Gynecologic Oncology 136 (2015) 472–477

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Central nervous system metastasis in gynecologic cancer: Symptom management, prognosis and palliative management strategies Adam C. Walter a,⁎, Camille C. Gunderson a, Sara K. Vesely b, Ozer Algan c, Michael Sughrue d, Katrina N. Slaughter a, Kathleen N. Moore a a

Division of Gynecologic Oncology, University of Oklahoma, Stephenson Cancer Center, 800 NE 10th Street Suite 5050, Oklahoma City, OK 73104, United States Division of Biostatistics, University of Oklahoma, 801 NE 13th Street, Oklahoma City, OK 73126, United States Division of Radiation Oncology, University of Oklahoma, Stephenson Cancer Center, 800 NE 10th Street Suite L100, Oklahoma City, OK 73104, United States d Department of Neurosurgery, University of Oklahoma, 1000 N. Lincoln Boulevard Suite 4000, Oklahoma City, OK 73104, United States b c

H I G H L I G H T S • CNS metastases are rare in gynecologic cancers; this work evaluates prognostic indices which have performed well in other solid tumors. • Provides a framework for workup and treatment in gynecologic cancer patients who develop CNS metastases • Thorough discussion summarizing the role of medical, surgical and radiotherapy interventions for gynecologic cancer patients with CNS metastases

a r t i c l e

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Article history: Received 18 August 2014 Accepted 1 December 2014 Keywords: Gynecologic CNS Metastasis Symptoms Palliation

a b s t r a c t Introduction. CNS metastasis (CNSmet) with gynecologic malignancy (GM) is associated with poor prognosis and symptom burden. Two prognostic indices, the recursive partitioning analysis (RPA) and graded prognostic assessment (GPA), used in other solid tumors to guide intervention options were evaluated among GM patients. Methods. Retrospective chart review was performed to identify patients with primary GM diagnosed with CNSmet from 2005–2014. RPA and GPA were applied and evaluated for goodness of fit. Long-term survivors (LTS) were those with survival time from CNSmet ≥9 months. Results. 35 patients were identified with median age of 62 years (range, 41–78). The majority had ovarian cancer (54%). Median survival was 4.5 months (0.1–25.9), and median time from initial diagnosis was 2.6 years (0–19.6). Presenting symptoms varied but headache (57%) and altered mental status (23%) were most common. 37% had a solitary CNS lesion, 31% had 2–8, and 31% N 8. 57% were treated with WBRT, 14% with stereotactic radiosurgery (SRS), and 20% with combinations of treatments, and 2 elected for hospice. 27% (9/33) of the patients were LTS. The GPA was not significantly associated with patient outcome (p = 0.46). The RPA predicted time to death (p = .0010). Conclusion. Prognostic indices used to guide therapeutic interventions perform poorly in GM. Detection and aggressive symptom management are critical in maintaining QOL. Multidisciplinary consultation is critical to optimize outcomes and symptom control. © 2015 Elsevier Inc. All rights reserved.

Introduction Brain metastases due to gynecologic malignancies are rare, although the incidence is increasing, particularly in ovarian cancer [1]. Metastases from ovarian cancer are the most prevalent with estimates ranging from 0.5–3%, and the cumulative incidence of brain metastasis from all

⁎ Corresponding author at: 800 NE 10th Street Suite 5050, Oklahoma City, OK 73104, United States. Fax: +1 405 271 1006. E-mail address: [email protected] (A.C. Walter).

http://dx.doi.org/10.1016/j.ygyno.2014.12.020 0090-8258/© 2015 Elsevier Inc. All rights reserved.

gynecologic cancers approximates 1% [2,3]. Due to low incidence, there is no indicated screening program in this population, and the majority presents symptomatically [4,5]. Symptoms vary widely, from mild cognitive impairment and subtle visual changes to seizures and severely altered mental status [6]. These patients can be clinically challenging to manage, as CNS treatment selection is related to prognosis. Prognosis can be difficult to assess given that 68% may have extra-cranial disease and many (37–51%) have poor performance status, with Karnofsky performance status (KPS) b 70 [3]. There are several validated scoring systems for prognosis following central nervous system (CNS) metastases including the Recursive

