over 3 weeks using 2.67 Gy per fraction (Fig. 1). Pre- and postoperative MRIs were registered to the planning simulation computed tomography scan to help delineate the edge of the resection cavity. After completion of treatment, patients were clinically evaluated with complete physical examinations including a detailed neurological exam along with an

MRI surveillance of the brain 1 month after the completion of radiotherapy and every 3 months thereafter. Additional evaluations were performed as clinically warranted. Characteristics, follow-up, and survival data were obtained for all patients. Local progression was defined as the presence of new nodular enhancement along the resection cavity on follow-up MRI. Distant recurrence was defined as the presence of new enhancing lesions consistent with brain metastases or leptomeningeal enhancement outside of the IFRT target volume. Time to local progression or distant recurrence was calculated from the date of surgery to the first MRI that showed evidence of recurrence. Patients were censored at the time of recurrence, and additional recurrence events after salvage therapy were not recorded, although patients continued to be followed for overall survival analysis. Kaplan– Meier estimates were used to determine the local progression-free survival, distant recurrence-free survival, and overall survival. All calculations were made using PASW software version 18.

Results Patient and Tumor Characteristics Table 1 summarizes the demographic and clinical data. Briefly, all patients had a single brain lesion, which Table 1. Patient and tumor characteristics

n

%

Men

11

33

Women Age, y

22

67

Characteristics Gender

Mean + SD Median (range) RPA class

57.6 + 12 56.6 (27– 82)

I

11

33

II III

22 0

67 0

70 80

1 11

3 33

90 Median (range)

21 90 (70– 90)

64

NSCLC Breast

13 9

39.4 27.3

Melanoma

8

24.2

Bladder Sarcoma

1 1

3.03 3.03

Ovary

1

3.03

KPS score

Primary cancer

Fig. 1. Treatment planning. (A) Preoperative MRI. (B) Dose distribution based on postoperative MRI fused onto planning CT scan.

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Tumor size, cm Mean + SD Median (range)

3.4 + 1.2 3.3 (1.7– 5.7)

Abbreviation: RPA,recursive partitioning analysis.

Connolly et al.: Involved field radiation therapy in brain metastases

Fig. 2. Kaplan–Meier analysis of local recurrence-free survival at the surgical bed.

was the solitary site of metastatic disease in 26 patients. Seven patients were asymptomatic at diagnosis; the remainder presented with neurological symptoms, which resolved for the majority (92%) after surgical resection. The most common primary sites of disease were lung (13 cases, all non-[N]SCLC), breast (9 cases), and melanoma (8 cases). Gross total resection was achieved in all 33 cases, and none had received prior radiotherapy to the brain. Twenty-seven patients are known to have received systemic chemotherapy at last follow-up. Among these 27 patients, 15 had received systemic chemotherapy prior to diagnosis of brain metastasis and 12 after diagnosis of brain metastasis; no patients were treated with concurrent chemotherapy at the time they received IFRT. The median age of the patients was 57 years, and the median KPS score was 90 at the time of therapy. The majority of patients were of recursive partitioning analysis class II, and the mean tumor size in largest dimension was 3.4 cm. The median time to start IFRT after surgery was 1 month (range, 0.5 –2.2 months). Seven patients had extracranial metastatic disease at time of diagnosis of the brain metastasis. An additional 8 patients developed extracranial metastasis during follow-up after having received IFRT.

Local Control/Distant Brain Recurrence and Salvage Therapy With a median follow-up time of 16 months (range, 2 –65 months), local control at the surgical bed was achieved in 28 patients (85%). Local control rates at 12 and 24 months were 90.3% and 85.8%, respectively (Fig. 2). New brain metastasis (distant brain recurrence) was observed in 13 patients (39%). A total of 15 patients progressed intracranially with local recurrence or distant new brain metastasis, 3 of whom had recurrence both in

Fig. 3. Kaplan–Meier analysis of distant recurrence-free survival in the CNS.

the resection cavity and in a new brain location. Only 2 patients (6.7%) were symptomatic from the new metastases. The 12- and 24-month actuarial rates of distant brain recurrence-free survival were 60.7% and 51.4%, respectively (Fig. 3). Among the 15 patients with progression of intracranial disease, salvage therapy was performed in 14 (42%). Salvage therapy included surgical resection and SRS (n ¼ 2), surgical resection and WBRT (n ¼ 1), SRS alone (n ¼ 8), WBRT alone (n ¼ 1), and IFRT and chemotherapy (n ¼ 2). The median survival following salvage therapy was 4 months (range, 0– 54 months). Overall Survival/Complications The 12- and 24-month overall survival rates were 65.6% and 61.5%, respectively (Fig. 4). Twelve-month overall survival rates for the most common primary tumors were 74.6% for NSCLC, 83.3% for breast cancer, and 50% for melanoma. Overall survival rates for the group with distant brain recurrence at 12 and 24 months were 61.5% and 51.3%, respectively, compared with 69.6% and 69.6%, respectively, in the group without distant brain recurrence (P ¼ ns). To date, 12 patients have died: 4 from progressive CNS disease, 5 from progressive systemic disease, and 3 from an unclear cause. None of the patients experienced additional neurological symptoms related to therapy. None of the patients in the study developed radiation necrosis or steroid-dependent edema.

