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Prognostic Factors for Functional Outcome and Survival After Reirradiation for In-Field Recurrences of Metastatic Spinal Cord Compression Dirk Rades, MD1,2 Volker Rudat, MD2 Theo Veninga, MD3 Lukas J. A. Stalpers, Peter J. Hoskin, MD5 Steven E. Schild, MD6
BACKGROUND. The purpose of the current study was to retrospectively investigate clinical outcome and potential prognostic factors after reirradiation (Re-RT) for in-field recurrence of metastatic spinal cord compression (MSCC). MD
4
METHODS. Re-RT with 1 3 8 Gy (n 5 48), 5 3 3 Gy (n 5 29), 5 3 4 Gy (n 5 30), 7 3 3 Gy (n 5 3), 10-12 3 2 Gy (n 5 11), or 17 3 1.8 Gy (n 5 3) was administered to 124 patients. Cumulative biologically effective dose (BED) (first course of RT plus re-RT) ranged from 77.5 Gy2 to 142.6 Gy2, and was 120 Gy2 in 114
1
Department of Radiation Oncology, University Hospital Schleswig-Holstein, Luebeck, Germany. 2
Department of Radiation Oncology, University Medical Center, Hamburg-Eppendorf, Germany. 3
Department of Radiotherapy, Dr. Bernard Verbeeten Institute, Tilburg, Netherlands. 4
Department of Radiotherapy, Academic Medical Center, Amsterdam, Netherlands. 5
Department of Clinical Oncology, Mount Vernon Cancer Center, Northwood, United Kingdom. 6 Department of Radiation Oncology, Mayo Clinic Scottsdale, Scottsdale, Arizona.
(92%) patients. Twelve potential prognostic factors were investigated for associations with motor function and survival.
RESULTS. Motor function improved in 45 (36%) patients, was stable in another 62 (50%) patients, and deteriorated in 17 (14%) patients. Upon multivariate analyses, the effect of Re-RT on motor function was significantly associated with the effect of the first course of RT (P 5 .048), Eastern Cooperative Oncology Group (ECOG) performance status (P 5 .020), time to development of motor deficits before ReRT (P 5 .002), and visceral metastases (P < .001). Survival was associated with ECOG performance status (P < .001), ambulatory status before Re-RT (P < .001), time to development of motor deficits (P 5 .018), and visceral metastases (P < .001). Re-RT dose schedule or cumulative BED had no significant impact on functional outcome or survival. Acute toxicity was mild, and late toxicity, such as radiation myelopathy, was not observed.
CONCLUSIONS. Given the limitations of a retrospective study and the relatively short follow up after Re-RT, spinal reirradiation appeared to be effective and safe when the cumulative BED is 120 Gy2. Motor function after Re-RT was associated with the effect of first irradiation, performance status, time to development of motor deficits, and visceral metastases, whereas the Re-RT schedule had no significant impact. Cancer 2008;113:1090–6. 2008 American Cancer Society.
KEYWORDS: metastatic spinal cord compression, spinal reirradiation, prognostic factors, motor function, survival. This work is dedicated to Professor Rainer Schmidt, PhD, one of the leading radiation physicists in Europe, who had been an outstanding personality and a true friend, and who died unexpectedly on the 13th of February 2008. Address for reprints: Dirk Rades, MD, Department of Radiation Oncology, University Hospital Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany; Fax: (011) 49451-500-3324; E-mail:
[email protected] Received February 25, 2008; revision received April 7, 2008; accepted April 8, 2008.
ª 2008 American Cancer Society
R
adiotherapy (RT) is the most frequently applied treatment for metastatic spinal cord compression (MSCC). Because of improved cancer therapy, which results in better survival rates, cancer patients are more likely to live long enough to develop a recurrence of their disease. In-field recurrence of MSCC can occur in the previously irradiated segment of the spine.1 Many patients with locally recurrent MSCC are not surgical candidates because of poor expected survival, poor performance status, or significant comorbidity.2 Re-irradiation (Re-RT) remains their primary treatment option. However, many radiation oncologists have reservations about implementing spinal Re-RT because of concerns that it may result in
DOI 10.1002/cncr.23702 Published online 18 July 2008 in Wiley InterScience (www.interscience.wiley.com).
