Originally published as JCO Early Release 10.1200/JCO.2005.08.193 on February 28 2005

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Short-Course Versus Split-Course Radiotherapy in Metastatic Spinal Cord Compression: Results of a Phase III, Randomized, Multicenter Trial

From the Radiation Oncology Center, Azienda Ospedaliera, Terni; Radiation Oncology Center, University School of Medicine, and Service of Medical Physics, Policlinico Hospital; Medical Oncology Service, Azienda Sanitaria n.2, Perugia; Radiation Oncology Center, Hospital, Arezzo; Radiation Oncology Center, Hospital, Lucca; and Radiation Oncology Center, University School of Medicine, Careggi Hospital, Firenze, Italy

Address reprint requests to Ernesto Maranzano, MD, U.O. di Radioterapia Oncologica, Azienda Ospedaliera ‘S Maria’, Via T di Joannuccio, 1, 05100 Terni, Italy; e.mail: ernesto.maranzano{at}libero.it

	ABSTRACT

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PURPOSE: Hypofractionated radiotherapy (RT) is often used in the treatment of metastatic spinal cord compression (MSCC). This randomized trial was planned to assess the clinical outcome and toxicity of two different hypofractionated RT regimens in MSCC.

PATIENTS AND METHODS: Three hundred patients with MSCC were randomly assigned to a short-course RT (8 Gy x 2 days) or to a split-course RT (5 Gy x 3; 3 Gy x 5). Only patients with a short life expectancy entered the protocol. Median follow-up was 33 months (range, 4 to 61 months).

RESULTS: A total of 276 (92%) patients were assessable; 142 (51%) treated with the short-course and 134 (49%) treated with the split-course RT regimen. There was no significant difference in response, duration of response, survival, or toxicity found between the two arms. When short- versus split-course regimens were compared, after RT 56% and 59% patients had back pain relief, 68% and 71% were able to walk, and 90% and 89% had good bladder function, respectively. Median survival was 4 months and median duration of improvement was 3.5 months for both arms. Toxicity was equally distributed between the two arms: grade 3 esophagitis or pharyngitis was registered in four patients (1.5%), grade 3 diarrhea occurred in four patients (1.5%), and grade 3 vomiting or nausea occurred in 10 patients (6%). Late toxicity was never recorded.

CONCLUSION: Both hypofractionated RT schedules adopted were effective and had acceptable toxicity. However, considering the advantages of the short-course regimen in terms of patient convenience and machine time, it could become the RT regimen of choice in the clinical practice for MSCC patients.

	INTRODUCTION

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Metastatic spinal cord compression (MSCC) is a frequent oncologic emergency that must be diagnosed early and promptly treated.¹ Magnetic resonance imaging (MRI) is the best tool for diagnosing MSCC.² When MSCC is diagnosed, radiotherapy (RT) is generally the treatment of choice, whereas surgery is reserved only for selected patients.^3-12 No published trial on RT for MSCC has stratified the results by RT dosing protocol and no standard RT regimen exists for the treatment of MSCC.^6-8,13-20 Studies regarding RT for patients with painful bone metastases have shown that with low fraction (one to five) regimens and high single doses (4 to 10 Gy) the clinical outcome is similar to that in more protracted regimens (also for those patients with vertebral metastases).^21-28 Obviously, few RT fractions give advantages in terms of patient convenience, machine time, and overall cost.^23-25,27,28

Given that higher RT doses per fraction may be a possible factor associated with radiation-induced late spinal cord morbidity, we adopted different fractionations in our previous trials on the basis of the individual patient’s life expectancy.²⁹ A safer fractionation of 30 Gy in 10 fractions during 2 weeks was given to patients with a long life expectancy (ie, favorable histologies, good motor and sphincter function, and good performance status). Fractionations with higher daily doses—a split-course of 5 Gy x 3 days plus 3 Gy x 5, to a total dose of 30 Gy in 2 weeks, or a short-course of 8 Gy x 2 to a total dose of 16 Gy in 1 week—were adopted for patients with short ( 6 months) life expectancy. Considering the feasibility and effectiveness of all of these regimens, on the basis of the above-mentioned selection criteria, the split- and short-course regimens were more often used, whereas 30 Gy in 10 fractions during 2 weeks was generally used only in a minority of patients (approximately 15%).^8,16,28-32

With this background, a prospective, randomized, phase III trial was performed comparing the aforesaid split-course and short-course regimens. Results and toxicity were recorded and compared. It is worth noting that this is the first randomized trial comparing different RT dose-fractionation regimens for MSCC.

