Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non–small cell lung cancer with brain metastases

Charu Singh Department of Neurosurgery, Yale New Haven Hospital, New Haven, Connecticut;

Search for other papers by Charu Singh in
Current site
Google Scholar
PubMed
Close
 MD
,
Jack M. Qian Memorial Sloan Kettering Cancer Center, New York, New York; and

Search for other papers by Jack M. Qian in
Current site
Google Scholar
PubMed
Close
 MD
,
James B. Yu Department of Radiation Oncology, Yale New Haven Hospital, New Haven, Connecticut

Search for other papers by James B. Yu in
Current site
Google Scholar
PubMed
Close
 MD
, and
Veronica L. Chiang Department of Neurosurgery, Yale New Haven Hospital, New Haven, Connecticut;

Search for other papers by Veronica L. Chiang in
Current site
Google Scholar
PubMed
Close
 MD
Full access

OBJECTIVE

Concurrent use of anti-PD-1 therapies with stereotactic radiosurgery (SRS) have been shown to be beneficial for survival and local lesional control in melanoma patients with brain metastases. It is not known, however, if immunotherapy (IT) confers the same outcome advantage in lung cancer patients with brain metastases treated with SRS.

METHODS

The authors retrospectively reviewed 85 non–small cell lung cancer (NSCLC) patients with brain metastases who were treated with SRS between January 2006 and December 2016. Thirty-nine PD-L1 antibody–positive patients received anti-PD-1 therapy with SRS (IT group) and 46 patients received chemotherapy (CT) with SRS (CT group). Results were obtained using chi-square, Kaplan-Meier, and Mann-Whitney U tests and Cox regression analyses.

RESULTS

Median survival following first radiosurgical treatment in the whole study group was 11.6 months (95% CI 8–15.5 months). Median survival times in the IT group and CT group were 10 months (95% CI 8.3–13.2 months) and 11.6 months (95% CI 7.7–15.6 months), respectively (p = 0.23). A Karnofsky Performance Status (KPS) score < 80 (p = 0.001) and lung-specific molecular marker Graded Prognostic Assessment (lungmol GPA) score < 1.5 (p = 0.02) were found to be predictive of worse survival.

Maximal percent lesional shrinkage and time to maximal shrinkage were not significantly different between the CT and IT groups. Of the lesions for which a complete response occurred, 94.8% had pre-SRS volumes < 500 mm3. The amount of lesion shrinkage and time to maximal shrinkage were not different between the IT and CT groups for lesions with volumes < 500 mm3. However, in lesions with volume > 500 mm3, 90% of lesions shrank after radiosurgery in the IT group compared with 47.8% in the CT group (p = 0.001). Median times to initial response and times to maximal shrinkage were faster in the IT group than in the CT group: initial response 49 days (95% CI 33.7–64.3 days) versus 84 days (95% CI 28.1–140 days), p = 0.001; maximal response 105 days (95% CI 59–150 days) versus 182 days (95% CI 119.6–244 days), p = 0.12.

CONCLUSIONS

Unlike patients with melanoma, patients with NSCLC with brain metastases undergoing SRS showed no significant benefit—either in terms of survival or total amount of lesional response—when anti-PD-1 therapies were used. However, in lesions with volume > 500 mm3, combining SRS with IT may result in a faster and better volumetric response which may be particularly beneficial in lesions causing mass effect or located in neurologically critical locations.

ABBREVIATIONS

BrMets = brain metastases; CR = complete response; GK = Gamma Knife; GPA = Graded Prognostic Assessment; IT = immunotherapy; KPS = Karnofsky Performance Status; lungmol GPA = lung-specific molecular marker GPA; NSCLC = non–small cell lung cancer; PD = progressive disease; PR = partial response; RANO-BM = Response Assessment in Neuro-Oncology Brain Metastases; SD = stable disease; SRS = stereotactic radiosurgery; WBRT = whole-brain radiation therapy.

OBJECTIVE

Concurrent use of anti-PD-1 therapies with stereotactic radiosurgery (SRS) have been shown to be beneficial for survival and local lesional control in melanoma patients with brain metastases. It is not known, however, if immunotherapy (IT) confers the same outcome advantage in lung cancer patients with brain metastases treated with SRS.