Prognostic Factors and Reirradiation/Rades et al
radiation myelopathy and severe neurological dysfunction. The risk of radiation myelopathy depends on the biologically effective dose (BED) delivered to the spinal cord,3-5 which takes into account both the total radiation dose and the dose per fraction. Re-RT of the previously treated spinal cord results in a comparably high cumulative BED (BED of the first course of RT plus BED of the Re-RT). There are only a few clinical studies that have investigated Re-RT for recurrent MSCC. The present study includes the largest series of patients re-irradiated for an in-field recurrence of MSCC. We performed this study in order to define patient clinical outcome and prognostic factors associated with motor function and survival. Prognostic factors may help guide the radiation oncologist to select an appropriate treatment regimen for the individual patient and to choose a proper stratification in future clinical trials.
MATERIALS AND METHODS Of a total of 164 MSCC patients who developed a recurrence of MSCC in the previously irradiated part of the spine, 124 patients were re-irradiated between Janurary 1995 and June 2007 and included in this retrospective study. The first RT was performed either with 1 3 8 Gy, 5 3 4 Gy, 10 3 3 Gy, 15 3 2.5 Gy, or 20 3 2 Gy. The radiation schedules varied with the participating medical center. Patients treated in the Netherlands or in the United Kingdom received short-course radiotherapy with 1 3 8 Gy or 5 3 4 Gy, whereas patients treated in Germany or the United States received longer-course radiotherapy with 10 3 3 Gy, 15 3 2 Gy, or 20 3 2 Gy. Before both first courses of RT and Re-RT, most patients were reviewed by a surgeon who determined the possibility of decompressive surgery for these patients. Surgery in patients who participated in the present study was not performed because the patients did not meet criteria of a study reported by Patchell et al2 or because the data for that study were not available at the time the patients were treated. All 124 patients had motor deficits of the lower extremities at the time of Re-RT due to MSCC of the thoracic or the lumbar spinal cord. Patients with metastases of the cervical spinal cord alone were not included so that we could achieve better study comparability concerning motor deficits of the lower extremities. All but 4 patients had received systemic therapy (chemotherapy and/or hormonal treatment) before Re-RT. Further inclusion criteria were as follows: stable or better motor function after the first course of RT, no previous surgery of the targetted spinal region, confirmation of in-field recurrence by
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TABLE 1 Patient Characteristics Potential Prognostic Factors Age at Re-RT, y 63 64 Sex Women Men Type of primary tumor Breast cancer Prostate cancer Myeloma/Lymphoma Lung cancer Other tumors Effect of first course of RT Improvement No change Time to recurrence, m 6 >6 Ambulatory status before Re-RT Ambulatory Nonambulatory ECOG PS at Re-RT 1-2 3-4 Time to motor deficits before Re-RT, d 1-7 8-14 >14 Visceral metastases at Re-RT No Yes No. of involved vertebrae at Re-RT 1-3 4 Re-RT schedule 1 d (1 3 8 Gy) 1 wk (5 3 3 Gy/5 3 4 Gy) >1 wk (7 3 3 Gy/10-12 3 2 Gy/17 3 1.8 Gy) Cumulative BED 100 Gy2
No. of Patients
Proportion, %
65 59
52 48
46 78
37 63
26 41 11 15 31
21 33 9 12 25
58 66
47 53
65 59
52 48
86 38
69 31
81 43
65 35
26 47 51
21 38 41
53 71
43 57
73 51
59 41
48 59 17
39 48 14
52 42 30
42 34 24
Re-RT indicates reirradiation; ECOG PS, Eastern Cooperative Oncology Group performance score; BED, biologically effective dose.
magnetic resonance imaging, no surgery for in-field recurrence, no history of other neurological disorders that may have led to motor deficits, and dexamethasone treatment at the time of Re-RT. The duration of dexamethasone treatment was strictly correlated with overall treatment time. The patients’ data were retrospectively obtained from the patients’ charts and from interviews with the patients and their general practitioners. Patient characteristics are summarized in Table 1.
