Abstract
Survival probabilities for high-grade glioma are estimated at the time of diagnosis and provide limited information following treatment. This study determined dynamic indices to predict post-diagnosis survival for high-grade glioma patients. Survival information for 2,743 patients with high-grade glioma, diagnosed in Los Angeles County during the years 1990–2000, were used to estimate conditional survival probabilities with 95 % confidence intervals, for patients still alive at 1, 2, 3, 4, or 5 years after diagnosis. The conditional probabilities of surviving one additional year increase as the post-diagnosis survival time increases (from 43 ± 2 % conditional on surviving 1 year after diagnosis to 91 ± 2 % conditional on surviving 5 years after diagnosis). Patients diagnosed with WHO grade III gliomas have higher conditional survival probabilities than those diagnosed WHO grade IV gliomas. However, as the years after diagnosis increase, the differences in the conditional probabilities between the two groups are attenuated. At the time of diagnosis, age and tumor histology (WHO grade), tumor site, primary treatment, time of treatment start after diagnosis, as well as whether the patient was treated at a teaching hospital were significantly associated with overall survival. By 4 years post-diagnosis however, with the exception of age, variables associated with survival at baseline were no longer significantly associated with survival. Conditional survival probabilities provide clinically relevant information for understanding the prognosis for patients with high-grade gliomas.
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Introduction
High-grade gliomas are the most common primary brain tumor, accounting for more than half of over 20,000 primary brain cancers diagnosed annually in the United States. These cancers are challenging to treat and are associated with relatively short survival [1]. Traditionally, estimates of survival are made at the time of diagnosis, most often utilizing median progression free and overall survival as well as 2- and 5-years survival rates. These estimates provide an overall prediction of disease outcome that are most helpful for cancer surveillance and public health intervention purposes. However, for individual survivors and physicians caring for these patients, these estimates are often not informative, or even misleading. For instance, patients who have survived a certain period of time after diagnosis (e.g. 2 years) likely have different probabilities of surviving the next 1 year from those that were estimated at the time of diagnosis. This is because a large proportion of patients will die within the first 1 or 2 years, and patients who have survived longer than 2 years likely have different survival patterns from those at the time of diagnosis. Conditional survival probabilities address this problem by calculating the survival probabilities based on the patients who have survived beyond a certain period of time, and therefore provide more accurate and dynamic estimates of survival after the initial diagnosis.
The present study, utilizing the Los Angeles County tumor registry data, was designed to answer the following question: What are the conditional survival probabilities of surviving one additional year, given that patients have already survived 1, 2, 3, 4 and 5 years after diagnosis of a high-grade glioma?
Methods
The population-based cancer registry, Cancer Surveillance Program (CSP) is both a member of the statewide population-based surveillance system, the California Cancer Registry (CCR), and part of the surveillance, epidemiology, and end results (SEER) program [2]. It extracts records of cancer patients from hospitals, institutes, clinics and medical laboratories equipped to diagnose cancer in Los Angeles County. The information collected by CSP includes demographic information, tumor characteristics, diagnostic information, extent of disease and limited treatment information, as well as the last follow-up date, vital status and cause of death.
Malignant glioma cases were identified using the International Classification of Diseases for Oncology (ICD-O-3) codes [3]. Cancer histology was characterized by the new World Health Organization (WHO) classification for brain tumors [4]. The selected glioma histology’s included malignant glioma, anaplastic astrocytoma, gemistocytic astrocytoma, glioblastoma, giant cell glioblastoma and gliosarcoma. Anaplastic oligodendroglial tumors were not included. 2,983 cases of high-grade glioma diagnosed in Los Angeles County from 01/01/1990 to 12/31/2000 were retrieved. Patients who were younger than 19 years old at the time of diagnosis or who were diagnosed with malignant gliomas in the brainstem, spinal cord, optic nerve or ventricle were excluded. A total 2,743 adult patients with supratentorial high-grade gliomas, WHO grade III or IV gliomas were included in this study. Cases were followed for survival through June 2004.
Overall survival was calculated as the time from the date of diagnosis (first surgery and pathological diagnosis) to the date of death for any reason, or the date the patient was last known to be alive. In contrast, the conditional survival was calculated as the time from the date of a landmark (e.g. 1 year anniversary post-diagnosis) to the date of death or the date the patient was last known to be alive, conditional on the patient surviving beyond the landmark date. Thus the conditional survival probabilities excluded patients who did not survive beyond the landmark date; stated differently, conditional survival analysis includes only those patients who are known to be alive and therefore still “at risk” of surviving or dying after the landmark date.
