Theo Veninga

Background: A previous score predicted death ≤ 2 months following radiotherapy for MSCC. For patients with a high probability of early death, best supportive care was recommended. However, some of these patients may benefit from radiotherapy regarding preservation or improvement of motor function. To identify these patients, an additional score was developed. Methods: Pre-treatment factors plus radiotherapy regimen were retrospectively evaluated for successful treatment (improved motor function or remaining ambulatory without aid) and post-treatment ambulatory status in 545 patients who died ≤ 2 months. Factors included age, interval from tumor diagnosis until MSCC, visceral metastases, further bone metastases, primary tumor type, sex, time developing motor deficits, pre-treatment ambulatory status, and number of affected vertebrae. Factors significant on both multivariable analyses were included in the score (worse outcomes 0 points, better outcomes 1 point). Results: On multivariable analyses, myeloma/lymphoma, time developing motor deficits > 14 days, and pre-treatment ambulatory status were significantly associated with both successful treatment and ambulatory status, affection of 1–2 vertebrae with successful treatment only. On univariable analyses, 1 × 8 and 5 × 4 Gy were not inferior to 5 × 5 Gy and longer-course regimens. Considering the three factors significant for both endpoints, three groups were designed (0, 1, 2–3 points) with treatment success rates of 4%, 15% and 39%, respectively (p < 0.0001), and post-treatment ambulatory rates of 4%, 43% and 86%, respectively (p < 0.0001). Conclusion: This score helps identify patients with MSCC who appear to benefit from palliative radiotherapy in terms of improved motor function or remaining ambulatory in spite of being near end of life.

Local progression-free survival (LPFS = stable or improved motor function/resolution of paraplegia during RT without in-field recurrence following RT) is important when treating metastatic spinal cord compression (MSCC). An instrument to estimate LPFS was created to identify patients appropriately treated with short-course RT instead of longer-course RT plus/minus decompressive surgery. In 686 patients treated with 20 Gy in 5 fractions alone, ten characteristics were retrospectively analyzed for LPFS including age, interval between tumor diagnosis and RT of MSCC, visceral metastases, other bone metastases, primary tumor type, gender, time developing motor deficits, pre-RT gait function, number of vertebrae affected by MSCC, and performance score. Characteristics significantly (p < 0.05) associated with LPFS on multivariate analyses were incorporated in the scoring system. Six-month LPFS rates for significant characteristics were divided by 10, and corresponding points were added. On multivariate analyses, visceral metastases (p < 0.001), tumor type (p = 0.009), time developing motor deficits (p < 0.001) and performance score (p = 0.009) were associated with LPFS and used for the scoring system. Scores for patients ranged between 24 and 35 points. Three groups were designed: 24–28 (A), 29–31 (B) and 32–35 (C) points. Six-month LPFS rates were 46, 69 and 92%, 12-month LPFS rates 46, 63 and 83%. Median survival times were 2 months (61% died within 2 months), 4 months and ≥ 11 months (median not reached). Most group A patients appeared sub-optimally treated with 20 Gy in 5 fractions. Patients with survival prognoses ≤2 months may be considered for best supportive care or single-fraction RT, those with prognoses ≥3 months for longer-course RT plus/minus upfront decompressive surgery. Many group B and most group C patients achieved long-time LPFS and appeared sufficiently treated with 20 Gy in 5 fractions. However, based on previous data, long-term survivors may benefit from longer-course RT.

This study provides separate comparisons of 1 × 8 Gy to 5 × 4 Gy for metastatic epidural spinal cord compression (MESCC) in patients with poor, intermediate and favorable survival prognoses. Patients receiving 1 × 8 Gy were matched to patients receiving 5 × 4 Gy for age, gender, performance status, tumor type, involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MESCC, ambulatory status and time developing motor deficits. From a study including patients with poor (N = 156) or intermediate (N = 86) survival prognoses, subgroup analyses were performed. Furthermore, 232 new patients with favorable prognoses matched the same way were included. In poor prognoses patients, 6-month survival rates were 10% after 1 × 8 Gy and 6% after 5 × 4 Gy (p = 0.38); in-field reRT rates in few patients alive at 6 months were 15 and 2% (p = 0.16). In intermediate prognoses patients, 6-month survival rates were 49% after 1 × 8 Gy and 58% after 5 × 4 Gy (p = 0.30). ReRT rates at 6 months were 23 and 13% (p = 0.25). In favorable prognoses patients, 6-month survival rates were 89% after 1 × 8 Gy and 91% after 5 × 4 Gy. ReRT rates at 6 months were 14 and 3% (p = 0.007). In no subgroup, RT regimen had a significant impact on motor function. Since in patients with poor prognoses, outcomes after 1 × 8 Gy and 5 × 4 Gy were not significantly different, 1 × 8 Gy may be an option. In patients with intermediate prognoses, a trend was found in favor of 5 × 4 Gy. In patients with favorable prognoses, need for in-field reRT was greater after 1 × 8 Gy.

