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Keywords:

  • metastatic spinal cord compression;
  • overall treatment time;
  • prognostic factors;
  • radiotherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The optimal treatment of patients with metastatic spinal cord compression (MSCC) is still being debated. The current observational multicenter study, performed prospectively by the authors, evaluated two radiotherapy (RT) schedules and prognostic factors with respect to functional outcome

METHODS

In the current study, 214 patients with MSCC were irradiated between April 2000 and September 2003 with 30 gray (Gy) per 10 fractions per 2 weeks (n = 110) or with 40 Gy per 20 fractions per 4 weeks (n = 104). Motor function and ambulatory status were evaluated before RT and until 6 months after RT. The following potential prognostic factors were investigated: RT schedule, performance status, age, number of irradiated vertebrae, type of primary tumor, pretreatment ambulatory status, and length of time developing motor deficits before RT.

RESULTS

Both groups were balanced for patient characteristics and potential prognostic factors. Motor function improved in 43% of patients after 30 Gy and in 41% of patients after 40 Gy (P = 0.799). Posttreatment ambulatory rates were 60% and 64% (P = 0.708), respectively. A multivariate analysis demonstrated that a slower progression of motor deficits before RT (P < 0.001), a favorable histology of the primary tumor (P < 0.001), and being ambulatory before RT (P = 0.035) were associated with a better functional outcome. RT schedule (P = 0.269) and other variables had no significant impact. Acute toxicity was mild, and late toxicity was not observed during the period of follow-up. Follow-up was 12 (6–28) months in patients surviving ≥ 6 months.

CONCLUSIONS

Thirty gray per 10 fractions was preferable to 40 Gy per 20 fractions, because it was associated with similar outcome, less treatment time, and lower costs. The type of tumor, pretreatment ambulatory status, and length of time developing motor deficits before RT were relevant prognostic factors and should be considered in future studies. Cancer 2004. © 2004 American Cancer Society.

Metastatic spinal cord compression (MSCC) occurs in approximately 5% of all patients with cancer. Radiotherapy (RT) is an important treatment modality for patients with MSCC. However, there is still debate regarding the most appropriate RT schedule in this setting.

To our knowledge, the current multicenter study is the first prospective evaluation that compares different RT schedules for the treatment of MSCC with respect to functional outcome. Furthermore, besides our own retrospective analysis,1 this is the first comparable study for MSCC that considers a new prognostic factor, i.e., the length of time of developing motor deficits before RT.2 In addition to the two well recognized prognostic factors, i.e., type of primary tumor and ambulatory status before RT, other potential prognostic factors such as age, performance status, and the number of irradiated vertebrae are investigated.3–8

The current study compares 2 RT schedules for functional outcome and posttreatment ambulatory status, one that is completed in 2 weeks and the other that lasts 4 weeks. The life expectancy for patients with MSCC is generally quite short.9 The daily visits to the RT department are associated with discomfort and stress for these often debilitated patients. Thus, a shorter treatment course would be preferable if it provided a similar outcome.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In the current observational study, performed prospectively, comprised 214 patients with MSCC. The patients were irradiated between April 2000 and September 2003 and were followed for 6 months. Inclusion criteria were as follows: motor dysfunction of the lower extremities, no previous surgery or RT of the spinal region concerned, no chemotherapy, and dexamethasone treatment (16–32 mg per day) during RT. Patients with a history of a brain tumor, brain metastasis, or other major neurologic diseases, which may also cause motor dysfunction, were excluded. The diagnosis of MSCC was confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scans for all patients. The median age for all 214 patients was 63 years (range, 24–87 years). One hundred and four patients (49%) were female and 110 patients (51%) were male. The distribution of the primary tumors was as follows: 59 breast carcinomas, 31 lymphomas/myelomas, 28 prostate carcinomas, 21 cancers of unknown primary, 17 lung carcinomas, 17 gastrointestinal carcinomas, 14 renal carcinomas, 2 melanomas, and 25 others.