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Primary RT and Re-RT were performed with 610 MV photon beams. Radiation doses were prescribed to the depth of the spinal cord and administered by using a direct posterior (PA) field, when the distance between the patient’s surface and the spinal cord was 5.5 cm; or with 2 opposed fields (AP:PA), when the distance between the patient’s surface and the spinal cord was >5.5 cm. The maximal dose to the spinal cord was 112% of the prescribed dose. The treatment volume encompassed 1 to 2 normal vertebrae above and below the metastatic lesions. The following 12 potential prognostic factors were evaluated for possible associations with motor function and survival after Re-RT, age (63 years vs 64 years, median age: 63 years), sex, type of primary tumor (breast cancer vs prostate cancer vs myeloma/lymphoma vs lung cancer vs other tumors), effect of the first course of RT on motor function (improvement vs no change), time to in-field recurrence of MSCC (6 months vs >6 months, with a median time to recurrence of 6 months), ambulatory status before Re-RT (ambulatory vs not ambulatory), Eastern Cooperative Oncology Group performance status (ECOG 1-2 vs ECOG 3-4), time to development of motor deficits before Re-RT (1-7 days vs 8-14 days vs >14 days), presence of visceral metastases at the time of Re-RT (yes vs no), number of involved vertebrae at the time of Re-RT (1-3 vs 4), Re-RT schedule according to the overall treatment time (1 day [1 3 8 Gy]) versus 1 week (5 3 3 Gy or 5 3 4 Gy) versus >1 week (7 3 3 Gy, 10-12 3 2 Gy or 17 3 1.8 Gy), and cumulative (first course of RT plus Re-RT) BED (100 Gy2). Patients treated in the Netherlands or the United Kingdom received a second short-course radiotherapy with 1 3 8 Gy, 5 3 3 Gy, or 5 3 4 Gy, whereas the patients treated in Germany or the US received a second longercourse radiotherapy with an overall treatment time of >1 week. Each series from a participating medical center represented an unselected series of patients who were treated over a certain period of time. The biologically effective dose (BED) can be calculated with the equation BED 5 D 3 [1 1 (d / a/b)], as derived from the linear-quadratic model; D 5 total dose, d 5 dose per fraction, a 5 linear (first-order dose-dependent) component of cell killing, b 5 quadratic (second-order dose dependent) component of cell killing, a/b-ratio 5 the dose at which both components of cell killing are equal.6,7 The a/b-ratio suggested for radiation myelopathy is 2 Gy for the cervical and thoracic spinal cord and 4 Gy for the lumbar spinal cord. We conservatively calculated the BED with an a/b-ratio of 2 Gy with no correction for the possible recovery of tolerance from
the first radiation exposure. The cumulative BED ranged between 77.5 Gy2 and 142.6 Gy2. One has to be aware that the application of the linear-quadratic model may have limitations if the dose per fraction exceeds 6 Gy. However, a reasonable alternative model has not yet been established. Motor function was evaluated before Re-RT, and at 1 month and at 3 months after Re-RT with a scale developed by Tomita et al8 as follows: grade 0, normal strength; grade 1, ambulatory without aid; grade 2, ambulatory with aid; grade 3, not ambulatory; grade 4, paraplegia. Improvement or deterioration of motor function was defined as a change of at least 1 point. Potential prognostic factors were included for possible associations with motor function by means of a multivariate analysis, which was performed with the ordered-logit model. Acute toxicity was evaluated according to US National Cancer Institute (NCI) Common Toxicity Criteria (CTC), and late toxicity was evaluated by using the Radiation Therapy Oncology Group (RTOG) score.9,10 Survival rates were referenced from the end of Re-RT and were calculated with the Kaplan-Meier method.11 The difference between the Kaplan-Meier curves was assessed in a univariate manner with the log-rank test. The prognostic factors found to be significantly (P < .05) associated with survival in the univariate analysis were included in a multivariate analysis performed with the Cox Proportional Hazards model. Multivariate analyses were performed with either ambulatory status or ECOG performance status but not both, as these are directly related and, thus, are confounding variables. An additional competing risk analysis to account for deaths was not performed, as all patients died of their malignant disease.
