Journal of Oncology

Journal of Oncology / 2014 / Article

Clinical Study | Open Access

Volume 2014 |Article ID 128240 | https://doi.org/10.1155/2014/128240

Carsten Nieder, Nicolaus Andratschke, Kent Angelo, Ellinor Haukland, Anca L. Grosu, "Development of a Score Predicting Survival after Palliative Reirradiation", Journal of Oncology, vol. 2014, Article ID 128240, 7 pages, 2014. https://doi.org/10.1155/2014/128240

Development of a Score Predicting Survival after Palliative Reirradiation

Academic Editor: Thomas E. Adrian
Received05 May 2014
Accepted02 Sep 2014
Published21 Sep 2014

Abstract

Purpose. To develop a prognostic model for predicting survival after palliative reirradiation (PR). Methods and Materials. We analyzed all 87 PR courses administered at a dedicated palliative radiotherapy facility between 20.06.2007 (opening) and 31.12.2009. Uni- and multivariate survival analyses were performed, the previously published survival prediction score (SPS) was evaluated, and a PR-specific prognostic score was calculated. Results. In multivariate analysis, four parameters significantly influenced survival: performance status, use of steroids, presence of liver metastases, and pleural effusion. Based on these parameters, a 4-tiered score was developed. Median survival was 24.5 months for the favorable group, 9.7 and 2.8 months for the two intermediate groups, and 1.1 months for the unfavorable group ( for comparison between the two favorable groups and for all other pair-wise comparisons). All patients in the unfavorable group died within 2 months. Conclusion. The performance of PR-specific score was promising and might facilitate identification of patients who survive long enough to benefit from PR. It should be validated in independent patient groups, ideally from several institutions and countries.

1. Introduction

Palliative reirradiation is currently used in a variety of clinical settings, including but not limited to bone and brain metastases or lung and gynecological cancers [14]. The number of scientific publications on this topic has increased in recent years [5]. In a well-defined geographical part of Norway, palliative reirradiation contributed 10% to all palliative radiotherapy series administered during a 12-month period [6]. Randomized trials comparing single versus multiple fractions for painful bone metastases reported retreatment rates of 11–42% after a single fraction and 0–24% after multiple fractions, as summarized by Chow et al. [1]. Comparable to palliative radiotherapy in general, clinicians attempt to tailor treatment regimens to patients’ prognosis, thereby minimizing undesirable over- and undertreatment. Decision aids such as prognostic scores and nomograms might facilitate rapid and reproducible assessment of patients’ survival expectation by transforming the complex set of patient- and disease-related prognostic factors into a standardized tool. Ideally, prognostic scores are easy to administer and valid across different institutions and countries [7]. The Survival Prediction Score (SPS), developed and validated by Chow et al. in patient cohorts treated with palliative radiotherapy, is among the tools that might be widely applicable, because it is based on three readily available parameters: primary cancer type, site of metastases, and performance status [8]. Its performance has never been tested specifically in patients undergoing palliative reirradiation. Together with a large number of other baseline factors potentially impacting survival, we analyzed SPS in a single-institution cohort study.