Irradiation was performed with 6–10 MV photon beams of a linear accelerator. RT doses were prescribed to the spinal cord using CT and MRI scans. The treatment volume encompassed one normal vertebra above and below the metastatic lesions. Irradiation was delivered through a single posterior field (depth to the spinal cord ≤ 5 cm) or through parallel opposed fields (depth to the spinal cord > 5 cm).

Two different RT schedules were administered, 30 Gy per 10 fractions over 2 weeks (n = 110) and 40 Gy per 20 fractions over 4 weeks (n = 104). The assignment of the treatment approach was related to the availability of RT appointments on the linear accelerators. Thus, the chronology of the schedules was simultaneous and not sequential. The patient characteristics related to the two treatment groups are summarized in Table 1.

Table 1. Comparison of the RT Schedules for Age, Gender, Performance Status, Number of Irradiated Vertebrae, Type of Primary Tumor, Time of Developing Motor Deficits before RT, and Pre-RT Ambulatory Status
Characteristics30 Gy/10 fractions40 Gy/20 fractionsP value
  1. RT: radiotherapy; Gy: grays; ECOG: Eastern Cooperative Oncology Group; SCLC: small cell lung carcinoma; NSCLC: nonsmall cell lung carcinoma.

Median age (yrs) (range)64 (24–87)62 (28–86)
Gender   
 Female50 (45%)54 (52%) 
 Male60 (55%)50 (48%)0.566
ECOG performance status   
 255 (50%)55 (53%) 
 355 (50%)49 (47%)0.841
Irradiated vertebra (no.)   
 3–447 (43%)42 (40%) 
 ≥ 563 (57%)62 (60%)0.888
Type of primary tumor   
 Favorable histology17 (16%)17 (16%) 
  Lymphoma/myeloma15 (14%)16 (15%) 
  SCLC 2 (2%) 1 (1%) 
 Intermediate histology72 (65%)71 (68%) 
  Breast carcinoma28 (25%)32 (31%) 
  Prostate carcinoma16 (15%)12 (11%) 
  Renal carcinoma 9 (8%) 5 (5%) 
  Gastrointestinal carcinoma 8 (7%) 9 (9%) 
  Others11 (10%)13 (12%) 
 Unfavorable histology21 (19%)16 (16%) 
  Unknown primary12 (11%) 9 (9%) 
  NSCLC 8 (7%) 6 (6%) 
  Melanoma 1 (1%) 1 (1%)0.878
Time of developing motor deficits before RT (days)   
 1–732 (29%)25 (24%) 
 8–1434 (31%)33 (32%) 
 > 1444 (40%)46 (44%)0.831
Ambulatory before RT58 (53%)58 (56%) 
Nonambulatory before RT52 (47%)46 (44%)0.841

Motor function and ambulatory status were evaluated before RT, at the end of RT, and at both 3 and 6 months after RT. Motor function was graded according to the American Spinal Injury Association and the International Medical Society of Paraplegia10 (Table 2). Improvement and deterioration of motor function were defined as a change of at least one point on the eight-point scale.

Table 2. Grading of Motor Function with an 8-Point Scale Modified According to the American Spinal Injury Association and the International Medical Society of Paraplegia4
0: Complete paraplegia
1: Palpable or visible muscle contractions
2: Active movement of the leg without gravity
3: Active movement of the leg against gravity
4: Active movement of the leg against mild resistance
5: Active movement of the leg against moderate resistance
6: Active movement of the leg against severe resistance
7: Normal strength

The chi-square test was used for univariate analysis to compare the two groups for patient characteristics, functional outcome, and ambulatory status. The chi-square test was also used to evaluate the possible impact of age, performance status, number of irradiated vertebrae, ambulatory status, type of primary tumor, and the time of developing motor deficits before RT on functional outcome (univariate analysis).