Numbers and percentages were used to summarize the study data. In univariate analysis, the log-rank test was used to test the association of overall survival with demographics, marital status, socioeconomic status, tumor characteristics at diagnosis, primary treatment, treatment start time, and type of treating hospital. The relative risk of death as well as associated 95 % confidence intervals were calculated based on the Pike estimate [5], using the observed and expected number of events from log-rank test statistic. Those factors significantly associated with overall survival in the univariate analysis were included in a multivariable analysis using the Cox proportional hazards model.
Kaplan–Meier plots were used to estimate and illustrate the probabilities of overall and conditional survival [6]. Bar charts were used to show the estimated probability of surviving 5 years from the time of diagnosis and conditional on having already survived for 1, or 2 or 3 years by age (≤55 years, 56–70 years and >70 years) and WHO status.
Results
A total of 2,743 malignant glioma patients meeting the inclusion criteria were identified in the CSP database. Baseline demographics and disease characteristics are summarized in Table 1. The median age at diagnosis was 64 years old; slightly more patients were male (55 %) than female (45 %). More patients were diagnosed with WHO grade IV gliomas (76 %) than with WHO grade III gliomas (24 %). After diagnosis, 83 % of patients underwent some form of treatment (i.e. surgery, radiation or chemotherapy). The associations of overall survival with demographics and disease baseline characteristics are shown in Table 2. Age at diagnosis, tumor site, WHO grade, primary treatment, time to start of treatment, as well as whether the patient was treated at a teaching hospital were statistically significantly associated with overall survival in univariate analysis (Table 2) and in multivariable analysis (Table 3, unconditional portion). Overall median survival and its 95 % confidence interval were 6.6 (6.2, 6.9) months with median follow-up of 8.6 years.
Trend of survival
The probability of overall survival (unconditional) at 1 year after diagnosis was 0.31 ± 0.01 and probability of surviving 2, 3, 4, and 5 years from diagnosis was 0.13 ± 0.01, 0.10 ± 0.01, 0.08 ± 0.01, and 0.06 ± 0.01, respectively (Fig. 1). In the conditional survival analysis, as patients remained alive longer (e.g. 1 and 2 years after diagnosis), the (conditional) probability of surviving additional years increased (Fig. 2a–d). The probabilities of survival at 1 year after diagnosis, and for one additional year conditional on having already survived 1, 2, 3, 4, and 5 post-diagnosis years are listed in Table 4. This increase was greatest during the first 2 post-diagnosis years, from 0.43 ± 0.02 conditional on surviving 1 year post diagnosis, to 0.72 ± 0.02 conditional on surviving 2 years after diagnosis, and leveled out as patients survived longer, i.e., 0.80 ± 0.03, 0.84 ± 0.03 and 0.91 ± 0.02 conditional on surviving 3, 4, and 5 years after diagnosis respectively.
The prognosis for patients with WHO grade III tumors was better than those with WHO IV gliomas, estimated by both unconditional and conditional survival probabilities—however, this difference, which was both substantial and statistically significant at the time of diagnosis and conditional on surviving 1 and 2 years, was no longer substantial or statistically significant once patients had survived 4 or 5 years; absolute differences in the probability of surviving one additional year were 0.47–0.26 = 0.21, 0.40, and 0.30 conditional on surviving 0, 1, and 2 years, but were 0.05, and 0.08, conditional on surviving 4 and 5 years, respectively. In both groups of patients, the conditional probability of one additional year of survival increased as patients survived longer (Table 4, Figs. 1, 2a–d). This trend was also seen in the probability of surviving 5 additional years survival conditioned on having survived for 1, 2, or 3 years (Fig. 3a).
A similar pattern was seen when patients were grouped by age: (1) younger patients manifested better one-year survival probabilities, (2) the conditional probabilities of one additional year of survival increased each year post-diagnosis, and (3) the differences among the age groups decreased as the time post-diagnosis increases (Fig. 3b).
Discussion
High-grade glioma is a relatively rare cancer with very poor survival. According to the Central Brain Tumor Registry in the United States during the years of 1998 to 2002, the estimated age-adjusted incidence of high-grade gliomas is 6.7 and 4.6 patients per 100,000 persons per year, for WHO grade III and grade IV gliomas respectively (Central Brain Tumor Registry in the United States, 2006). Gliomas account for 1.4 % of all new cancer cases and 2.3 % of all cancer deaths in the United States [2]. In general, non-Hispanic whites have the highest incidence of glioma and mortality rates from glioma among all the ethnic groups [2]. Among all the newly diagnosed cases of primary brain cancer in the United States, approximately 50 % are histologically classified as glioma and 50 % of all gliomas are glioblastoma (WHO grade IV) [7].