METHODS

The authors retrospectively reviewed 85 non–small cell lung cancer (NSCLC) patients with brain metastases who were treated with SRS between January 2006 and December 2016. Thirty-nine PD-L1 antibody–positive patients received anti-PD-1 therapy with SRS (IT group) and 46 patients received chemotherapy (CT) with SRS (CT group). Results were obtained using chi-square, Kaplan-Meier, and Mann-Whitney U tests and Cox regression analyses.

RESULTS

Median survival following first radiosurgical treatment in the whole study group was 11.6 months (95% CI 8–15.5 months). Median survival times in the IT group and CT group were 10 months (95% CI 8.3–13.2 months) and 11.6 months (95% CI 7.7–15.6 months), respectively (p = 0.23). A Karnofsky Performance Status (KPS) score < 80 (p = 0.001) and lung-specific molecular marker Graded Prognostic Assessment (lungmol GPA) score < 1.5 (p = 0.02) were found to be predictive of worse survival.

Maximal percent lesional shrinkage and time to maximal shrinkage were not significantly different between the CT and IT groups. Of the lesions for which a complete response occurred, 94.8% had pre-SRS volumes < 500 mm3. The amount of lesion shrinkage and time to maximal shrinkage were not different between the IT and CT groups for lesions with volumes < 500 mm3. However, in lesions with volume > 500 mm3, 90% of lesions shrank after radiosurgery in the IT group compared with 47.8% in the CT group (p = 0.001). Median times to initial response and times to maximal shrinkage were faster in the IT group than in the CT group: initial response 49 days (95% CI 33.7–64.3 days) versus 84 days (95% CI 28.1–140 days), p = 0.001; maximal response 105 days (95% CI 59–150 days) versus 182 days (95% CI 119.6–244 days), p = 0.12.

CONCLUSIONS

Unlike patients with melanoma, patients with NSCLC with brain metastases undergoing SRS showed no significant benefit—either in terms of survival or total amount of lesional response—when anti-PD-1 therapies were used. However, in lesions with volume > 500 mm3, combining SRS with IT may result in a faster and better volumetric response which may be particularly beneficial in lesions causing mass effect or located in neurologically critical locations.

In Brief

The authors compared survival and local CNS lesional control after stereotactic radiosurgery (SRS) in patients with non–small cell lung cancer brain metastases who had received either chemotherapy or immunotherapy. It is important to understand how immunotherapy changes outcomes in patients with brain metastases who undergo SRS treatment.

Non–small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases.12 Approximately 230,000 patients will be diagnosed with lung cancer in 2018. About 20%–40% of these patients will develop brain metastases (BrMets) and 7%–10% will already have BrMets at the time of initial diagnosis.12 Traditionally the treatment for BrMets has included surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). SRS has now emerged as a first-line treatment for BrMets given concerns over neurocognitive decline after WBRT.2,3,6,16

Several immunotherapy (IT) agents are now FDA-approved for treatment of melanoma and NSCLC. While various clinical trials with anti-PD-1 agents have also demonstrated evidence of good response in metastatic melanoma patients with BrMets, the BrMet response rates are only in the range of 30% using IT alone compared with 90%–95% response when combined with SRS.12 Additional benefit has also been seen in both survival and rate of local lesional control in melanoma patients with BrMets when SRS is used concurrently in combination with IT.10,11

IT is rapidly becoming a first-line treatment for NSCLC patients. Only limited data exist, however, to show if IT confers the same outcome advantage in lung cancer patients with BrMets when combined with SRS as has been reported in metastatic melanoma patients.

In this retrospective study we compared survival and response outcomes in NSCLC patients with BrMets treated with both SRS and anti-PD1 therapy during their BrMet treatment course versus those treated with SRS and then chemotherapy (CT) only.