2. Methods

We retrospectively reviewed the records of all consecutive patients who received palliative reirradiation at a single hospital with dedicated palliative radiotherapy unit. The patients started their treatment in the time period from June 20, 2007 (date of opening of the dedicated palliative radiotherapy unit), to December 31, 2009. Reirradiation was defined as partial or complete field overlap (examples of partial overlap: initial course included thoracic vertebrae Th4-6 and reirradiation Th6-8; initial course of radical prostate radiotherapy followed by pelvic bone metastasis irradiation). A total of 87 reirradiation courses were studied. Stereotactic radiotherapy was unavailable and thus not included in the present series. All medical records, treatment details, and information on date of death were available in the hospital’s electronic patient record (EPR) system. The survival status and date of death or last follow-up of the patients were obtained from the EPR. Patients who were lost to follow-up were censored on the date of last documented contact (personal appointment, telephone conversation, and blood test). Median follow-up for all surviving/censored patients was 5.4 months. Survival time was measured from the start of reirradiation. Actuarial survival curves were generated by Kaplan-Meier method and compared by log-rank test (analyses performed with IBM SPSS Statistics 20). Multivariate analyses were performed by Cox regression (backward conditional method). We assigned SPS as described by Chow et al. [8], that is, based on three variables (nonbreast cancer, metastases other than bone, and Karnofsky performance status (KPS) ≤ 60): poor prognosis group when all three were present, intermediate prognosis group when two were present, and good prognosis group when 0-1 were present. Our own prognostic scores were developed as previously described by Rades et al. [9, 10]. In brief, the score for each predictive factor was determined by dividing the actuarial death rate at prespecified time points (given as the percentage) by 10. For example, patients with good KPS were assigned 0 points and those with poor KPS 1.5 points (rate of death at 1 month (15%) divided by 10). The total score represented the sum of the scores for each predictive factor. Two time points reflecting poor prognosis or short survival were chosen, 1 month and 2 months, because there is no generally agreed definition of sufficient survival expectation, justifying initiation of palliative radiotherapy. Given that recent research and discussions focused on overtreatment, for example, use of radiation therapy in the last 30 days of life, we felt that predicting short survival might be more important [1114].

3. Results

Median age at the time of reirradiation was 67 years (range 38–90 years). Prostate (29%) and non-small cell lung cancer (NSCLC, 11%) were the most common primary tumors. Additional baseline information is shown in Table 1. Bone metastases were the prevailing target for reirradiation. The most common regime consisted of 10 fractions of 3 Gy (43%). Other common regimes included 8 Gy single fraction (uncomplicated bone metastases) and 5 fractions of 4 Gy (various sites and indications). Five courses (6%) remained incomplete, typically because of earlier than expected clinical deterioration. Median survival of this small group of patients was 2.8 months. Overall median survival from reirradiation was 8.6 months and 1-year survival rate 42% (Figure 1). Six percent of patients received radiotherapy during the final month of life. Seventeen percent of patients died within 2 months.


CharacteristicNo.%

Entire cohort87
Gender
 Male6575
 Female2225
Family status1
 Single2023
 Married5563
 Partner56
 Missing information78
Karnofsky performance status
 90–1003136
 70–803034
 ≤602630
Primary tumor site
 Prostate2529
 Breast910
 Lung (non-small cell)1011
 Colorectal89
 Bladder56
 Kidney67
 Skin (malignant melanoma)33
 Other2124
Dose/fractionation (intention-to-treat)
 10 fractions of 3 Gy2428
 Single fraction of 8 Gy1922
 5 fractions of 4 Gy1517
 12–15 fractions of 2.5 Gy45
 Other2529
Reirradiation target types
 Bone metastases6979
 Brain metastases56
 Lung metastases or primary tumor67
 Other78
Known brain metastases
 No8092
 One or more78
Known liver metastases
 No 6878
 One or more1922
Known lung metastases
 No6575
 One or more2225
Known adrenal gland metastases
 No 7687
 One or more1113
Known bone metastases
 No1416
 One or more7384
Metastatic spinal cord compression
 No8092
 Yes (radiologic or symptomatic)78
Pleural effusion
 No8193
 Yes (radiologic or symptomatic)67
Number of metastatic sites
 01011
 1 (e.g., lungs only)3743
 2 (e.g., lungs and brain)2731
 31113
 422
Progressive disease outside RT target volume1
 No2731
 Yes5563
 Missing information56
Systemic cancer treatment1
 No2326
 Within 4 weeks before RT2124
 Within 3 months before RT1416
 Earlier1720
 Missing information1214
Use of opioid analgetics at start of RT1
 No2124
 Yes5462
 Missing information1214
Use of steroids at start of RT1
 No3237
 Yes3844
 Missing information1720
Serum hemoglobin1
 Low26676
 Normal1618
 Missing information56
Serum albumin1
 Low21720
 Normal4248
 Missing information2832
Serum lactate dehydrogenase1
 Normal21416
 Elevated3540
 Missing information3844
Serum alkaline phosphatase1
 Normal22529
 Elevated2933
 Missing information3338
Serum creatinine1
 Low21315
 Normal4855
 Elevated1517
 Missing information1113
Serum C-reactive protein1
 Normal22023
 Elevated but less than 30 mg/L2731
 Elevated 30–60 mg/L1416
 Elevated >60 mg/L1720
 Missing information910
Thrombocyte count1
 Low21113
 Normal4552
 High1922
 Missing information1214
Charlson comorbidity index1
 078
 1-24451
 3 or more2832
 Missing information89
Smoking status1
 Current smoker3439
 No3439
 Missing information1922