A.C. Walter et al. / Gynecologic Oncology 136 (2015) 472–477

Partitioning Analysis (RPA), Score Index for Radiosurgery (SIR), Basic Score for Brain Metastasis (BSBM), and the Graded Prognostic Assessment (GPA) [7,8]. The RPA is considered the gold standard for prognostic evaluation of patients with brain metastasis; however, the GPA recently outperformed the RPA in breast and small cell lung cancer populations [9,10]. The GPA has also performed well in patients with tumors rarely metastasizing to the CNS and is a more specific predictor of prognosis [11]. Neither index has been evaluated in the gynecologic population with brain metastasis. Several treatment modalities are available for patients with brain metastasis including whole brain radiation therapy (WBRT), surgery or stereotactic radiosurgery (SRS) in combination with WBRT, and SRS alone [6,12–14]. Treatment selection is based on specific patient factors and prognosis, specifically, among patients for whom survival beyond CNS metastasis could extend N6 months. In this population, avoidance of WBRT or incorporation of hippocampal sparing techniques to avoid neuro-cognitive sequelae is indicated [6,13,14]. Our investigation characterizes presenting symptoms of CNS metastasis and evaluates RPA and GPA performance in predicting survival time and long term survivors (LTS) in the gynecologic oncology population. We assessed each treatment modality and its impact on CNS tumor control and rates of recurrence. Finally, we provide a detailed discussion of the role of radiation therapy and neurosurgical intervention in the treatment of CNS metastasis in the gynecologic oncology population.

473

Table 1 RPA and GPA scoring with LTS distribution. Died b 9 months

Lived ≥ 9 months

Censored before 9 months

RPA class Class I: Age b 65 years, KPS ≥ 70, controlled 1 primary tumor, no extracranial metastases Class II: All patients not in class I or III 13 Class III: KPS b70 10

1

1

8 0

1 0

GPA classa 1: 0–1 2: 1.5–2.5 3: 3 4: 3.5–4

3 5 0 1

0 2 0 0

13 8 3 0

a Scoring: Age in years: 50–59 = 0.5, b50:1; KPS: 70–80 = 0.5, 90–100 = 1; number of CNS metastases: 2–3 = 0.5, 1 = 1; extracranial metastases: absent = 1.

Results A total of thirty-five patients who had a primary diagnosis of a gynecologic malignancy and who either presented with or ultimately developed brain metastases were identified. Patient, tumor and treatment characteristics are shown in Table 2. Median age was 62 years (range, 41–78). The majority had ovarian cancer (54%); 37% had endometrial Table 2 Patient demographics, presenting symptoms, and prognostic score.

Methods After obtaining institutional review board (IRB #3746) approval, consecutive patients with brain metastasis from our institution were identified from radiation oncology and neurosurgery patient databases from 2005–2014 and selected if they had a primary diagnosis of ovarian, endometrial, or cervical cancer. Data were collected retrospectively from electronic medical records and abstracted for original diagnosis, stage at initial diagnosis, histology, symptoms at presentation of metastatic disease, number of metastasis, presence of extra-cranial disease, control of primary tumor based upon follow-up imaging, treatment modality, performance status, and survival. Survival was calculated from the date of diagnosis of brain metastases to date of death or last follow-up. The decision to administer radiation therapy and the type of radiation therapy utilized was individualized at the level of the treating physician. The most commonly utilized regimens were WBRT 3000cGy given in 10 fractions or 3750cGy given in 15 fractions. If targeted stereotactic treatments were utilized, it was done in a single fraction (stereotactic radiosurgery) on a gamma knife (Elekta, Kungstensgatan, Stockholm) unit or in 3–5 fractions (stereotactic radiation therapy, SRT) on a linear accelerator. SRT doses varied from lesion to lesion depending on the size and location of the metastases and whether or not the patient had received prior radiation therapy to this region. The most commonly used SRT doses were either 25Gy in 5 fractions or 21Gy in 3 fractions. Descriptive statistics were calculated. Patients were considered LTS if they survived 9 months or longer. The RPA (class I, II, or III) and GPA (0–1, 1.5–2.5, 3, 3.5–4) scores were calculated and grouped for each patient according to historical prognostic survival distributions from the literature (Table 1) [8]. To evaluate the predictive power of the RPA and GPA in the gynecologic population Kaplan–Meier curves were created and log-rank tests were performed to compare survival times. The proportion of long-term survivors by RPA and GPA group were compared using Fisher's exact test. Other individual prognostic factors were also evaluated using Kaplan–Meier curves and log-rank tests. Recurrence and treatment type were compared with Fisher's exact test. SAS version 9.3 (SAS Institute; Cary, NC) was used for statistical analyses.