	PATIENTS AND METHODS

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Study Design
The primary objectives of this trial were to determine whether a short-course RT (8 Gy, 6-day rest, and then 8 Gy, to a total dose of 16 Gy in 1 week) is as effective as split-course RT (5 Gy x 3, 4-day-rest, and then 3 Gy x 5, to a total dose of 30 Gy in 2 weeks) in MSCC patients with regard to symptom control (ie, back pain, and motor and sphincter function), duration of response, and survival. Secondary objectives were to compare the acute and late adverse effects of the two treatment arms; to determine whether there are any differences in outcome with respect to radiation-induced acute oral or esophageal toxicity, diarrhea, and emesis; and to determine whether there are any differences in outcome regarding development of radiation-induced late spinal cord morbidity.

The study was designed as a two-arm, phase III, randomized, controlled trial with one-to-one randomization to the two arms (short-course v split-course RT). Patients with MSCC diagnosed by MRI or computed tomography (CT) entered onto the study. They were selected according to the criteria listed in Eligibility Criteria. Patients were randomly assigned, allocation was performed by a centralized registration, and investigators were notified of assignment by telephone and fax. Treatment groups were not stratified.

Eligibility Criteria
The definition of epidural MSCC has changed during the last few decades. The most recent version includes both clinical and radiographic criteria and encompasses the anatomy of the cord as well as the cauda equina. The Princess Margaret Hospital (Toronto, Canada) defines MSCC as "compression of the dural sac and its contents (spinal cord and/or cauda equina) by an extradural tumor mass. The minimum radiologic evidence for cord compression is indentation of the theca at the level of clinical features. Clinical features include any or all of the following: pain (local or radicular), weakness, sensory disturbance, and/or evidence of sphincter dysfunction."¹³ According to this definition, which is adopted in our institution, patients with local or radicular pain have MSCC even in the absence of neurologic symptoms, provided that cord compression is revealed at MRI and/or CT.

Aiming at an early diagnosis, MRI or CT were prescribed for all cancer patients with back pain, osteolysis, and/or positive bone scan, even in the absence of neurologic symptoms of spinal cord compression. All patients fulfilled the inclusion criteria in the following list. First, MSCC had to be diagnosed by MRI or CT in patients with progressive neoplastic disease. Second, there were no criteria indicating a primary surgical approach (ie, none of the following was present: diagnostic doubt, spinal instability, a vertebral body collapse causing bone impingement on the cord or nerve roots, or previous irradiation in the same area). Third, patients had to have a short life expectancy ( 6 months) because of unfavorable histologies (ie, lung, kidney, GI, head and neck carcinoma, melanoma, or sarcoma) or favorable histologies (ie, lymphoma, seminoma, myeloma, and breast or prostate carcinoma) provided that motor or sphincter dysfunction and/or low performance status were also manifest. Fourth, all patients provided informed consent. The trial was approved by the Umbrian Ethical Committee.

All of these criteria were chosen in an attempt to enroll only MSCC patients with short life expectancy, whereas those with a longer life expectancy because of the presence of favorable histologies, good motor or sphincter function, and good performance status underwent 30 Gy in 10 fractions during 2 weeks or other more protracted RT schedules according to the choice of each center participating in the study.

Treatment
Parenteral dexamethasone (8 mg bid) was administered from the first day of clinical-radiologic diagnosis until 4 to 5 days after the end of RT, and then tapered off during 10 days. No responders continued taking corticosteroids.