Twelve years ago, a randomized trial demonstrated that a radiosurgery boost added to whole-brain radiotherapy (WBRT) improved intracerebral control (IC) in patients with one to three cerebral metastases. Overall survival (OS) was improved only in the subgroup of patients with a single metastasis but not in the entire cohort. The present study compared both regimens in a different scenario outside a randomized trial. A total of 252 patients with one to three cerebral metastases were included. Eighty-four patients receiving WBRT plus a planned stereotactic boost and 168 patients receiving WBRT alone were individually matched 1:2 for nine factors including fractionation of WBRT, age, gender, performance score, primary tumor, number of cerebral metastases, extracerebral metastases, recursive partitioning analysis class, and time between cancer diagnosis and WBRT. Each group of three patients was required to match for all nine factors. Both groups were compared for IC and OS. IC rates at 6, 12, 18 and 24 months were 88, 71, 45 and 22% after WBRT plus stereotactic boost vs. 75, 48, 38 and 22% after WBRT alone (p = 0.005). OS rates at 6, 12, 18 and 24 months were 76, 53, 32 and 25% after WBRT plus stereotactic boost and 67, 45, 29 and 20% after WBRT alone (p = 0.10). In patients with a single lesion, OS rates were also not significantly different (p = 0.12). Similar to the previous randomized trial from 2004, this matched-pair study showed that a stereotactic boost in addition to WBRT significantly improved IC but not OS.

This matched-pair study was initiated to validate the results of a retrospective study of 186 patients published in 2007 that compared whole-brain irradiation (WBI) alone and radiosurgery (RS) alone for up to three brain metastases. One-hundred-fifty-two patients receiving WBI alone for up to three brain metastases were matched with 152 patients treated with RS of fractionated stereotactic radiotherapy (FSRT) alone 1:1 for each of eight factors (age, gender, Eastern Oncology Cooperative Group (ECOG)-performance score, nature of tumor, brain metastases number, extra-cerebral spread, period from cancer detection to irradiation of brain metastases, and recursive partitioning analysis (RPA)-class. Groups were analyzed regarding intracerebral control (IC) and overall survival (OS). On univariate analysis of IC, type of irradiation did not significantly affect outcomes (p = 0.84). On Cox regression, brain metastases number (p < 0.001), nature of tumor (p < 0.001) and period from cancer detection to irradiation of brain metastases (p = 0.013) were significantly associated with IC. On univariate analysis of OS, type of irradiation showed no significant association with outcomes (p = 0.63). On multivariate analyses, OS was significantly associated with ECOG performance score (p = 0.011), nature of tumor (p = 0.035), brain metastases number (p = 0.048), extra-cerebral spread (p = 0.002) and RPA-class (p < 0.001). In this matched-pair study, RS/FSRT alone was not superior to WBI alone regarding IC and OS. These results can be considered a revision of the findings from our retrospective previous study without matched-pair design, where RS alone resulted in significantly better IC than WBI alone on multivariate analysis.

To investigate the impact of the overall treatment time (OTT) of whole-brain irradiation (WBI) with 10×3 Gy on outcomes in patients with brain metastases. Seventy-three patients who started WBI on Monday (OTT=12 days, including one weekend without irradiation) were compared to 257 patients who began WBI on Tuesday to Friday (OTT=14 days, including two weekends) for intracerebral control and survival. Seven additional factors were analyzed, including age, gender, Karnofsky performance score (KPS), tumor type, number (N) of brain lesions, extracerebral metastases and interval between cancer diagnosis and WBI. On univariate analysis, age (p=0.039), KPS (p<0.001) and N brain metastases (p=0.006) were associated with intracerebral control; OTT had no significant impact (p=0.20). Age (p<0.001), KPS (p<0.001), N brain metastases (p=0.037) and extracerebral metastases (p<0.001) were associated with survival; OTT had no significant impact (p=0.37). OTT (12 vs. 14 days) had no significant impact on outcomes after WBI with 10×3 Gy.