Endometrial Ovary Overall cancer cancer sample (n = 35) (n = 19) (n = 13) Variable Age at original diagnosis (years) Age at CNSmet diagnosis (years) Time original treatment to CNSmets (years) Cancer type Ovary Endometrial Cervix Number of metastases 1–2 3–8 Diffuse KPS category ≥70 b70 Treatment type WBRT SRS SBRT Surgery Hospice Chemotherapy Extracranial disease Controlled primary Symptoms (may have more than one symptom) Headache Ataxia Altered mental state Dizzy Seizures N/V Weakness Stroke Vision changes GPA 4 (best) 3 (middle) 2 (middle) 1 (worst) RPA 1 (best) 2 (middle) 3 (worst)

Median 59.3 62.1 2.6 n (%) 19 (54) 13 (37) 3 (9)

Median Median 50.9 62.0 62.1 62.5 3.4 0.7 n (%) n (%) 19 (100) 0 0 13 (100) 0 0

14 (40) 10 (29) 11 (31)

5 (26) 7 (37) 7 (37)

6 (46) 3 (23) 4 (31)

25 (71) 10 (29)

13 (68) 6 (32)

9 (69) 4 (31)

20 (57) 5 (14) 2 (6) 5 (14) 2 (6) 1 (3) 32 (91) 6 (14)

12 (63) 3 (16) 0 (0) 2 (11) 1 (5) 1 (5) 17 (89) 3 (16)

7 (54) 2 (15) 2 (15) 1 (8) 1 (8) 0 (0) 12 (92) 2 (15)

20 (57) 6 (17) 8 (23) 4 (11) 4 (11) 3 (9) 5 (14) 5 (14) 1 (3)

12 (63) 2 (11) 5 (26) 4 (21) 2 (11) 2 (11) 1 (5) 2 (11) 0 (0)

7 (54) 2 (15) 2 (15) 2 (15) 1 (8) 1 (8) 4 (31) 2 (15) 1 (8)

1 (3) 3 (9) 15 (43) 16 (46)

1 (5) 1 (5) 8 (42) 9 (47)

0 (0) 1 (8) 5 (38) 7 (54)

3 (9) 22 (63) 10 (29)

2 (11) 11 (58) 6 (32)

1 (8) 8 (62) 4 (31)

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cancer, and 9% had squamous cell cervical cancer. The overall survival for the entire patient population is shown in Fig. 1. Median survival was 4.5 months (range, 0.1–25.9) from diagnosis of CNS metastases, with only 9 patients surviving 9 months or beyond and classified as LTS by our definition (2 patients were censored since follow-up was less than 9 months). Median time from initial diagnosis to CNSmet event was 3.6 years (range, 0–19.2); only 2 patients were diagnosed concurrently with their primary. The most common presenting symptoms were as follows: 57% headache, 23% altered mental status, 17% ataxia, 14% generalized weakness, 14% stroke, 11% seizures, 9% nausea/vomiting and 3% with vision changes only. Sixty percent of the patients had a combination of symptoms, with headache and ataxia the most common combination. The majority of patients (71%) had a good performance status (KPS ≥ 70). Thirty-seven percent had a solitary CNS metastasis, 31% had 2–8 lesions, and 31% had more than 8 CNS metastases at the time of initial imaging. 57% of patients were treated with whole brain radiation therapy (WBRT), 14% stereotactic radiosurgery alone (SRS), 14% combined surgery and SRS, 6% combined SRS + WBRT, and 2 patients best supportive care with hospice. Seventeen percent of patients had a CNSmet recurrence; 3/5 patients initially treated with surgery + SRS had a recurrence, 2/20 initially treated with WBRT had a recurrence, and 1/5 treated with SRS only had a recurrence. The recurrence proportion in patients receiving directed therapy as compared to WBRT was not statistically different (31% (4/13) vs. 10% (2/20), p = .18). All patients who had a recurrence had KPS ≥ 80; number of CNS lesions, histologic type and presence of extra-cranial disease were not associated with CNSmet recurrence (all p N 0.05). Of the 6 patients that had a recurrence, 4 had retreatment with WBRT and achieved CNS tumor control and 2 patients elected for hospice. All successfully salvaged patients had local therapy initially, while the 2 patients that had WBRT and had a recurrence both elected for hospice. The two prognostic indices, RPA and GPA were applied and evaluated for association with survival time and LTS. The GPA was not associated with survival time (p = 0.4599) in this group (Fig. 2), nor with LTS, placing only 1 of 9 long term survivors into the most favorable prognostic group, and incorrectly placing 3 of 9 long term survivors into the worst prognostic group (Table 1, p = .1854). RPA was associated with survival time (p = .001, Fig. 3) placing LTS 3 of 9 (33%) into the most favorable group, and perhaps more importantly, no LTS were placed into the