As already published,²⁸ all patients treated with fields covering the upper abdomen (ie, fields between T8 and L3 with an area of 100 cm²) received oral or parenteral adjuvant antiemetics (a 5-hydroxitriptamine-3 receptor antagonist) 30 to 60 minutes before each RT fraction.

Emergency RT was started within 24 hours of the radiologic diagnosis and delivered from a 4- to 18-MV linear accelerator. Two vertebral bodies above and below the involved vertebrae and paravertebral mass were included in the treatment portal.

Assessment
Response to treatment was evaluated according to the patients’ walking capacity, bladder function, and back pain before and after RT. On the basis of physical examination, motor performance was graded according to Tomita’s groups: group I, ability to walk without support; group II, ability to walk with support; group III, inability to walk; and group IV, paraplegic.¹⁸ Bladder function was defined by the need of a urinary catheter. Pain was graded according to the classifications of no pain, pain controlled with minor analgesics, and pain requiring narcotics.

The response criteria adopted were as follows. Patients who were able to walk before and after treatment, as well as those unable to walk before RT who recovered walking ability after RT, and those patients who maintained or recovered sphincter function were considered responders. Regarding back pain, response was divided into three categories: complete responders, those patients who had no pain after RT; partial responders, patients using narcotics or minor analgesics before RT who had pain requiring minor analgesics after RT; and nonresponders, patients with no pain before RT who developed pain or those with pain requiring minor analgesics who starting taking narcotics after RT. This scale is derived from a questionnaire compiled by the patient and given to the physician at each follow-up. Analysis of response was performed 1 month after the end of RT and the follow-up examination was continued once a month for 1 year, and four times per year until death. In the vast majority of patients, follow-up data were recorded by the treating physician at clinical visits, although telephone interviews were allowed (mainly for geographic reasons).

Percentage of response and duration of improvement, survival, and toxicity were evaluated according to the RT schedule adopted (split v short course), pretreatment and post-treatment ambulatory status, and histology of the primary tumor (favorable v unfavorable). For patients who started out in a response condition, duration of response was calculated from the date of first treatment to worsening of their condition; for the other patients, duration of response was calculated as time from improvement to regression of improvement.

For diarrhea and esophageal or pharyngeal toxicity, the National Cancer Institute Common Toxicity Criteria were adopted. For emesis, the following classification was used. Nausea was graded according to a 0 to 3 scale: 0, no episodes; 1, mild (did not interfere with normal daily life); 2, moderate, (interfered with normal daily life); and 3, severe (patient bedridden because of nausea). Vomiting was also graded according to a 0 to 3 scale: 0, no episodes; 1, one to two episodes per day; 2, more than two but 10 episodes per day; 3, more than 10 episodes per day.

Recurrence was diagnosed by MRI, which was prescribed only for patients with symptomatic progression.

Statistical Methods
Response rate was chosen as the primary determinant of sample size. To test the hypothesis for this equivalence trial that a short-course RT (8 Gy x 2) is at least as effective in producing a response as a split-course RT (5 Gy x 3; 3Gy x 5), it was calculated that 270 patients (approximately 135 in each arm) would be needed. This was intended to ensure an 80% probability (power) that the two-sided 95% CI for the difference in response rates would be within the interval –15% to +15% if the two response rates were in fact equal and approximately 70%. Moreover, considering a dropout rate of 10% of patients, a final accrual of 300 patients was planned.³³

Overall survival was measured from the date of random assignment of treatment to the date of death as a result of any case. Overall survival curves were calculated by the Kaplan-Meier method and compared by the log-rank test. The relative risk was estimated with 95% CIs. The Fisher’s exact test or ² test was applied for categoric data. A P value of .05 (two sided) was considered the limit of significance for each analysis. All of the analyses were conducted using SAS software (version 6.0; SAS Institute, Cary, NC).

