Abstract
Purpose
We aimed to determine the efficacy of gamma knife stereotactic radiosurgery (SRS) to control brain metastases (BM) from GI primaries and report on the patient outcomes.
Materials/methods
We retrospectively evaluated patients who had undergone SRS at our institution for the treatment BM from GI primaries from 2000 to 2016. Actuarial rates for overall survival (OS) and local control (LC) were calculated. Survival rates were computed via the Kaplan-Meier method from the day of SRS. Multivariate analysis (MVA) using proportional hazards regression was done to determine prognostic factors for OS and LC.
Results
53 patients with a total of 148 BM were treated with SRS. The median age at SRS was 60 years and the median treatment dose was 18 Gy. SRS was given as an adjuvant treatment to 30.4% of lesions. Twelve patients underwent second course of SRS for new/recurrent lesions at a median of 8 months from the first SRS (range 2-25.5). Twelve patients (22.6%) received salvage whole brain radiation. The median follow up time from the diagnosis of BM was 6 months. Local control rate at 6 months was 74.33% and 57.21% at 12 months. The OS at 1 year was 34% and 8% at 3 years. On MVA, higher GK dose was associated with better LC, and and >10 BM trended towards higher risk of local recurrence (LR). None of the tested factors proved to be significant for OS on MVA. No radiographic radionecrosis was observed on follow up MRI.
Conclusions
SRS is a safe treatment modality for the management of CNS metastases from GI primary. Consideration for dose-escalated approaches may improve LC rates.
Keywords: stereotactic radiosurgery, brain metastases, gastrointestinal cancers, radiotherapy
Introduction
Malignancies of the gastrointestinal (GI) tract represent significant global health concern and account for nearly 33% of cancer death worldwide [1]. Over the past decade, our understanding of the molecular basis of gastrointestinal GI cancers has broadened which has resulted in expansion of systemic treatment options. This progress, coupled with advancements in imaging, surgical methods and radiotherapy has significantly improved prognosis of various GI malignancies [2, 3].
Brain metastases (BM) are a late manifestation of GI cancers and signify poor prognosis [4]. As patients are living longer with better controlled systemic diseases, the incidence of BM, although relatively rare from GI malignancies, is on the rise and hence will be encountered more by clinicians. SRS can deliver large doses of radiation to a well-defined anatomic area while sparing dose to the surrounding normal tissues. Compared to fractioned whole brain ration therapy (WBRT), stereotactic radiosurgery (SRS) offers simplicity in delivery with single fraction treatment and has less impact on long term neurocognitive functions [5, 6]. Therefore, SRS has been increasingly utilized for patients with up to 10 metastases, and its efficacy has been well established for cancers originating from various sites [7-10]. However, literature is dominated by outcomes of treatment of BM from more common thorax primaries and given the relative rarity, robust data on the efficacy of SRS and optimal treatment regimen for controlling brain metastasis from GI primary is lacking.
In our current study, we aimed to determine the efficacy of gamma knife SRS to control BM from GI primaries and report on the patient outcomes. We also aimed to identify prognostic factors that affect local control (LC), overall survival (OS) and can impact clinical decision-making.
Methods
We retrospectively identified patients aged >18 years who had undergone SRS for definitive or adjuvant treatment of BM from histologically proven GI primary cancers from 2000 to 2016. This study was approved by our Institutional Review Board. Only patients who had at least one follow up MRI after SRS treatments were included.
Radiosurgery
All patients were treated at a single institution with the Leskell Gamma Knife 4c® or Leskell Gamma Knife Perfexion® treatment system (Elekta, Stockholm, Sweden). Patients underwent stereotactic head frame placement followed by contrast MRI or a double contrast MRI on the morning of SRS treatment. All treatment plans were reviewed in the treatment planning software by a neurosurgeon, radiation oncologist, and medical physicist before determination of dose and treatment initiation. In the definitive treatment setting, a gross tumor volume (GTV) encompassed all gross disease seen on imaging and no additional margin was given for clinical target volume (CTV) or planning target volume (PTV). In the adjuvant setting, CTV constituted the postoperative surgical cavity plus postoperative enhancement; no additional margin was given for PTV. Doses were determined by radiation oncologist and the neurosurgeon. Lesions ≤ 2.0 cm were commonly prescribed a maximal dose of 20 Gy, resection cavities were routinely prescribed 16 Gy per our institutional practice and other doses were determined using the Radiation Therapy Oncology Group (RTOG) 90-05 parameters [7]. All treatment doses were prescribed to the 50% isodose line.