Discussion According to autopsy studies, single brain metastasis is noted in 40% –47% of cancer patients who have

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brain metastases.15 Historically, WBRT alone had remained the standard of care for these patients. In 2 prospective randomized trials done in the 1990s, surgical resection followed by WBRT resulted in improved overall survival and better neurological outcomes compared with WBRT alone.3,16 These trials established the role of surgical resection and raised questions about the role of WBRT in this select group of patients. In a subsequent randomized trial, the omission of WBRT after surgical resection did not reduce overall survival or functionally independent survival.4,5 Postoperative WBRT did, however, result in improved control of disease in the brain, both at the site of resection (10% vs 46%) and elsewhere (14% vs 37%). WBRT also reduced deaths from neurological causes.3

Fig. 4. Kaplan–Meier analysis of overall survival.

With improvements in systemic therapy leading to longer survival from many cancers, the delayed effects of WBRT become a more serious issue. Adverse outcomes reported in children after therapeutic cranial irradiation include neurocognitive dysfunction, dementia, pituitary dysfunction, and decreased IQ.17,18 Similarly, in a small series of adult patients treated with WBRT, DeAngelis et al19 noted dementia, ataxia, urinary incontinence, and pituitary dysfunction. Chang et al20 showed in a prospective randomized trial that WBRT in addition to SRS in limited brain metastases was associated with significant decline in learning and memory function. Aoyama et al,21 in another randomized trial, demonstrated higher incidence of radiation necrosis and leukoencephalopathy in patients who were given WBRT in addition to SRS compared with SRS alone for limited brain metastasis. An added disadvantage of WBRT is that it can delay the administration of chemotherapy, necessary for systemic control, possibly affecting patients’ overall survival. There is also evidence that WBRT followed by systemic chemotherapy can worsen the incidence of neurocognitive dysfunction.17 As a result, techniques of delivering focal postoperative radiotherapy using either SRS10 – 14 or brachytherapy8,9 are being explored, keeping WBRT as a salvage procedure. Local control in these studies has varied from 73% to 94%, comparable to results of WBRT after surgical resection. Survival results have ranged from 9.2 to 20.6 months in these trials.8 – 14 Not surprisingly, the incidence of development of new brain metastasis in these studies was 28%– 63%, higher compared with WBRT. However, the need for salvage with WBRT was only 7% –31%, indicating the feasibility of these approaches (Table 2). A major disadvantage of SRS is in identifying the target volume as the surgical cavity collapses in the postoperative period, and many lesions may be too large to safely undergo the procedure. Availability, technical details of achieving uniformity of dose, and radiation safety issues prevent generalization of the use of

Table 2. Comparison of different treatment options as adjuvant for limited brain metastasis following resection Modalities of Adjuvant Treatment

Local Failure

Distant Brain Recurrence

Radiation Necrosis/ Steroid-Dependent Edema

Survival (mo)

Median Follow-up (mo)

SRS boost Do et al10

6 –27%

28– 63%

0–6.6%

12 –16.4

11– 13

7 –18%

32– 44%

5.5–17%

9.2– 16

16

10%

14%

11%

10 –20.6

10– 11

16.7%

33.3%

0%

30.7

17

Jagannathan et al11 Karlovits et al12 Narayana et al13 Quigley et al14 Brachytherapy Petr et al8 Rogers et al9 DeAngelis et al6 Patchell et al4 Vecht et al16 Postop IFRT (present study)

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brachytherapy. Another drawback of these techniques is the relatively high risk for late effects, including steroid dependence and/or brain necrosis, which has ranged from 5% to 17%.8,9 The arguments in favor of IFRT are that the planning target volume definition and dose prescription are uniform and that treatment planning is easy and reproducible. The present study is the first to our knowledge that has shown the feasibility of this approach. Our patients had lesions with a mean diameter of 3.4 cm, and a majority (79%) of our patients had neurological symptoms. In addition, 7 (21%) of these patients initially presented with extracranial metastasis, and 8 (24%) patients developed extracranial metastasis during the follow-up period. Despite these poor prognostic features, we achieved excellent local control at the surgical bed of 85% and a 12-month overall survival of 65.6%. No cases of brain necrosis or steroid dependence were noted. Only 2 patients needed eventual salvage with WBRT, and only 4 patients died of intracranial disease progression. The limitations of the present study are primarily that it involved a small number of highly select patients, all of whom had a single brain metastasis that was completely resected. This makes it difficult to compare our outcomes with those of historical randomized trials. In addition, this is a retrospective collection of data, and formal collection of neurocognitive data was not obtained. However, the results look promising enough to

warrant a prospective clinical trial to validate this approach.

Conclusions For patients with newly diagnosed single brain metastases treated with surgical resection, postoperative IFRT to the resection cavity achieves reasonable rates of local control and may be an excellent alternative to WBRT in select patients.

Acknowledgments Portions of this work were presented in poster form at the 20th annual meeting of the American College of Radiation Oncology, Orlando, FL, February 25 – 27, 2010. Conflict of interest statement. The authors report no conflict of interest concerning the materials or methods used or the findings specified in this paper.

Funding We did not receive any funding for this research.

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