worst prognostic group (Table 1, p = 0.0403). The relationship between individual factors and survival time was also evaluated. KPS (median survival time in months: b70 = 1.7; ≥70 = 7.6, p = .0002) (Fig. 4) was associated with survival, while the number of metastasis (p = .5104), and control of primary tumor (p = .0834) were not significantly associated with survival time. Discussion Brain metastases from gynecologic cancers are uncommon, and the treatment outcomes are not well studied. This study provides data from a cohort of patients with brain metastases from primary gynecologic neoplasms. Not surprisingly, the presence of brain metastasis portends a grim prognosis; however, our experience indicates that multimodality treatment for these patients can provide local and symptomatic control for these patients as only 2/33 (6%) treated patients died with progressive CNS disease. Untreated brain metastases are typically fatal in a short time period; however, treatments for these patients are generally effective at controlling brain disease [15]. Treated patients typically do not die of their CNS disease, making prognosis in these patients largely dependent on the extent and control of the systemic disease. For nearly all patients with symptomatic brain metastases, corticosteroid therapy is recommended to provide immediate symptom improvement, with dexamethasone being the corticosteroid of choice with starting doses of 4–8 mg/day while 16 mg/day is appropriate for those with signs of increased intra-cranial pressure [4]. For patients with short predicted survival, there may be no benefit to treatment beyond symptom management with corticosteroids [15]. Role of radiation therapy In the setting of gynecologic cancer metastases to the CNS, any treatment should be considered palliative with the goal of improving or preserving quality of life by alleviating neurological symptoms, or by attempting to delay the formation of new neurologic symptoms [2,5]. Previously, the role of radiation therapy was limited to WBRT either alone or as adjuvant therapy following surgical resection [14,16,17]. WBRT is highly effective (60% complete response rate) in controlling CNS lesions, with total treatment dose of 30Gy to 40Gy, and has the benefit of controlling tumor micro-deposits unseen on imaging [6,17].

Fig. 1. Overall survival following diagnosis of CNS metastasis.

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Fig. 2. Survival according to GPA class.

Several chemosensitizing agents have been evaluated in trying to improve response further, however none have been successful thus far [18]. Although highly effective in control of cerebral tumor, treatmentrelated cognitive effects with WBRT may be profound [19,20]. Significant impairment in working memory, ability to learn, and recognition have been demonstrated on formal testing within 8 weeks of WBRT [21]. Profound progressive dementia has been described in patients receiving more than 3Gy of WBRT daily [17]. Due to the concern for delayed neurotoxicity, more focused treatments (SRS) have been evaluated [22]. There are several delivery systems for these focused therapies, but in general, multiple convergent beams are used to deliver high dose radiation to a specific target with surrounding tissues receiving minimal doses. Generally, stereotactic treatments, given either in a single fraction or in several fractions, are recommended for patients

with 1–3 brain metastases and an expected survival greater than 3–6 months, such that they are at risk of developing neurocognitive deficits from WBRT. The use of SRS in patients with four or more metastases is more controversial, with strong proponents on both sides. There is an ongoing randomized phase III trial attempting to better resolve this controversy. Recently the role of SRS has been evaluated alone, and in combination with WBRT and surgery [12]. RTOG 95-08 investigated the role of SRS in addition to WBRT in patients with RPA class I or II, and 1–3 brain metastases [12]. In this patient population, there was no significant overall survival benefit; however, there was a significant improvement in local control and KPS for those receiving SRS and WBRT in patients with 1–3 metastases. Given the improvement with the addition of SRS, several studies have investigated SRS alone, potentially avoiding

Fig. 3. Overall survival according to RPA class.

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Fig. 4. Overall survival according to KPS.