Follow Up
All patients were clinically followed with a physical exam and an MRI in 1-3 months after SRS and every 3-6 months thereafter until lost to follow up or clinically indicated. Response to treatment was assessed using the response assessment criteria for brain metastases (RANO-BM) [11]. Treated lesions were defined as having local recurrence (LR) or not and no distinction was made between stable disease, partial response or complete response. LR for treated intact lesion was defined as ≥ 20% increase in the sum of the longest distance relative to the nadir. For treated resection cavity, LR was defined as nodular enhancement within the resection cavity that progressed in size on serial MRIs and was consistent with recurrence per neuroradiology review with incorporation of perfusion MRI assessment. If patients had multiple lesions treated, LR was registered if any of the treated sites recurred. Distant brain metastases (DBM) was defined as new metastatic lesions in the brain parenchyma outside the area of the surgical cavity or treatment site. Information on death was retrieved from patient’s chart and death registries and determined as due to neurologic or systemic complications. This was based on an evaluation of several criteria, including the patient’s neurologic and systemic status, radiologic findings and clinician’s note at the time of death.
Statistical Analysis
Categorical variables were summarized by frequencies and percentages, while continuous variables were summarized by means, standard deviations, standard errors, medians, and interquartile ranges. Time to event analyses were measured from the date of SRS. Six months and 1-year rate of LC and OS were calculated using Kaplan-Meier estimates. In initial modeling, separate tumor primary sites were considered. However, there were too few observations in each site other than in colon for their parameters to be estimated separately, and in a revised model colon versus other primary sites was considered. Multivariate analysis using proportional hazards regression was done to determine prognostic factors that affect LC and OS. All clinically relevant variables were fit in the model. Summary statistics, Kaplan-Meier estimates and Cox proportional hazard models were all conducted in SAS v9.4.
Results
From 2000 to 2016, a total of 79 patients underwent SRS for brain metastasis from GI primary sites. Twenty-three patients did not have follow-up MRI and three additional patients did not have sufficient SRS information and were excluded from this study. Fifty-three patients met all the criteria and were included in the analysis. A total of 110 lesions were treated with SRS during the first course of treatment. Twelve patients underwent second course of SRS and three patients underwent SRS for the third time for treatment of recurrent or new BM. Altogether, a total of 148 lesions were treated with SRS. The characteristics of the patients are shown in Table 1. The median age at the time of SRS was 60 years (range, 21–84). Majority of the patients (47, 88.7%) presented with neurological symptoms that led to the diagnosis of BM. Majority of the patients (39, 73.6%) also had systemic metastatic disease at the time of diagnosis of BM. The median Karnofsky Performance Status (KPS) was 90 (range 70-100).
Table 1.
Patient characteristics (N =53)
| Characteristics | N (%) |
| Age | |
| Median | 60 |
| Range | 21-84 |
| Sex | |
| Male | 31(58.5) |
| Female | 22 (41.5) |
| Neurologic Symptoms at the time of brain metastasis | |
| Yes | 47 (88.7) |
| No | 6 (11.3) |
| Systemic disease | |
| Yes | 39 (73.6) |
| No | 14 (26.4) |
| Karnofsky Performance Status (KPS) | |
| Median | 90 |
| Range | 70-100 |
Table 2 shows tumor characteristics. The most common primary tumor site was colon (N=25; 47.1%). All except two patients had tumors with adenocarcinoma histology. Most of the patients (88.6%) had supratentorial metastasis. The median time from initial diagnosis to detection of CNS metastases was 19 months (range 0-191). Table 3 lists treatment details for BM. Six patients had undergone WBRT prior to SRS with a median dose of 30 Gy. Forty-five lesions were surgically removed, and SRS was given as an adjuvant treatment to the cavity. The median maximal preoperative lesion size was 3 cm (range 1.3-5.5 cm). One hundred and three lesions received SRS as definitive treatment. The median SRS dose was 18 Gy (range 10-20Gy) and a median of 2 lesions were treated with SRS (range 1-13). The median time interval between first and second course of SRS was 8 months (range 2-25.5m).
Table 3.