Methods

Patient Population

Institutional review board approval was obtained to retrospectively review the medical records of 85 patients with NSCLC BrMets treated with Gamma Knife (GK) SRS between January 2006 and December 2016. Patients in the IT group all had pathology-proven NSCLC that tested positive for PD-L1. In this group all patients received first-line CT treatment but did not undergo SRS treatment until progression of disease and following initiation of IT. This group was treated with SRS between 2013 and 2016. Targeted therapy clinical trials were initiated in 2010 at our institution, often regardless of EGFR-mutational status. To avoid selection biases in how our patient population was treated systemically, patients in the CT cohort were chosen from the NSCLC patients treated in the 3 years prior to 2010. The CT group therefore included consecutive patients chosen from the pre-IT era and all had never received any IT during their entire treatment course. This CT group was treated with SRS between 2006 and 2009. All patients had to have more than 6 months of imaging follow-up to be included in the study. Demographic data recorded included patient age, sex, KPS, lesion site, number of lesions, previous WBRT, subsequent WBRT, lung-specific molecular marker Graded Prognostic Assessment (lungmol GPA),14 date of death, and date of last follow-up. SRS treatment parameters included tumor volume, margin dose, number of GK sessions, and number of lesions treated per session; the total number of lesions treated and dimensions of the lesions were also recorded.

Gamma Knife

All patients were treated using either the Leksell Perfexion or the ICON (Elekta Medical Systems, Inc.) GK. Prescription doses were determined using standardized institutional modifications of Radiation Therapy Oncology Group (RTOG) 90-05 dosing recommendations based on tumor volume and radioresistance, number of metastases, and history of prior WBRT.5,13 T1-weighted, gadolinium-enhanced MRI of the whole brain was obtained on the day of SRS treatment and at each follow-up.

Follow-Up

Time from first SRS treatment to death or last follow-up was used to calculate survival. Follow-up MRIs were obtained at 1.5, 3, 6, 9, and 12 months and lesional volumes were calculated at all available time points. To determine lesion response, the maximal diameter of the T1 contrast-enhancing portion of each SRS-treated lesion was measured in 3 orthogonal planes at the time of treatment and at each follow-up. Lesion volumes were calculated with the formula (length × width × height)/2 as previously published.8 Volume changes at each follow-up were normalized to the baseline treatment volume. Response to SRS was defined as volume decrease of 65% or greater. Time to response was defined as time from SRS to time point at which lesion volume decreased > 65%, per the criteria of the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group. RANO-BM criteria were used to define complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). PD was defined as an increase of > 20% in the longest diameter as compared to the initially treated tumor.7

Statistical Analysis

Statistical analysis was performed using SPSS software. Chi-square (for categorical variables) and Mann-Whitney U (for continuous variables) tests were used to compare patient and treatment characteristics and lesional outcomes between cohorts. Kaplan-Meier analysis and Cox regression tests were used to estimate overall survival per patient from the time of first SRS treatment, and the log-rank test was used to compare median survival between groups. Univariate and multivariate analyses were performed to determine if patient and treatment variables correlated with survival in each cohort. A p value < 0.05 was considered significant.

Results

Patient Characteristics

A total of 85 patients with 531 lesions treated with SRS were included in the study. Thirty-nine patients received IT (IT group) and 46 patients received CT (CT group). Median patient age was 62.4 years (range 28–88 years), 61.8 years in the IT group and 62.5 years in the CT group (p = 0.8); 58.8% of patients were female. Median Karnofsky Performance Status (KPS) score was 80 in the IT group and 90 in the CT group. The median lungmol GPA score was 1.5 in the IT group and 2 in the CT group (p = 0.001). The median follow-up was 12 months (range 6 months–11 years). The IT group consisted of 72.5% patients with adenocarcinoma; 15% with squamous cell carcinoma, 7.5% with poorly differentiated carcinoma, and 2.5% with adenosquamous carcinoma. In the CT group, 63% of patients had adenocarcinoma, 6.5% squamous cell carcinoma, 2% undifferentiated carcinoma, and 4% poorly differentiated carcinoma. Twenty-five patients (29.1%) had received prior WBRT (6 in the IT group and 19 in the CT group, p = 0.007) and 12 patients had WBRT after SRS (7 in the IT group and 5 in the CT group, p = 0.37).