Furthermore, multivariate analysis (multiple logistic regression) was performed to determine the effect of RT on motor function (improvement, no change, or deterioration). The P values for inclusion and exclusion were 0.05 and 0.10, respectively. The following variables were evaluated for impact on functional outcome: fractionation pattern, performance status, age, number of irradiated vertebrae, ambulatory status (ambulatory versus nonambulatory; the latter means paraparetic and paraplegic patients who are not able to walk even with aid), type of primary tumor (favorable histology [i.e., myeloma, lymphoma, small cell lung carcinoma, testicular seminoma] vs. unfavorable histology [i.e., cancer of unknown primary, nonsmall cell lung carcinoma, melanoma] vs. intermediate histology [i.e., other tumors]), and length of time developing motor deficits before RT (over a period of 1–7 days, 8–14 days vs. > 14 days).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The potential prognostic factors were investigated with respect to functional outcome. The data from the univariate analysis are summarized in Table 3. For the type of primary tumor (P < 0.001), the pretreatment ambulatory status (P = 0.031), and the length of time developing motor deficits before RT (P < 0.001), a significant impact on functional outcome was observed. Age (P = 0.823), performance status (P = 0.598), and the number of irradiated vertebrae (P = 0.970) were not significantly associated with functional outcome. The comparison of the 2 RT schedules (i.e., 30 Gy in 10 fractions and 40 Gy in 20 fractions) did not reveal a significant impact on motor function (Table 4).

Table 3. Impact of Potential Prognostic Factors on Motor Function (Univariate Analysis, Chi-Square Test)
CharacteristicsImprovement of motor functionNo change of motor functionDeterioration of motor functionP value
  1. ECOG: Eastern Cooperative Oncology Group; RT: radiotherapy.

Age (yrs)    
 ≤ 6339% (44/112)34% (38/112)27% (30/112) 
 ≥ 6445% (46/102)31% (32/102)24% (24/102)0.823
ECOG performance status    
 246% (51/110)31% (34/110)23% (25/110) 
 337% (39/104)35% (36/104)28% (29/104)0.598
Irradiated vertebra (no.)    
 3–443% (38/89)31% (28/89)26% (23/89) 
 ≥ 541% (52/125)34% (42/125)25% (31/125)0.970
Type of histology    
 Favorable65% (22/34)29% (10/34) 6% (2/34) 
 Intermediate44% (63/143)36% (52/143)20% (28/143) 
 Unfavorable13% (5/37)22% (8/37)65% (24/37)< 0.001
Ambulatory before RT52% (60/116)32% (37/116)16% (19/116) 
Nonambulatory before RT30% (30/98)34% (33/98)36% (35/98)0.031
Time of developing motor deficits before RT (days)    
 1–7 7% (4/57)30% (17/57)63% (36/57) 
 8–1434% (23/67)45% (30/67)21% (14/67) 
 > 1470% (63/90)26% (23/90) 4% (4/90)< 0.001
Table 4. Impact of the RT Schedule on Motor Function, Evaluated Directly after RT, at 3 Months after RT, and at 6 Months after RT, with Respect to the Score before RT (Univariate Analysis, Chi-Square Test)
Characteristics30 Gy/10 fractions40 Gy/20 fractionsP value
  1. RT: radiotherapy; Gy: grays.

Directly after RT   
 Improvement43% (47/110)41% (43/104) 
 No change30% (33/110)36% (37/104) 
 Deterioration27% (30/110)23% (24/104)0.799
3 mos after RT   
 Improvement49% (46/93)46% (42/91) 
 No change28% (26/93)36% (33/91) 
 Deterioration23% (21/93)18% (16/91)0.580
6 mos after RT   
 Improvement55% (42/76)51% (37/72) 
 No change32% (24/76)36% (26/72) 
 Deterioration13% (10/76)13% (9/72)0.928

The findings of the univariate analysis were further supported by the multiple logistic regression analysis. A better outcome was associated with a slower development of motor dysfunction before RT (P < 0.001), favorable histology (P < 0.001), and ambulatory status before RT (P = 0.035). In accordance with the univariate analysis, no significant impact on functional outcome was observed for performance status (P = 0.202), age (P = 0.481), and the number of irradiated vertebrae (P = 0.704).

Ambulatory rates before and after RT were not significantly different for the two treatment groups (Table 5). Thirty percent (29 of 98) of the patients, who were not ambulatory before RT, regained the ability to walk, 29% (15 of 52) after 30 Gy and 30% (14 of 46) after 40 Gy (P = 0.999).