Treatment details for brain metastasis (patient, N=53, brain lesions, n=148)
| Prior WBRT (N=53) | |
| Yes | 6(11.3%) |
| No | 47(88.7%) |
| Average dose of prior WBRT (Gy) | 27.2 |
| Brain lesions treated with SRS | 148 |
| Median | 2 |
| Range | 1–13 |
| Dose of SRS (Gy) | |
| Median | 18 |
| Range | 10–20 |
| Intent of SRS (n=148) | |
| Definitive | 103(70%) |
| adjuvant | 45(30%) |
| SRS (patients, N=53) | |
| First course | 53 |
| Second Course | 12 |
| Third Course | 3 |
| Interval between first and second course of SRS (m) | |
| Median | 8 |
| No | 2–25.5 |
| Size of resected lesions (cm) | |
| Median | 3 |
| Range | 1.3–5.5 |
SRS: stereotactic radiosurgery; WBRT: whole brain radiation therapy
Table 2.
Tumor characteristics (N =53)
| Characteristics | N (%) |
| Gastrointestinal (GI) primary sites | |
| Colon | 25 (47.1) |
| Esophagus | 9 (17) |
| Rectum | 6(11.3) |
| Stomach | 5(9.4) |
| Liver | 3(5.7) |
| Pancreas | 3(5.7) |
| Bile Duct | 1(1.9) |
| Gallbladder | 1(1.9) |
| Histology | |
| Adenocarcinoma | 51(96.2) |
| Neuroendocrine | 2(3.8) |
| Tumor Location | |
| Supratentorium | 31(58.5) |
| Infratentorium | 6(11.3) |
| Both | 16(30.2) |
| Time from initial diagnosis to detection of CNS metastases | |
| Median | 19m |
| Range | 0–191m |
Treatment outcomes are listed in Table 4. The median follow-up time from the diagnosis of BM was 6 months (range 1 to 109). At the last MRI, 26 (49%) had new DBM and 12 patients (22.6%) subsequently received salvage WBRT to a median dose of 30 Gy (range 18-35). For those patients receiving salvage WBRT the median time from SRS to WBRT initiation was 4.6 months (range 1.6 – 15). Twenty-seven patients (51%) had no further CNS progression on their last brain MRI. Cause of death was unknown for 24 patients, attributed to intracranial and systemic disease in 9 (17 %) and 18 (34 %) patients respectively. Only 2 patients were alive at the time of this analysis. There were 38 local recurrence events. Local control rate at 6 months was 74.33% (95% CI, 58.2- 85%) and 57.21% (95% CI, 37.6-72.7%) at 12 months (Table 4, Figure 1a). Median survival was 9 months from the time of BM diagnosis. The overall survival at 1 year was 34% (95% CI, 21.4-47%) and 8% (95% CI, 2.5-11.4%) at 3 years (Table 4, Figure 1b). Patients were also classified based on diagnosis specific graded prognostic assessment (ds-GPA) for GI tumors [12]. Majority of patients had higher ds-GPA score. The overall survival at 1 year for patients with ds-GPA 1, 2 and 3 were 14.29%, 11.77% and 35.53% respectively. On multivariate analysis, higher GK dose was a significant predictor of better LC and >10 brain metastasis trended towards poorer LC, p=0.09 (Table 5). For OS, higher KPS and ds-GPA score were significant for improved OS and utilization of salvage WBRT was significant for lower OS on UVA. However, none of the factors were significant on MVA (Table 6).
Table 4.
Treatment outcomes (N =53)
| Follow-up from the time of diagnosis of BM (m) | |
| Median | 6 |
| Range | 1-109 |
| Local recurrence (n=148) | 38 (25.7%) |
| Median time between SRS and LC (m) | 4.2 |
| Range | 1-33.3 |
| Local Control (LC) | |
| at 6 m | 74.33% |
| at 12 m | 57.21% |
| New distant metastasis at last MRI (n=53) | |
| Yes | 26(49%) |
| No | 27(51%) |
| Salvage WBRT | |
| Yes | 12 (22.6) |
| No | 41 (77.4) |
| Time to WBRT after SRS (m) | |
| Median | 4.6 |
| Range | 1.6-15 |
| Overall Survival (OS) | |
| at 1 yr | 34% |
| at 3 yr | 8% |
| OS at 1 year | |
| ds-GPA=1 | 14.29% |
| ds-GPA=2 | 11.77% |
| ds-GPA=3 | 35.53% |
| Cause of Death (n=51) | |
| Neurologic | 9 (17%) |
| Systemic | 18 (34%) |
| Unknown | 24 (45.3%) |
SRS: stereotactic radiosurgery; WBRT: whole brain radiation therapy
Figure 1.