SRS Treatment Parameters

A total of 531 lesions were treated with SRS in this study, 356 in the IT group and 175 in the CT group. Only 466 of the 531 treated lesions had > 6 months of imaging follow-up available and therefore 65 lesions (without adequate follow-up) were removed from the analysis, leaving 291 lesions for analysis in the IT group and 175 in the CT group. Median number of lesions treated per GK session was 10 for the IT group and 4 for the CT group (p = 0.009). Median cumulative treated volume in the CT group was 2240 mm3 (range 45–18,305 mm3) and in the IT group was 1440 mm3 (range 25–27,475 mm3). The difference in cumulative treated volume was not statistically significant between the two groups (p = 0.27). Median number of GK sessions per patient was 1 in both groups (range 1–4). Median tumor volume overall was 89.4 mm3 (equivalent diameter 6 mm, volume range 2–16,368 mm3, diameter range 1–35 mm) and was similar in both the groups (IT group 105.5 mm3, CT group 74.13 mm3, p = 0.131). Median marginal dose prescribed was 18 Gy (range 12–24 Gy) in both groups (Table 1).

TABLE 1.

Patient characteristics and treatment parameters

Patient CharacteristicIT Group (n = 39)CT Group (n = 46)p Value
Age in yrs61.9 (28–87.5)62.5 (31.8–79.4)0.8
Sex0.08
 Male12 (30.7%)23 (50%)
 Female27 (69.2%)23 (50%)
Deceased at last follow-up87.2%95.7%0.2
Pretreatment KPS score80 (50–100)90 (60–100)0.06
Lungmol GPA score1.5 (0–3)2 (0.5–3)0.001
Prior WBRT6 (15.4%)19 (41.3)0.007
SRS-treated lesions3561750.001
Lesions per GK treatment10 (1–20)4 (1–13)0.009
Lesion size105.5 mm3 (4.4–9654.9 mm3)74.13 mm3 (2–16,368 mm3)0.13
Marginal dose18 Gy (12–24 Gy)18 Gy (12–24 Gy)0.15
GK sessions1 (1–4)1 (1–3)
Immunotherapy type (no. of patients)Nivolumab (20), pembrolizumab (14), ipilimumab/nivolumab (4), atezolimumab (1)

Values are presented as number (%) or median (range) unless otherwise indicated.

Immunotherapy

Of the 39 patients treated with IT, 20 received nivolumab, 13 received pembrolizumab 10 mg/kg, 1 received pembrolizumab 2 mg/kg, 4 received combination ipilimumab/nivolumab, and 1 patient received atezolizumab.

Survival

Median survival following SRS in the whole study group was 11.6 months (95% CI 8–15.5 months). Median survival in the IT group was 10 months (95% CI 8.3–13.2 months) and in the CT group was 11.6 months (95% CI 7.7–15.6 months, p = 0.23) (Fig. 1). Karnofsky Performance Status (KPS) score of < 80 (p = 0.001) and lungmol GPA score < 1.5 (p = 0.02) were found to be predictive of worse survival on both univariate and multivariate analysis. Survival was not significantly associated with patient age, patient sex, tumor volume, prior WBRT, SRS dose or timing (concurrent vs nonconcurrent treatment), and type of IT relative to SRS. Median survival in patients who had concurrent IT (IT within 4 weeks of GK) was 290 days (10 months), range 177–754 days (6 months–2.1 years) versus 364 days (12.1 months), range 179–2251 days (6 months–6.2 years) for nonconcurrent IT.

FIG. 1.
FIG. 1.

Kaplan-Meier survival curve. Cum = cumulative. Figure is available in color online only.

Rate of progression of systemic disease at time of last follow-up was not significantly different between the two groups (77% in the IT group vs 67% in the CT group). Four patients (10.2%) in the IT group and 5 patients (10.9%) in the CT group had a primarily neurological cause of death.

Response Analysis

Of the 466 lesions that had imaging follow-up, 226 lesions (48.5%) had a CR as defined by RANO-BM criteria,8 184 (39.5%) had a PR, 41 (8.8%) remained stable (SD), and 15 lesions (3.2%) progressed after treatment (PD).