Table 5. Impact of the RT Schedule on Posttreatment Ambulatory Status, Evaluated Directly after RT, at 3 Months after RT, and at 6 Months after RT (Univariate Analysis, Chi-Square Test)
Characteristics30 Gy/10 fractions40 Gy/20 fractionsP value
  1. RT: radiotherapy; Gy: grays.

Directly after RT   
 Ambulatory60% (66/110)64% (67/104) 
 Nonambulatory40% (44/110)36% (37/104)0.708
3 mos after RT   
 Ambulatory68% (63/93)71% (65/91) 
 Nonambulatory32% (30/93)29% (26/91)0.791
6 mos after RT   
 Ambulatory75% (57/76)79% (57/72) 
 Nonambulatory25% (19/76)21% (15/72)0.777

Sixty-three patients, 33 patients in the 30-Gy group and 30 patients in the 40-Gy group, died within 6 months after RT. Three patients were lost to follow-up, 1 patient in the 30-Gy group and 2 patients in the 40-Gy group. The data of patients who died before the follow-up was complete are summarized and compared with the data of patients with complete follow up in Table 6. Functional outcome was better for long-term survivors. The patients with complete follow-up of ≥ 6 months responded better to RT than the patients who died before 6 months after RT. The rate of patients with complete follow-up was 69% in both groups, 76 of 110 patients in the 30-Gy group and 72 of 104 patients in the 40-Gy group. A potential bias due to differences in survival by treatment group could be excluded.

Table 6. Effect of RT on Motor Function in Patients who Died before Follow-Up was Complete and in Patients with Complete Follow-Up
CharacteristicsPatients who died within 6 weeks after RT (n = 8)Patients who died within 12 weeks after RT (n = 30)Patients who died within 24 weeks after RT (n = 63)Patients with complete follow-up (n = 148)
  1. RT: radiotherapy; Gy: grays.

30 Gy/10 fractions    
 Improvement  0% (0/0) 6% (1/17)15% (5/33)55% (42/76)
 No change  0% (0/0)35% (6/17)27% (9/33)32% (24/76)
 Deterioration100% (3/3)59% (10/17)58% (19/33)13% (10/76)
40 Gy/20 fractions    
 Improvement  0% (0/0) 8% (1/13)20% (6/30)51% (37/72)
 No change  0% (0/0)31% (4/13)30% (9/30)36% (26/72)
 Deterioration100% (5/5)62% (8/13)50% (15/30)13% (9/72)

In both groups, no relevant acute or late RT-related toxicity was observed. Acute toxicity did not exceed Grade 1 according to the National Cancer Institute Common Toxicity Criteria.11 Late toxicity such as RT myelopathy did not occur during the period of follow-up. In the patients surviving ≥ 6 months, the median follow-up period was 12 months (range, 6–28 months) in the whole series, 12 months (range, 6–26 months) after 30 Gy per 10 fractions, and 13 months (range, 6–28 months) after 40 Gy per 20 fractions, respectively.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

There is a lack of prospective studies evaluating functional outcome in patients with MSCC. The current multicenter trial is the first prospective study that compared different RT schedules with respect to subsequent functional outcome of patients with MSCC. This is a nonrandomized study. However, well conducted observational studies can provide the same level of internal validity as randomized, controlled trials. Furthermore, randomized trials often produce inconsistent results and can have limited external validity (generalizability).12–16

In addition, the current study considers a new prognostic factor, i.e., the length of time developing motor deficits before RT, which was of prognostic importance (P < 0.001). A slower development of motor dysfunction was associated with a better functional outcome. The worse prognosis after rapid development of motor dysfunction may be explained by disruption of the arterial blood flow by a rapidly constricted spinal cord, which leads to spinal cord infarction. A slower growing lesion is suggested to first cause venous congestion, which is more reversible.17

The only other prospective study focusing on functional outcome in patients with MSCC was presented recently as an abstract by Patchell et al.18 However, the design of that study was much different from the current study. Patchell et al. included only patients with a single area of cord compression. Their study did not compare different RT schedules, but compared spinal RT of 30 Gy with or without decompressive surgery. Furthermore, Patchell et al. did not consider the prognostic importance of the length of the time developing motor deficits before RT, i.e., the finding that a slower development of motor dysfunction before RT is associated with better functional outcome.