Kaplan-Meier curve showing a) Rate of local control after GK-SRS, b) Overall survival in 53 patients after developing BM from GI primaries
Table 5.
Predictors for Local Control (LC)
| Univariate analysis | Multivariate analysis | |||||
| Variables | HR | 95% CI | P-value | HR | 95% CI | P-value |
| Age> 60 | 0.31 | 0.08–1.15 | 0.08 | 0.88 | 0.36-2.13 | 0.77 |
| Site: colon vs. other | 1.39 | 0.44–4.38 | 0.57 | |||
| KPS >90 | 0.50 | 0.16–1.60 | 0.24 | 4.93 | 0.28-88.41 | 0.29 |
| ds-GPA | 0.41 | 0.14–1.21 | 0.11 | 0.22 | 0.02-2.57 | 0.23 |
| Presence of Systemic mets | 2.08 | 0.56–7.68 | 0.27 | |||
| Time from Ca dx to BM | 1.00 | 0.98–1.02 | 0.78 | |||
| Detection with symptoms | 3.19 | 0.41–24.84 | 0.27 | 0.84 | 0.09-8.30 | 0.88 |
| Prior WBRT | 4.35 | 1.39–13.58 | 0.01 | 1.08 | 0.32-3.62 | 0.90 |
| GK given as definitive | 0.74 | 0.29–1.89 | 0.53 | |||
| GK given as adjuvant | 1.87 | 0.74–4.77 | 0.19 | |||
| GK dose (Gy) | 0.99 | 0.99–1.00 | 0.07 | 0.998 | 0.996-0.99 | 0.008 |
| Number of BM | 0.37 | 0.05–3.10 | 0.36 | 1.39 | 0.56-3.47 | 0.48 |
| 2 vs 10 | 4.48 | 1.30–15.36 | 0.02 | 4.35 | 0.80-23.50 | 0.09 |
| >10 | ||||||
BM: brain metastasis; dx: diagnosis; GK: Gamma Knife; GPA: graded prognostic assessment; KPS: Karnofsky performance status; WBRT: whole brain radiation therapy
Table 6.
Predictors for Overall survival (OS)
| Univariate analysis | Multivariate analysis | |||||
| Variables | HR | 95% CI | P-value | HR | 95% CI | P-value |
| Age> 60 | 1.21 | 0.75-1.95 | 0.44 | |||
| Gender: Male vs. female | 1.36 | 0.83-2.23 | 0.22 | |||
| Site: colon vs. other | 0.63 | 0.38-1.03 | 0.06 | |||
| KPS >90 | 0.28 | 0.16-0.47 | <0.0001 | |||
| ds-GPA | 0.41 | 0.28-0.60 | <0001 | 0.79 | 0.32-1.99 | 0.62 |
| Status of Systemic mets | 0.69 | 0.42-1.13 | 0.14 | |||
| Time from Ca dx to BM | 0.99 | 0.98-1.00 | 0.14 | |||
| Detection with symptoms | 0.73 | 0.18-3.00 | 0.66 | |||
| Prior WBRT | 1.61 | 0.87-3.00 | 0.13 | |||
| GK given as definitive | 1.35 | 0.80-2.30 | 0.26 | |||
| GK given as adjuvant | 0.79 | 0.47-1.32 | 0.36 | |||
| Number of BM | 1.03 | 0.60-1.77 | 0.92 | 2.08 | .96-4.49 | 0.06 |
| 2 vs 10 | 2.05 | 0.97-4.36 | 0.06 | 6.61 | 0.68-64.70 | 0.10 |
| >10 | ||||||
| Salvage WBRT | 2.48 | 1.44-4.28 | 0.001 | 2.10 | 0.86-5.11 | 0.10 |
BM: brain metastasis; dx: diagnosis; GK: Gamma Knife; GPA: graded prognostic assessment; KPS: Karnofsky performance status; WBRT: whole brain radiation therapy
Discussion
The incidence of BM from GI primaries is rare and ranges between 1-4% depending on the primary site [13]. In our current study, we determined the efficacy of SRS in controlling BM from GI cancers at a single institution and attempted to identify prognostic factors for survival. The LC rate in the current series of BM metastasis after SRS either in a definitive or adjuvant setting at 6 months was 74.33% and 57.21% at 12 months. Rates of LC have been reported in the range of 64- 94% in other GI-SRS series [14-17]. The wide range is likely due to variability in patient numbers, primary sites and follow up time. Other studies have found LC rates of 67%-73% at 1 year in patients with 1-4 brain metastasis when all primary sites were included [5, 6, 18]. Our rates appear to be lower than these published reports. Multiple studies have suggested that GI tumors are radioresistent, [19]; furthermore in our study, higher GK dose predicted for better LC. Other studies have also identified SRS dose, treatment with WBRT, active extracranial disease and larger tumor size as significant for LC [15, 16, 20]. Twelve patients underwent a second course of SRS at a median of 8 months and no radiographic radionecrosis was observed. Taken together, SRS is safe and can be used in multiple sessions safely if distant metastases eventually do develop in the brain. Given the observed LC rates and suggestion of a dose response, consideration for dose-escalated approaches should be given to improve LC rates.