When lesions were subdivided by systemic therapy groups, there was no statistical difference between the percentages of lesions achieving CR: 132 (45.4%) in the IT group and 94 (53.7%) in the CT group (Table 2). Similarly, an equivalent number of lesions progressed (PD) despite SRS: 9 lesions in the IT group (3.1%) and 6 in the CT group (3.4%), p = 0.9. In contrast, PR was achieved in 144 lesions (49.5%) in the IT group compared with only 40 (23%) in the CT group (p = 0.006), and SD was achieved in 6 lesions (1.5%) in the IT group compared with 35 (20%) in the CT group (p = 0.001).

TABLE 2.

Local response to SRS subdivided by systemic therapy

Total (n = 466)IT Group (n = 291)CT Group (n = 175)p Value
CR226 (48.5%)132 (45.4%)94 (53.7%)0.47
PR184 (39.5%)144 (49.5%)40 (23%)0.006
SD41 (8.8%)6 (1.5%)35 (20%)0.001
PD15 (3.2%)9 (3.1%)6 (3.4%)0.9

Median maximal percent volume shrinkage in responding lesions (CR and PR) was 96.6% (65.1%–100%) in the IT group and 97.5% (65.7%–100%) in the CT group at the last follow-up. Time to start of shrinkage and time to maximal shrinkage were also not significantly different between the groups: 6-week median volume shrinkage 68.9% in the CT group versus 73.2% in the IT group (p = 0.56) and 3-month median volume shrinkage 92.6% in the IT group versus 92% the CT group (p = 0.7).

Analysis of timing of IT relative to SRS showed that 167 lesions were treated with concurrent IT (defined as receiving IT within 4 weeks of SRS) and 124 lesions with nonconcurrent IT. Again, no difference was found in the percentage of lesions achieving CR and PR between the 2 groups: 94.6% lesions concurrent versus 94.4% nonconcurrent (p = 0.5). Time to initial response, however, was faster (p = 0.04) in concurrent versus nonconcurrent IT (76 days [range 69–83 days] vs 126 days [100–152 days]).

Further subanalysis was performed to determine factors that might contribute to lesions achieving CR versus PR versus SD response. Median volume of lesions achieving CR in both the cohorts was 40.6 mm3 (range 2–2036 mm3, median equivalent diameter 4 mm), whereas volume in those that achieved PR or SD was 303.12 mm3 (range 3–16,368 mm3, median equivalent diameter 9 mm) (p = 0.001). Graphical distribution of volumes revealed that 94.8% (220/226) of lesions that achieved CR were < 500 mm3 and 24% of IT lesions and 26% of CT lesions were > 500 mm3 in volume. Stratifying by volume independent of systemic therapy, time to maximal shrinkage was not different between the IT and CT groups for lesions with volumes < 500 mm3. However, in lesions with volume > 500 mm3, 4.3% achieved CR, 85.7% achieved PR, and 1.4% remained stable after SRS in the IT group compared with 6.5%, 41.3%, and 41.3% achieving CR, PR, and SD, respectively, in the CT group (Table 3). For CR and PR lesions taken together, 90% of lesions > 500 mm3 shrank after SRS and IT compared with only 47.8% after SRS and CT. This difference in response was statistically significant (p = 0.001). In addition, median time to initial response and time to maximal shrinkage was faster in the IT group than the CT group (initial response 49 days [95% CI 33.7–64.3 days] vs 84 days [95% CI 28.1–140 days], p = 0.001; maximal response 105 days [95% CI 59–150 days] vs 182 days [119.6–244 days], p = 0.12) (Fig. 2).

TABLE 3.

Local response in lesions > 500 mm3

Total (n = 116)IT Group (n = 70)CT Group (n = 46)p Value
CR6 (5.2%)3 (4.3%)3 (6.5%)
PR79 (68.1%)60 (85.7%)19 (41.3%)0.001
SD20 (17.2%)1 (1.4%)19 (41.3%)0.001
PD11 (9.5%)6 (8.6%)5 (10.8%)
FIG. 2.
FIG. 2.