RESULTS Patients who were still alive at the study’s last followup evaluation were followed until death or from 354 months (median, 11 months). Median follow-up in survivors was 10 months after 1 3 8 Gy of Re-RT, 11 months after 5 3 3 Gy/5 3 4 Gy of Re-RT, and 13 months after longer-course Re-RT (overall treatment time >1 week), respectively. Within the entire cohort, motor function after Re-RT improved in 45 (36%) patients. Motor function was stable in another 62 (50%) patients, and 17 (14%) patients had deterioration of motor deficits despite Re-RT. On multivariate analysis, the effect of Re-RT on motor function was significantly associated with the effect of the first course of RT, the ECOG performance status, the time to development of motor deficits before Re-RT, and visceral metastases at Re-RT. A trend was
Prognostic Factors and Reirradiation/Rades et al
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TABLE 2 Potential Prognostic Factors for Motor Function After Re-RT
Age at Re-RT, y 63 64 Sex Women Men Type of primary tumor Breast cancer Prostate cancer Myeloma/Lymphoma Lung cancer Other tumors Effect of first course of RT Improvement No change Time to recurrence, m 6 >6 Ambulatory status before Re-RT Ambulatory Nonambulatory ECOG PS at Re-RT 1-2 3-4 Time to motor deficits before Re-RT, d 1-7 8-14 >14 Visceral metastases at Re-RT No Yes No. of involved vertebrae at Re-RT 1-3 4 Re-RT schedule 1 d (1 3 8 Gy) 1 wk (5 3 3 Gy/5 3 4 Gy) >1 wk (7 3 3 Gy/10-12 3 2 Gy/17 3 1.8 Gy) Cumulative BED 100 Gy2
Improvement No. (%)
No Change No. (%)
Deterioration No. (%)
P
24 (37) 21 (36)
31 (48) 31 (52)
10 (15) 17 (12)
.74
17 (37) 28 (36)
24 (52) 38 (49)
15 (11) 12 (15)
.75
12 (46) 18 (44) 17 (64) 13 (20) 15 (16)
12 (46) 18 (44) 14 (36) 16 (40) 22 (71)
12 (8) 15 (12) 10 (0) 16 (40) 14 (13)
.11
29 (50) 16 (24)
25 (43) 37 (56)
14 (7) 13 (20)
.048
18 (28) 27 (46)
35 (54) 27 (46)
12 (18) 15 (8)
.47
38 (44) 17 (18)
36 (42) 26 (68)
12 (14) 15 (13)
.07
38 (47) 17 (16)
34 (42) 28 (65)
19 (11) 18 (19)
.020
13 (12) 16 (34) 26 (51)
15 (58) 25 (53) 22 (43)
18 (31) 16 (13) 13 (6)
.002
31 (58) 14 (20)
20 (38) 42 (59)
12 (4) 15 (21)
6 Ambulatory status before Re-RT Ambulatory Nonambulatory ECOG PS at Re-RT 1-2 3-4 Time to motor deficits before Re-RT, d 1-7 8-14 >14 Visceral metastases at Re-RT No Yes No. of involved vertebrae at Re-RT 1-3 4 Re-RT schedule 1 d (1 3 8 Gy) 1 wk (5 3 3 Gy/5 3 4 Gy) >1 wk (7 3 3 Gy/10-12 3 2 Gy/17 3 1.8 Gy) Cumulative BED 100 Gy2
52 59
38 33
.94
64 49
38 34
.41
83 59 55 9 40
55 48 44 NA 13