The median overall survival was 9 months from the time of BM diagnosis. Other single institution series have reported median survival time ranging between 5.1 9 months for all GI malignancies [14, 15, 17, 21]. The overall survival at 1 year was 34% and only 8% at 3years. Often, patients with BM also have systemic metastatic disease which is a competing risk factor for survival. In our series 73.6% of the patients had systemic metastatic disease at the time of BM disease diagnosis. For the patients whose cause of death was available, 18 (62%) died of complications from systemic diseases. Systemic disease also indicates risk for continued new DBM development and as such, almost half of the patients (49%) in our study had DBM at the time of last follow up MRI. Twelve (22.6%) patients underwent salvage WBRT at a median time of 4.6m. Although higher KPS and GPA score were significant for improved OS and salvage WBRT significant for worse OS on UVA, none of the tested factors were significant on MVA. Page et al identified craniotomy for resection of brain metastasis, an absence of extracranial disease, and prolonged time to distant brain failure as prognostic for improved survival in GI-BM (14). Hasegawa studied 39 patients with BM from GI primaries and only found prior surgical resection as a significant factor on MVA (11). Trifiletti et al studied 86 patients with 261 BM from GI primary and on MVA, higher KPS and luminal primary location were each associated with improved OS (15). Similarly, study by Da Silva et al identified KPS score (≤ 70 vs ≥ 80) as the only significant factor for improved survival (12). The Graded Prognostic Assessment (GPA) classification scheme based on data from five randomized RTOG studies involving brain metastases identified age at diagnosis, presence of extracranial disease, KPS, and number of brain metastasis as being prognostic for survival [12, 22]. As expected, lung cancer consisted of majority of the primary site in this analysis. The diagnosis- specific GPA to estimate survival from BM by primary site grouped all GI cancers together and identified KPS as the only significant prognostic index for survival [12, 23].
There are a number of limitations of this study. First, it is a single institution, retrospective study with relatively limited number of patients. Secondly, given the rarity of the clinical scenario, there is significant heterogeneity in patient population, including a proportion of patients with treatments preceding SRS. This study included all GI primary sites over a lengthy study timeline (2000-2016). Lastly, we have not included details of systemic therapies. During this era of study a number of more effective systemic cancer therapies in GI malignancies have shown promise [24-27], which may limit the applicability of these results to current populations which likely have improving overall oncologic outcomes. However, given the rarity of BM from GI primary sites, this study contributes to the limited repertoire of literature in SRS for BM from GI primaries.
Conclusions
SRS is a safe treatment modality for the treatment of CNS metastases from GI primary. Consideration for dose-escalated approaches may improve LC rates. While the majority of patients were able to avoid WBRT, patients with BM from GI primaries have poor overall oncologic outcomes. The combination of effective systemic treatments and optimal multidisciplinary strategies including SRS for BM control has the potential to affect the clinical outcomes.
Acknowledgments
Authors’ disclosure of potential conflicts of interest
Tim J Kruser has a consulting relationship with Varian Medical Systems Inc., has served on an advisory board for Abbvie Inc, and is a member of the speaker’s bureau for AstraZeneca. Other authors report no conflicts of interest.
Author contributions
Conception and design: Nitika Paudel, Tim J Kruser
Data collection: Nitika Paudel, Liam Kane
Data analysis and interpretation: Irene Helenowski, Nitika Paudel, Tim J Kruser
Manuscript writing: Nitika Paudel
Final approval of manuscript: Sean Sachdev, Orin Bloch, Matthew Tate, James P. Chandler, Tim J Kruser
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