Time to response for lesions > 500 mm3. IT median time 49 days (95% CI 33.7–64.3 days); CT median time 84 days (95% CI 28.11–140 days) (p = 0.001). Figure is available in color online only.

Steroid Use

Data on steroid use was only available for 20 of 46 patients in the CT group. Of these 20 patients, 6 were not treated with any steroids around the time of their SRS. Of the remaining 14 patients, median time to wean off steroids was 21 days (range 12–30 days). Median total dose of dexamethasone used was 168 mg (range 56–240 mg). In comparison, only 8 of the 39 patients in the IT group were treated with steroids around the time of SRS. Median time to weaning off steroids in these patients was also 21 days (range 7–111 days) and median total dose of dexamethasone was 126 mg (range 28–448 mg). No statistically significant difference was found between the two groups for steroid use.

Toxicity

Progression analysis was divided into local and distant progression. Local progression was defined as any lesion growing after radiosurgery to > 20% above its original treatment volume. Causes of local progression were then subdivided into cases of true progression (due to tumor growth) versus radiation necrosis (demonstrated in all cases by histopathology or resolving transient imaging changes). Median time to local failure due to true progression was not significantly different between the CT and IT groups (6.4 months vs 3.6 months, p = 0.74). Time to distant failure was also not significantly different between the two groups (CT 6.17 months vs IT 4.67 months, p = 0.086). Overall progression-free survival based on local true progression and distant progression was 5.23 months in the IT group and 6.7 months in the CT group (p = 0.064).

Four patients (10.2%) in the IT group developed radiation necrosis compared with 5 patients (10%) in the CT group (p = 0.7). Median time to development of radiation necrosis was 18 months across all patients (range 9–70 months, 11.7 months in the IT group and 29.6 months in the CT group, p = 0.9). Of the 9 patients, 6 were treated with steroids alone and the necrosis resolved without intervention, 2 patients required treatment with laser interstitial thermal therapy (LITT), and 1 patient required resection. Median survival in these patients who developed radiation necrosis was 2.4 years (6 months to 11 years).

Discussion

Among the many cancer types, metastatic melanoma was the first for which IT was found to be successful in conferring significant patient survival benefit. With the adoption of IT as a first-line treatment for melanoma patients, evidence was also seen of a beneficial effect in patients with BrMets. Several studies have shown not only a beneficial interaction between IT and SRS in the local control of melanoma BrMets, but also an association of this combination with an overall improvement in survival.10

Immunotherapies have also more recently profoundly changed the treatment of patients with advanced lung cancer. Meta-analysis of published studies shows significantly improved progression-free survival and improved overall survival in lung cancer patients.1 In addition, an increasing number of preclinical and phase II studies have suggested that treatments using combinations of radiotherapy and immunoregulatory agents have demonstrated improved durable systemic antitumor immune responses that may lead to abscopal-like responses in some patients, especially when radiotherapy is delivered in single high-dose regimens.15 To our knowledge, however, no reports exist in the literature regarding whether IT confers the same beneficial interaction with radiotherapy in lung cancer patients with BrMets. This study was therefore performed to determine if similar benefit might be found in patients with lung cancer BrMets treated with radiosurgery and IT compared with those treated with radiosurgery and CT. In order to remove the possible confounding effect of IT alone in improving survival, patients who received both CT and IT during their treatment course for brain metastasis were not studied.

This study shows that, overall, the combination of radiosurgery and IT did not improve overall survival in NSCLC patients. Higher pretreatment KPS score was the only factor associated with improved survival. In addition, IT did not improve overall brain metastasis response to radiosurgical treatment. With stratification by lesion size, however, radiosurgery in combination with IT (especially if delivered concurrently) was found to result in faster lesional response and higher percentage of shrinkage in lesions with treatment volumes > 500 mm3.