The major goal of the current study was to investigate whether a reduction of the overall treatment time was as effective as a longer treatment program for the patients in a palliative situation such as patients with MSCC. The two RT schedules were compared with respect to functional outcome.

The effect of a RT schedule on tumor control and on late toxicity depends on both the total dose and the dose per fraction. The dose per fraction was 3 Gy in the 30-Gy group and 2 Gy in the 40-Gy group. The 2 schedules can be compared with the equivalent dose in 2-Gy fractions (EQD2), which is calculated using the equation EQD2 = D × ([d + α/β]/[2 Gy + α/β]) derived from the linear-quadratic model, where D = the total dose, d = the dose per fraction, α = the linear (first-order, dose-dependent) component of cell killing, β = the quadratic (second-order, dose dependent) component of cell killing (more reparable), and α/β ratio = the dose at which both components of cell killing are equal.19, 20 The α/β ratio suggested for tumor control is 10 Gy, resulting in an EQD2 of 32.5 Gy for the schedule 30 Gy per 10 fractions. The EQD2 for 40 Gy per 20 fractions is 40 Gy. Thus, the schedule 40 Gy per 20 fractions could be expected to be more effective. However, our results did not reveal a significant difference between the two RT schedules in their effect on functional outcome or ambulatory status. Thus, the difference in EQD2 did not appear clinically relevant in the treatment of MSCC.

The results of the univariate analysis were supported by the multivariate analysis, which did not show a significant impact on functional outcome for the RT schedule, whereas well recognized prognostic factors did have an effect on functional outcome. Slower development of motor deficits before RT (P < 0.001), favorable histology (P < 0.001), and ambulatory status before RT (P = 0.035) were associated with better motor function after RT.

Both treatment groups were balanced with respect to the three significant prognostic factors and with respect to age, gender, performance status, and number of irradiated vertebrae (Table 1). Thus, the distribution of these factors did not influence the results in a relevant manner.

Relevant acute or late RT-related toxicity was not observed in our series during the follow-up. In the patients alive at 6 months after RT, the median follow-up was approximately 12 months in both groups, which appears to be quite a long time for patients with MSCC.9 The tolerance dose (5% late toxicity within 5 years) for RT myelopathy is 45–50 Gy for conventional fractionation (a dose per fraction of 1.8–2 Gy).21 For the end point myelopathy, the EQD2 must be calculated with an α/β ratio of 2 Gy, resulting in an EQD2 of 37.5 Gy for the schedule 30 Gy per 10 fractions and an EQD2 of 40 Gy for the schedule 40 Gy per 20 fractions.19, 20 Thus, relevant late toxicity appears to be extremely unlikely.

According to the literature, a combined approach of RT and chemotherapy is effective for the treatment of MSCC, especially for patients with lymphoma and myeloma.22–25 Several authors suggested a combined approach to be even more effective than single modality treatment alone with respect to local control, event-free survival, and overall survival.22–24 However, toxicity may be enhanced if chemotherapy is administered during or immediately after RT. Wallington et al.24 reported 6 deaths among 34 patients (18%) in their series of patients with lymphoma and myeloma to be related to toxicity from chemotherapy.

Both RT schedules were comparably effective for the treatment of patients with MSCC. Application of 30 Gy per 10 fractions instead of 40 Gy per 20 fractions leads to a reduction of the overall treatment time from 4 weeks to 2 weeks and to a reduction of the number of treatment sessions from 20 sessions to 10 sessions. As life expectancy in patients with MSCC is limited, a shorter treatment time is desirable. Each treatment session can cause discomfort and inconvenience for the patients. Furthermore, a longer program increases the costs of therapy. Thus, the shorter schedule (30 Gy per 10 fractions per 2 weeks) is preferable. A further reduction of the overall treatment time may be possible. Future studies performed to determine the optimal treatment of patients with MSCC should consider the type of primary tumor, the pretreatment ambulatory status, and the length of time developing motor deficits before RT, as these are all relevant prognostic factors.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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