Metastatic spinal cord compression (MSCC) is an oncological emergency. Many elderly patients cannot tolerate intensive treatment and need individual approaches accounting for a patient's remaining lifetime. The goal of the present study was to develop a survival score for elderly prostate cancer patients with MSCC. Nine characteristics were analyzed in 243 patients: age, performance status, interval from prostate cancer diagnosis until MSCC, affected vertebrae, ambulatory status, further bone lesions, visceral metastases, time developing motor deficits, fractionation schedule. Pre-radiotherapy ambulatory status (p<0.001), visceral metastases (p<0.001) and time developing motor deficits (p<0.001) were significant for survival on Cox regression analysis and included in the survival score. Four groups were defined: 9-12, 13-16, 17-19 and 21-23 points. Six-month survival rates were 7%, 28%, 71% and 95%, respectively (p<0.001). The present study identified four groups with different survival probabilities that require treatment strategies with different priorities ranging from symptom control to prolongation of life.

Cancers of unknown primary (CUP) account for about 10% in elderly patients with MESCC. Immediate treatment is indicated. Personalizing treatment for MESCC requires for clear understanding of the patients' survival prognosis. In this case, a tool for estimating survival would be valuable. In 104 elderly CUP patients, nine factors were investigated: age, gender, performance score, number of affected vertebrae, ability to walk at presentation for radiotherapy, additional bone metastases, visceral metastases, time developing motor weakness, radiotherapy program. In multivariate analysis, the ability to walk (p=0.011) and visceral metastases (p<0.001) were associated with survival. The following scores were assigned: unable to walk=0, able to walk=1, visceral metastases=0, no visceral metastases=1. Three groups were formed (0, 1 and 2 points) with 6-month survival rates of 7%, 18% and 73% (p<0.001). This specific tool assists the physician to estimate survival and select for the most suitable radiotherapy program in elderly CUP patients with MESCC.

It is currently not possible to get an approval of our ethics committee for a randomized trial cmparing 5x4 Gy and 10x3 Gy for MSCC that includes patients with favorable survival prognoses. Therefore, this matched-pair study following strict matching criteria was perfomed instead. In this study, 142 receiving 5x4 Gy were retrospectively matched (1:1) to 142 patients receiving 10x3 Gy with respect to ten characteristics. These characteristics included age, gender, performance status, tumor type, involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MSCC, pre-RT ambulatory status, and time developing motor deficits. On multivariate analysis, post-RT motor function was associated with performance status (p < 0.001), tumor type (p < 0.001), and time developing motor deficits (p < 0.001). RT was successful in 76% of patients receiving 5x4 Gy and 69% receiving 10x3 Gy (p = 0.14). Pre.RT ambulatory status showed a strong trend with respect to local control (LC) of MSCC in the multivariate analysis (p = 0.058). 1-year LC rates were 87% after 5x4 Gy and 93% after 10x3 Gy (p = 0.16). On multivariate analysis, survival (OS) was associated with performance score (p < 0.001), visceral metastases (p < 0.001), and pre-RT ambulatory status (p = 0.004). 1-year OS rates were 68% after 5x4 Gy and 73% after 10x3 Gy (p = 0.64). In patients irradiated for MSCC who had favorable survival prognoses, post-RT motor function, LC and OS were not significantly different after 5x4 Gy and after 10x3 Gy.

The present study investigated efficacy and toxicity of re-irradiation for an in-field recurrence of spinal cord compression due to metastasis (SCCM) in elderly patients. Data of 60 patients aged ≥65 years who were irradiated for an in-field recurrence of SCCM were retrospectively analyzed. The fractionation regimen of re-irradiation and eight additional potential prognostic factors were evaluated for motor function. Median time to in-field recurrence was 6 (2-45) months. After re-irradiation, 25 patients (42%) showed improvement of motor function, 28 (47%) no change, and 7 (12%) deterioration. No second in-field recurrences were observed. Post-treatment motor function was not associated with the fractionation regimen. Radiation myelopathy was not observed. The cumulative biologically-effective dose for myelopathy was 80-137 Gy2. Re-irradiation for in-field recurrences of SCCM in elderly patients appears safe and effective. Myelopathy appears unlikely, if the cumulative biologically effective dose is 137 Gy2 or less. The fractionation regimen had no significant impact on motor function.