Median survival after SRS for patients treated with IT and radiosurgery was 10 months in this study. This length of survival is similar to that reported by Pike et al. (2017)9 but is significantly shorter than that reported by Chen et al. (2018).4 In the study by Pike et al. patients received both WBRT and radiosurgery for treatment of BrMets.9 While there appeared to be an initial benefit to the addition of radiation to IT, subsequent analysis using time-dependent covariates did not support this conclusion. Median survival after radiation for the lung cancer subgroup in their study was 18 months compared with 52 months for their melanoma group, suggesting that the benefit seen in melanoma is not translated into lung cancer patients.9 In comparison, Chen et al. reported that in patients treated with radiosurgery for BrMets, the concurrent use of IT increased median survival from 12.9 and 14.5 months in patients who received no or nonconcurrent IT to 24.7 months in those who received concurrent IT.4 All cohorts in this study, however, included a combination of patients with lung cancer, renal cell cancer, or melanoma, and no lung cancer–specific data were reported. Similar to our study, in these previous studies there are no clear data to suggest that IT (whether concurrent or nonconcurrent) confers a survival advantage in patients with lung cancer BrMets.

Our study does suggest, however, that although the total volumetric response to radiosurgery is also not improved by IT, the response to radiosurgery can be improved by IT in lesions with volumes > 500 mm3 (equivalent to lesion diameter of 10 mm). In the IT group, SRS treatment of these larger lesions resulted in 90% of the lesions shrinking after radiosurgery (combined complete and partial response) and 1.4% remaining as SD compared with only 47.8% shrinking and 41.3% remaining as SD in the CT group. In addition, median time to the start of shrinkage and time to maximal shrinkage was also shorter in the IT group (initial response 49 vs 84 days and maximal response 105 vs 182 days). Unfortunately, steroid use data were not available for comparison in the CT group and so the clinical significance of this finding remains unclear at this time.

Interestingly, 94.8% of lesions achieving complete response had volumes of ≤ 500 mm3 regardless of systemic therapy. Wolf et al. (2018) have previously reported that with the use of SRS alone, 100% local control could be obtained in BrMets that were > 6 mm in diameter, with an increasing rate of failure as lesional diameter increased.16 It is possible then that the same finding may be corroborated in the present study, in which SRS treatment of lesions with median diameters of 4 mm resulted in CR, whereas in those with median diameters of 9 mm resulted more often in PR or SD.

The findings in this study could be limited by several factors. First, this is a retrospective study and therefore while the demographic characteristics seemed to be the same between the two groups, the CT group was clearly derived from a chronologically separate time and therefore treatment paradigms may not be completely comparable. In addition, there was no standardization of timing of CT and IT relative to radiosurgery. Second, the indications for use of radiosurgery within this single institution seem to have changed. Not only were the median KPS and lungmol GPA scores lower in the IT group, but in addition, more patients had received WBRT prior to SRS in the CT group and a significantly larger number of lesions were being treated at each SRS session per patient in the IT group. It is possible then that the expected survival of the IT group might have been worse than the CT group at the time of SRS and therefore this masked any improved outcome in this group. Last, the number of patients in the study is small and a larger, multicentered study would help confirm these findings.

Conclusions

Unlike IT treatment in melanoma patients with BrMets, IT in NSCLC patients was not found in this study to improve overall survival or overall local control of BrMets. Analysis of time to response does, however, suggest that IT may improve the response of BrMets to SRS lesions with volumes > 500 mm3. Further studies are required to confirm these findings.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Chiang, Yu. Acquisition of data: Singh, Qian. Analysis and interpretation of data: Singh. Drafting the article: Singh. Critically revising the article: Chiang, Yu. Statistical analysis: Singh. Administrative/technical/material support: Chiang, Yu. Study supervision: Chiang, Yu.

Supplemental Information

Previous Presentations

Portions of this work were presented at the 19th Leksell Gamma Knife Society Meeting, Dubai, UAE, March 5–7, 2018.