	RESULTS

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Patient Characteristics
Between February 1998 and November 2002, 300 patients entered onto the trial, of which 276 (92%) are assessable and 24 (11 in the short-course and 13 in the split-course arms) are not assessable because they were lost to follow-up (seven patients) or because of early death (17 patients). These last patients died 2 to 10 days from the start of RT as a result of cardiogenic shock (four patients), disseminated intravascular coagulation (four patients), septicemia (three patients), hypercalcemia (two patients), and unidentified causes (four patients). Median follow-up was 33 months (range, 4 to 61 months). The diagnosis of MSCC was established by MRI in 214 patients (76%) and by CT in the other 62 patients (24%).

Patients were well balanced for sex, age, performance status, ambulatory status, and histology. The short-course regimen was assigned to 142 patients (51%) and the split-course regimen was assigned to the remaining 134 patients (49%). At the time of MSCC diagnosis, 262 (95%) of 276 patients had back pain. Regarding pretreatment ambulatory status, 184 patients (67%) were able to walk (107 patients [39%] without support and 77 patients [28%] with support), another 75 patients (27%) were nonwalking, and the remaining 17 patients (6%) were paraplegics. Before RT, bladder dysfunction was found in 29 patients (11%). Table 1 lists patient distribution in the two treatment arms.

The sites of MSCC were as follows: cervical spine (8%), thoracic (50%), lumbar (23%), sacral (7%) cervicothoracic (1%), thoracolumbar (6%), and lumbosacral (2%). In eight patients (3%) there were two compression sites both simultaneously treated with RT. In 72 patients (26%), the only site of metastasis was in the spine (vertebral bone and epidural compression); 113 (41%) patients had only multiple bone metastases; and the remaining 91 (33%) patients had bone and visceral metastases in the liver, lung, and/or brain.

Antiemetic prophylaxis was administered to 167 patients (60%) considered at risk because they were treated with fields covering the upper abdomen.

Primary Outcomes
Pain relief was achieved in 157 patients (56.9%; 95% CI, 51.1 to 62.7), of which 92 (33.3%; 95% CI, 27.7 to 38.9) had a complete response and 65 (23.6%; 95% CI, 18.6 to 28.6) had a partial response. Regarding motor function, there were 192 (69.6%; 95% CI, 63.9 to 75.3) responders.

Of 29 patients with sphincter dysfunction, four (14%) regained urinary control, only four (2%) with good bladder function worsened and required an indwelling catheter after RT, and the others maintained urinary control (total response rate, 89%). No significant difference in response rates was found comparing short- versus split-course regimens. After RT, 56% and 59% patients had back pain relief, 68% and 71% were able to walk, and 90% and 89% had good bladder function, respectively (Table 2).

View larger version (12K): [in this window] [in a new window]   Fig 1. Actuarial survival curves comparing split- and short-course radiotherapy regimens (two-sided P value).

Secondary Outcomes
Grade 1 to 2 oral or esophageal dysphagia was observed in 39 of patients (14%). Grade 3 esophagitis occurred in three patients (1%) treated in the thoracic area, two with the split-course and one with the short-course regimen. Only in one patient (0.5%) was a grade 3 pharyngeal dysphagia registered as a result of split-course RT on the cervical spine. Twenty patients (7%) had grade 1 to 2 diarrhea and only four patients (1.5%) developed grade 3 diarrhea, two after a short-course RT on the thoracolumbar region and the remaining two after RT to the sacral area with the split-course regimen.

Of 167 patients treated with antiemetic prophylaxis, grade 1 to 2 vomiting occurred in 22 patients (13%) and grade 3 vomiting occurred in only five patients (3%), with the same incidence in the two RT regimens employed. Nausea occurred in 21 patients (12%): grade 1 to 2 in 16 patients (9%) and grade 3 in five patients (3%). Of patients who did not receive antiemetic prophylaxis because the treated spine was not at risk, seven (6%) had grade 1 nausea, six (5.5%) had grade 1 to 2 vomiting, and only one (1%) had grade 3 vomiting. In this study, no relationship was found between the RT regimen adopted and acute adverse events. Late spinal cord morbidity was never recorded.