RT: radiotherapy.
1Missing information in some cases.
2Hematology and blood chemistry results refer to institutional limits of normal; only test results obtained within one week before RT were considered.

We analyzed the potential prognostic impact of all baseline parameters shown in Table 1 and assigned SPS score. However, the performance of this score was unsatisfactory because two of the three patient groups had similar survival (Figure 2). As shown in Table 2, two components of the SPS score (metastases location and performance status) significantly influenced survival, while primary tumor type did not. In multivariate analysis, a total of four parameters significantly influenced survival: KPS, use of steroids, presence of liver metastases, and pleural effusion. Based on these parameters, a new 4-tiered prognostic score was developed. As described in Section 2, we compared two different variants, which are shown in Table 3. When applying a short-survival-definition of 1 month (variant 1), the resulting survival curves separated clearly (Figure 3). Median survival was 24.5 months for the favorable group, 9.7 and 2.8 months for the intermediate groups, and 1.1 months for the unfavorable group ( for comparison between the two favorable groups and for all other pair-wise comparisons). Thirty-three percent of patients in the unfavorable group died within 1 month and all within 2 months. When applying a short-survival-definition of 2 months (variant 2), the resulting survival curves separated equally clear (Figure 4). Median survival was exactly the same as in variant 1 ( for comparison between the two favorable groups and for all other pair-wise comparisons). Since the unfavorable group included exactly the same patients, 33% died within 1 month and all within 2 months. Because of its superior significance level, variant 2 might be the preferred assignment method.


CharacteristicMedian survival (months)value
Univariate1Multivariate

Karnofsky PS
 90–10018.30.00010.0001
 70–809.4
 ≤602.1
Known brain metastases
 No 9.70.008n.s.
 Yes3.6
Known liver metastases
 No9.70.0370.039
 Yes2.8
Pleural effusion
 No9.40.0070.039
 Yes1.3
Number of metastatic sites
 Max. 29.70.054n.s.
 3 or more2.8
Progressive disease outside RT target volume
 No12.60.033n.s.
 Yes5.5
Use of opioid analgetics
 No24.50.02n.s.
 Yes5.2
Use of steroids
 No12.20.0020.015
 Yes3.6
Serum albumin
 Low9.70.001n.s.
 Normal2.8
Serum alkaline phosphatase
 Normal15.10.027n.s.
 Elevated4.1
Serum creatinine
 Low1.60.0001n.s.
 Normal9.7
 Elevated15.1
Serum C-reactive protein
 Normal18.30.0001n.s.
 Elevated but less than 30 mg/L12.6
 Elevated 30–60 mg/L5.3
 Elevated >60 mg/L2.6
Thrombocyte count
 Low12.70.038n.s.
 Normal9.7
 High4.0
Number of abnormal blood tests2
 Max. 112.7
 25.80.008n.s.
 3 or more3.0
Smoking status
 Current smoker4.30.063n.s.
 No9.7
Time from first cancer diagnosis
 Shorter than median (47 months)5.30.089n.s.
 Longer than median9.7

RT: radiotherapy; PS: performance status.
1If more than 2 groups, value from log-rank test pooled over all strata.
2All tests shown in Table 1 were considered.
Significance levels were not corrected for multiple tests.

