The Optimal Dose Fractionation Schema for Malignant Extradural Spinal Cord Compression

Surgical Management of MESCC

A multi-institutional, randomized control trial by Patchell et al^[12] randomized 101 patients with magnetic resonance imaging–confirmed MESCC (cauda equina lesions excluded) to receive decompressive surgical resection with radiation 14 days later or radiation (RT) alone of 30 Gy in 10 fraction treatments. All patients were directed to receive dexamethasone 100 mg bolus + 96 mg daily (dose reduced for patients with relative contraindications to high-dose steroids). Patients were stratified by institution, tumor type, ambulatory status, and spinal stability; 38% of accrued patients had spinal instability.

The authors reported that patients undergoing surgery in addition to radiotherapy (30 Gy/10) were more likely to retain or maintain their ambulatory status longer compared to patients receiving radiotherapy alone (84% vs. 57%, P = 0.001). In addition, patients assigned to the combined-modality arm experienced a longer period of ambulation (122 vs. 13 days, P = 0.003), urinary continence (74% vs. 57%, P = 0.005), duration of continence (median 157 vs. 17 days, P = 0.016), and functional status (maintenance of Frankel and American Spinal Injury Association scores, P = 0.001). There was a difference in survival favoring the combined-modality arm (median 126 vs. 100 days, P = 0.033).

Surgery is associated with significant morbidity, which needs to be considered when deciding between surgery and radiation for medically operable patients with a single area of compression and no spinal instability or bony compression. Minimally-invasive techniques may decrease the morbidity of the procedure, shorten the recovery period, and maintain the procedure's efficacy.^[13] Despite this, it would be reasonable to select patients for surgery who have the longest life expectancy (groups D and E of the MESCC prognostic scale).^[10]

Within two weeks of surgery, patients should have postoperative RT of 30 Gy in 10 fractions, per the Patchell et al trial.^[12]

Optimal Dose Fractionation Schedule

Poor-Prognosis Patients

Maranzano and colleagues^{[6] and [7]} have conducted and reported two randomized control trials addressing the question of a dose fractionation schedule for poor prognosis patients. These patients were defined as having poor-histology tumors (melanoma or lung, sarcoma, gastrointestinal, head and neck, or kidney) or good-histology tumors with any functional impairment or poor performance status. It may be reasonable to extrapolate the results of these trials to the MESCC prognosis groups A, B, and C.^[10]

The first study, reported in 2005, randomized 300 patients 1:1 to a split course of radiation (15 Gy in three fractions, 4-day break, then 15 Gy in five fractions) or hypofractionated radiotherapy (8 Gy in two fractions, one week apart).^[6] All patients were given dexamethasone 16 mg daily during RT, tapered off posttreatment. Patients were assessed for ability to ambulate (with/without assistance), duration of ambulation, bladder function, OS, toxicity, and pain relief. There were 276 analyzable patients, and the median follow-up (presumably of survivors) was 33 months. There were no significant differences in any of these outcomes (Table 3).

The Italian group's second study, reported in 2009, randomized 327 poor-prognosis patients (as above) to 16 Gy in two fractions over one week vs. 8 Gy for one fraction.^[7] Dexamethasone 16 mg/day was given to both groups. There were 303 analyzable patients; median follow-up was not reported (but appears to be approximately five months from the Kaplan-Meier plots). Again, no significant differences were reported between the treatment arms for ambulation, duration of ambulation, bladder control, pain response, and OS (see Table 3). Of note, there was a nonsignificant trend toward greater in-field failures favoring the two-fraction arm in this study (2.5% vs. 6.0%, P = 0.12).

Good-Prognosis Patients

For patients who are ineligible for surgery and have a good prognosis for their MESCC, clinical trials are needed to determine the role of dose-escalating RT to improve outcomes.

A prospective, international nonrandomized study of 231 patients (SCORE-1 study) treated with different RT schedules concluded that longer fractionation schemes were predictive of progression-free survival (12 months 72% vs. 55%, P = 0.034) and local control (12 months 77% vs. 61%, P = 0.032) and that the RT schedule held up on a multivariate analysis.^[14] There was no relationship between length of RT scheme and OS or motor status posttreatment. Patients were not selected but tended to be a better-prognosis group than usually reported (median OS five months).

In their retrospective prognostic study, Rades et al^[10] reported that longer fractionation schemes were associated with improved OS. In another prospective study by Rades et al,^[15] 40 Gy in 20 fractions did not improve functional outcomes or ambulatory status compared to 30 Gy in 10 fractions. Confirmation in a prospective randomized control trial should be done to determine whether this is true or whether there are patient selection factors that explain the observations. In sum, there are insufficient data to support dose escalation above 8 Gy in good-prognosis patients.

An international consortium of trialists is running a trial of one vs. multiple fractions of RT (SCORAD) for all prognosis patients; patients should be entered if possible to confirm the benefit of longer vs. shorter fractionation treatments.

Conclusions

MESCC is a dreaded complication of malignancy and, fortunately, not common. Despite many patients being identified early with no or minimal functional losses, their prognosis is poor. A single fraction of 8 Gy is just as effective as multiple fractions for poor-prognosis patients. For good-prognosis patients, surgery and radiation should be considered. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.