Subgroup Analysis
Survival time and duration of improvement were also calculated according to pretreatment and post-treatment walking capacity and histology. When the walking capacity was considered, median survival was 5 months for walking patients pretreatment and 3 months for nonwalking patients pretreatment (P = .025), and 5 months for walking patients post-treatment and 2 months for nonwalking patients post-treatment (P = .0001). Histology also influenced significantly the median survival, which was 6 months for favorable cancers and 3 months for unfavorable cancers (P = .0001; Table 4). The median duration of motor capacity improvement was independent of the patient’s walking capacity and only primary tumor type influenced the median duration of improvement in walking capacity, which was 6 months for favorable histologies and 3 months for unfavorable histologies (P = .0001; Table 5).

In-Field Recurrences
There were five in-field recurrences, all identified in patients submitted to the short-course RT regimen (ie, 2% of all patients and 3.5% of the short-course RT group). Diagnosis of recurrence was obtained by MRI that was performed because patients had symptomatic progression (ie, presence of neurologic signs and/or symptoms that suggested myelo-radicular compression). Table 6 details the characteristics of these patients, the RT schedules used for re-treatment, and the outcome. Considering that no RT schedule was prescribed for re-treatment in the protocol, different RT doses were administered according to the choice of each physician. The median interval between the end of the first RT and diagnosis of recurrence was 5 months (range, 3 to 7 months). Two of the three patients walking before re-treatment maintained the function, whereas one became paraparetic. Both the nonwalking patients remained so. Four of five patients died, with a median survival time of 3.5 months (range, 1 to 7 months) after re-treatment. One patient is alive at 20 months. No spinal cord morbidity was found in this group. Although in-field recurrences occurred only in patients treated with the short-course RT regimen, no significant difference was found in the median duration of walking capacity improvement, which was 3.5 months in both treatment arms.

	DISCUSSION

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No difference in outcome was found between the two RT schedules adopted. Considering the entire group of patients who entered in the trial, results were satisfactory and similar to those published in literature.^{1,4-9,14-20,28} After RT, only 9% walking patients worsened, about one third (35%) of nonwalking patients regained ability to walk, and no paraplegics improved. The majority of patients with good sphincter control at diagnosis remained so after RT and 14% of cystoplegics regained urinary function. Back pain was well controlled in 57% of patients. Median survival time was 4 months for both arms and improvement obtained after the treatment generally lasted until death.

Patient tolerance to treatment was generally good and, regarding the outcome, no difference was found in toxicity between the two RT arms. Oral or esophageal dysphagia and diarrhea were registered in a minority of patients, whereas late spinal cord morbidity was never found. Among patients receiving antiemetic prophylaxis, grade 3 vomiting occurred in only five patients (3%) and grade 3 nausea occurred in another five patients (3%) independent of the RT regimen used. Of patients who received no antiemetic prophylaxis because the treated spine was not at risk, only one patient (1%) had grade 3 vomiting. The precautional use of 5-hydroxitriptamine-3 antagonists in patients with a high risk of developing nausea and/or vomiting and the administration of dexamethasone to the whole group could explain the tolerance of RT despite the high single fractions given (5 and 8 Gy). We recommend prescribing antiemetics in clinical practice when the upper abdomen is irradiated.

After RT, the incidence of second-occurrence spinal metastasis within the radiation port is approximately 4% to 7%.^34,35 In this trial there were five in-field recurrences (3.5%), all diagnosed in patients receiving the short-course RT regimen. Although in-field recurrences occurred only in patients treated with the short-course RT regimen, no statistical difference was found in the duration of response between split- and short-RT regimens (3.5 months). These patients were re-irradiated with satisfactory results when there was early diagnosis of relapse. As reported by Schiff et al,³⁶ and in our limited experience, re-treatment was feasible without remarkable acute or late toxicity.

In conclusion, both regimens of hypofractionated RT adopted were effective with no severe adverse effects. However, considering the convenience of the short-course regimen in terms of time sparing for patients, who can be treated in a few days, and the advantage for radiation oncology centers, which are often overloaded by long patient waiting lists, short-course therapy could be the hypofractionated RT regimen of choice in clinical practice for patients with MSCC.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
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Submitted August 29, 2003; accepted August 12, 2004.

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