ParameterDied within 1 monthPoints1Died within 2 monthsPoints1

Karnofsky PS
 70–1002%07%1
 ≤6015%1.539%4
Known liver metastases
 No4%08%1
 Yes11%149%5
Pleural effusion
 No4%014%1
 Yes33%350%5
Use of steroids
 No3%010%1
 Yes11%128%3
Minimum sum score04
Maximum sum score6.517

PS: performance status.
1Death rate divided by 10.

4. Discussion

Palliative reirradiation is an important treatment option, providing symptom improvement in many patients with bone metastases [1] and other conditions [15]. While most previous studies were small and often retrospective, the randomized bone metastases study by Chow et al. comparing different fractionation regimens included 850 patients [1]. Median survival in the two arms was 9.3 and 9.7 months, respectively. This result is comparable to the 8.6 months reported in our own, bone metastases-dominated study. However, survival of individual patients might be as short as few days or as long as several years (Figure 1). Therefore, prognostic scores might be valuable decision aids when prescribing palliative reirradiation. Chow et al. have previously published several reports on a score for patients receiving palliative radiotherapy in general, the SPS. Development of this prediction model started in 395 patients referred to their palliative radiotherapy program [16]. Later, they refined their original six-parameter-model by reducing the number of variables to three (primary cancer type, site of metastases, and performance status), arriving at the SPS [8, 17]. We hypothesized that this score might also predict survival of patients receiving reirradiation but discovered that further studies, which also include other models, are needed. The performance of the SPS score (Figure 2) can be explained by the fact that not all adverse SPS features (nonbreast cancer, metastases other than bone, and poor performance status) influenced prognosis of reirradiated patients. In the present study, metastases location and performance status significantly influenced survival, while primary tumor type did not.

Disadvantages of our study include its retrospective design and limited number of patients, especially regarding subgroups. Not all patients had complete information on all baseline parameters recorded in the EPR system. The majority of reirradiation courses consisted of hypofractionated regimens, mostly 1–15 fractions, with dose/fractionation parameters reflecting a patient’s expected prognosis (clinical estimate). We did not use any particular prognostic models or scores when assigning treatment regime during the time period covered in our study. Nevertheless, more than 90% of patients who were offered reirradiation also completed their treatment. Only 6% were treated during the final month of life, suggesting that our clinical decision making was largely successful, even if further improvement should be attempted.

Our score based on KPS, use of steroids, presence of liver metastases, and pleural effusion performed promisingly. To the best of our knowledge, no other scores related specifically to palliative reirradiation exist. One of the clinical aims of applying prognostic scores might be avoidance of overtreatment in patients with very short survival [18]. Recently, Tanvetyanon et al. have reported on use of radiotherapy in the last 30 days of life in the United States [19]. They used a SEER-Medicare linked database to obtain a large study cohort of 202,299 patients who died as a result of lung, breast, prostate, colorectal, and pancreas cancers (top five cancer causes of death) between January 1, 2000, and December 31, 2007. The rate of radiotherapy in the last 30 days of life, by many regarded as inappropriate overtreatment, though this point of view is controversial, was 7.6%. No data on reirradiation were reported in this study, and no attempt was made to develop predictive models. Before our new score can be widely implemented, external validation is necessary. In the future, it might become possible to study narrowly defined patient groups, if sufficiently large databases can be created. For example, Tanvetyanon et al. have published prognostic factors for survival after salvage reirradiation in patients with head and neck cancer [19]. Rades et al. have developed scores specific to metastatic spinal cord compression [20, 21], and Sperduto et al. to brain metastases [22], both related to first line treatment rather than reirradiation.

5. Conclusions

Prognostic factors for survival might change during the course of disease, for example, from first line to subsequent treatments. The performance of the newly developed score was promising and might facilitate identification of patients who survive long enough to benefit from palliative reirradiation. It should be validated in independent patient groups, ideally from several institutions and countries.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

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Copyright © 2014 Carsten Nieder et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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