the toxicity associated with WBRT. A recent meta-analysis evaluated patients with limited metastases who had either WBRT or SRS or both, and demonstrated no difference in overall survival (10.9 months WBRT versus 10.7 months SRS). However, the relapse rate (31% vs. 19%) and death due to intracranial progression (44% vs. 28%) were significantly higher in the SRS alone group [23]. A neurocognitive study addressing SRS vs. SRS plus WBRT was stopped early due to safety concerns as patients receiving combination therapy were 28% more likely to show significant deficits in learning and memory function measured 4 months post-treatment [19]. Neurocognitive effects of radiation therapy The aforementioned studies demonstrate that even though WBRT results in fewer recurrences in the brain, this gain is associated with a potential for increased neurocognitive deficit among those patients who survive beyond 4 months. Several recently reported trials have attempted to reduce the potential for neurocognitive deficit from WBRT. RTOG 0933 was a phase II trial evaluating both the feasibility and the effectiveness of hippocampal avoidance during WBRT (HA-WBRT). This study, presented in abstract form only thus far, demonstrated on average a 7% decline in the Delayed Recall Scale of the Hopkins Verbal Learning Test (HVLT) at 4 months after HAWBRT compared to a 30% decline in a historical control group. By 6 months, the decline in the HVLT score was down to 2%, suggesting HA-WBRT was able to better preserve the hippocampal dependent functions of memory and learning compared to standard WBRT [24]. RTOG 0614 was a randomized phase III trial evaluating the addition of memantine to patients receiving WBRT and continuing it for a total of 24 weeks. The addition of memantine resulted in reduced probability of cognitive function failure and delayed time to cognitive decline when compared to patients taking placebo, as measured by the HVLT delayed recall, MMSE, and oral word association tests [24]. The risk of cognitive function failure at 24 weeks was 53.8% in the memantine group versus 64.9% in the placebo group. This 17% relative reduction in the risk of cognitive decline was preserved even after the memantine treatment was completed. The utilization of memantine was generally well tolerated with no significant adverse events noted. It is likely that future studies will incorporate combined approaches to help further reduce the neurocognitive deficits that can occur from brain irradiation,

especially when large volume of brain is irradiated. It is also important to realize that there are multiple factors, in addition to the volume of brain tissue irradiated, that impact the development of neurocognitive deficits [19,20]. With the diagnosis of recurrence and/or metastasis, patients are often anxious about an uncertain future and can become depressed. Similarly, chemotherapy has been shown to cause neurocognitive deficits in certain settings and surgery, depending on the location and extent of surgical location, and has the potential to cause neurocognitive deficits as well [25,26]. It is therefore very important to have a multidisciplinary approach in the management of these patients, not only to improve outcomes, but also to preserve and potentially improve quality of life and neurocognitive function. Role of surgery Surgery can be a critical component of treatment for patients with brain metastases. As surgical techniques evolve, removal of these tumors can be performed safely and effectively often via minimally invasive techniques. Unlike infiltrating tumors such as gliomas, these tumors do not contain functional brain within the lesion, allowing safe removal even from locations in the brain such as that housing motor or speech centers with good results. Surgery can rapidly improve brain edema, and reduce disease burden immediately, which improves survival for these patients [1]. Level 1 data supports the statement that surgical resection alone often is insufficient, and that adjuvant radiation, even following gross total resection, provides superior rates of local tumor control [14]. Thus, surgery is typically reserved for large, and symptomatic metastasis, those which have failed radiation based therapies, or as a part of multi-modality therapy to treat small lesions, and tumor resection cavities. Surgery for small lesions does not eliminate the need for radiation, and thus is not usually performed in these cases. Conclusion CNS metastases occur rarely in patients with a gynecologic malignancy, and thus there is no recommended screening in this population. The majority of GM patients who with present with CNSmets have persistent or multiple neurologic complaints. These patients need prompt evaluation and appropriate imaging to enable rapid initiation of

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palliative therapy. In our study, outcomes were poor with a median survival of only 4.5 months from the time of brain metastasis. Palliative treatments including surgery, localized radiotherapy, or WBRT are all excellent options in appropriately selected patients. Patients receiving WBRT can experience neurocognitive deficits as early as 4 months following treatment, while profound neurocognitive symptoms typically manifest about 12 months post treatment. Identifying potential LTS following development of brain metastases is crucial in identifying those that may benefit from neurocognitive sparing therapies to preserve quality of life. The RPA was associated with survival time, and was able to identify all patients with short survival. Unfortunately, neither prognostic index reliably identified LTS in our cohort, likely related to the high proportion of patients with uncontrolled extra-cranial disease. For gynecologic patients with brain metastasis and KPS ≥ 70, multidisciplinary collaboration is needed to determine the most appropriate treatment course for patients. While patients with poor performance status and short expected survival require aggressive symptom management, family support and early hospice intervention as the best palliative approach. Conflicts of interest Neither I nor my co-authors have any conflicts of interest to disclose.

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Central nervous system metastasis in gynecologic cancer: symptom management, prognosis and palliative management strategies.

CNS metastasis (CNSmet) with gynecologic malignancy (GM) is associated with poor prognosis and symptom burden. Two prognostic indices, the recursive p...
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