References

  • 1

    Anichini A, Tassi E, Grazia G, Mortarini R: The non-small cell lung cancer immune landscape: emerging complexity, prognostic relevance and prospective significance in the context of immunotherapy. Cancer Immunol Immunother 67:10111022, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al.: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:24832491, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al.: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:10371044, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Chen L, Douglass J, Kleinberg L, Ye X, Marciscano AE, Forde PM, et al.: Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int J Radiat Oncol Biol Phys 100:916925, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Colaco RJ, Yu JB, Bond JS, Bindra RS, Contessa JN, Knisely JPS, et al.: A contemporary dose selection algorithm for stereotactic radiosurgery in the treatment of brain metastases—an initial report. J Radiosurg SBRT 4:4352, 2016

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al.: Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 29:134141, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al.: Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 16:e270e278, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Patel TR, McHugh BJ, Bi WL, Minja FJ, Knisely JP, Chiang VL: A comprehensive review of MR imaging changes following radiosurgery to 500 brain metastases. AJNR Am J Neuroradiol 32:18851892, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Pike LRG, Bang A, Ott P, Balboni T, Taylor A, Catalano P, et al.: Radiation and PD-1 inhibition: favorable outcomes after brain-directed radiation. Radiother Oncol 124:98103, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Qian JM, Yu JB, Kluger HM, Chiang VL: Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer 122:30513058, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Rahman R, Cortes A, Niemierko A, Oh KS, Flaherty KT, Lawrence DP, et al.: The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity. J Neurooncol 138:299306, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Schuette W: Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer 45 (Suppl 2):S253S257, 2004

  • 13

    Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, et al.: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291298, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W: A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70:510514, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Walshaw RC, Honeychurch J, Illidge TM: Stereotactic ablative radiotherapy and immunotherapy combinations: turning the future into systemic therapy? Br J Radiol 89:20160472, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Wolf A, Kvint S, Chachoua A, Pavlick A, Wilson M, Donahue B, et al.: Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery. J Neurosurg 128:2331, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand

Image from Ryu et al. (pp 442–455).

  • FIG. 1.

    Kaplan-Meier survival curve. Cum = cumulative. Figure is available in color online only.

  • FIG. 2.

    Time to response for lesions > 500 mm3. IT median time 49 days (95% CI 33.7–64.3 days); CT median time 84 days (95% CI 28.11–140 days) (p = 0.001). Figure is available in color online only.

  • 1

    Anichini A, Tassi E, Grazia G, Mortarini R: The non-small cell lung cancer immune landscape: emerging complexity, prognostic relevance and prospective significance in the context of immunotherapy. Cancer Immunol Immunother 67:10111022, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al.: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:24832491, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al.: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:10371044, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Chen L, Douglass J, Kleinberg L, Ye X, Marciscano AE, Forde PM, et al.: Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int J Radiat Oncol Biol Phys 100:916925, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Colaco RJ, Yu JB, Bond JS, Bindra RS, Contessa JN, Knisely JPS, et al.: A contemporary dose selection algorithm for stereotactic radiosurgery in the treatment of brain metastases—an initial report. J Radiosurg SBRT 4:4352, 2016

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al.: Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 29:134141, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al.: Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 16:e270e278, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Patel TR, McHugh BJ, Bi WL, Minja FJ, Knisely JP, Chiang VL: A comprehensive review of MR imaging changes following radiosurgery to 500 brain metastases. AJNR Am J Neuroradiol 32:18851892, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Pike LRG, Bang A, Ott P, Balboni T, Taylor A, Catalano P, et al.: Radiation and PD-1 inhibition: favorable outcomes after brain-directed radiation. Radiother Oncol 124:98103, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Qian JM, Yu JB, Kluger HM, Chiang VL: Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer 122:30513058, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Rahman R, Cortes A, Niemierko A, Oh KS, Flaherty KT, Lawrence DP, et al.: The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity. J Neurooncol 138:299306, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Schuette W: Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer 45 (Suppl 2):S253S257, 2004

  • 13

    Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, et al.: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291298, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W: A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70:510514, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Walshaw RC, Honeychurch J, Illidge TM: Stereotactic ablative radiotherapy and immunotherapy combinations: turning the future into systemic therapy? Br J Radiol 89:20160472, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Wolf A, Kvint S, Chachoua A, Pavlick A, Wilson M, Donahue B, et al.: Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery. J Neurosurg 128:2331, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 3399 236 0
Full Text Views 691 298 53
PDF Downloads 585 166 21
EPUB Downloads 0 0 0