In the present study, data were analyzed from a large cohort of 2,743 adult patients with supratentorial high-grade glioma diagnosed in Los Angeles County between the years of 1990 and 2000, the largest reported study of conditional survival analyses in patients with high-grade glioma. In this study conditional probabilities to predict patients’ survival were used. The study showed that as patients survived longer after initial diagnosis, their probability of subsequent survival markedly increased.
The traditional estimates of survival are the survival rates which vary greatly depending upon prognostic characteristics and thus are challenging to apply for individual patients [8–11]. Conditional survival probabilities are estimated among a specific cohort of patients by excluding those who did not survive to the start of the landmark or time point of interest. Therefore, this conditioned cohort study represents a subpopulation of patients, in contrast to the analysis beginning at the time of diagnosis when all patients were included. In the present study, the estimated chance of 5-year survival after diagnosis is 6 % (136 out of 2,743 of patients survived 5 years after diagnosis—Fig. 1), a figure often cited in the literature and based on university brain tumor treatment centers [12–14]. However, when analyzed by conditional survival probabilities and conditional median survival times, the data demonstrate that as patients survive longer after diagnosis, their probabilities of surviving an additional one year increases (ranging from 43 % conditioned on 1-year survival to 91 % conditioned on 5-year survival) (Table 4), irrespective of original glioma grade.
The survival rate among the study population dropped steeply after diagnosis and overall median survival is approximately 6.6 months (Fig. 1). The very short median survival, nearly 40 % of that reported in clinical trials in patients with glioblastoma (median survival 14.6 months), reflects perhaps more accurately survival in a large urban community treating all patients without the restrictions imposed by trial inclusion or exclusion criteria [15] and in a wide variety of hospitals. Polley et al. [16] recently reported the overall and conditional probabilities of survival on 498 patients treated on 6 Phase II trials between 1975 and 2002; although 128 of these 498 received temozolomide, their outcome was not significantly different from patients on the pre-temozolomide protocols. Overall in the Polley series, the 4 year survival was 7 % (95 % CI: 5, 10 %); this was doubled what was observed in the group of WHO grade IV patients in this manuscript which was 3 % (95 % CI: 2, 4 %). As with the series reported in this manuscript, the conditional probabilities increased as the time post diagnosis increased (Fig. 4). Interestingly however, the (unconditional) survival during the first year was nearly doubled in the Polley series (58 % (95 % CI: 54, 63 %) vs. 26 % (95 % CI: 24 %, 28 %)). Selecting patients by way of entry into clinical trials, usually by specifying independence in activities of daily living (i.e. a Karnofsky performance status >60) and age (<71 years), results in what might be expected as optimal survival rates based on contemporary treatment paradigms. Rarely reported are trials designed for elderly patients with high-grade gliomas or for patients with compromised neurological performance. Los Angeles County, the site of the present study, is a large ethnically diverse community with a significant proportion of socioeconomically challenged patients that negatively impacts survival in essentially all cancer diagnoses.
Age is a well recognized negative prognostic factor for high-grade glioma and this study recapitulates its prognostic significance (Fig. 3b) [17–19]. However, the study data also suggests that when a high-grade glioma was diagnosed in the older age cohort, defined as patient’s ≥56 years of age, the probabilities of surviving one additional year increase substantially as patients survive longer (Table 4).
In conclusion, the present study examines the outcome of 2,743 patients with high-grade glioma, all identified in a population-based database, making it an ideal platform for performing conditional survival analyses. Although the CSP, the source where the data in this study was retrieved, is a California based cancer registry, the results are generalizable to patients with high-grade glioma in the United States. However, as a population-based cancer registry, CSP description of disease treatment is not exact. For example, it does not differentiate chemotherapy regimen, extent of surgery resection, types of salvage therapy, baseline performance status, etc. In addition, the data collection in the present study involves patients diagnosed between 1990 and 2000; the vast majority of these patients received all of their therapy prior to 2004 (when the data were abstracted). This is before temozolomide (Temodar [TMZ], Merck Pharmaceutical, Whitehouse Station, NJ), together with concurrent radiotherapy, became the standard of care for patients with newly diagnosed glioblastoma [7]. Therefore, this study does not reflect the impact of newer treatment, similar to other large comprehensive datasets [20]. This study suggests that conditional survival probability may be helpful to predict prognosis for patients with not only high-grade glioma, but other diseases with changing hazards over time. In summary, estimated by conditional survival method, patients diagnosed with high-grade glioma appear to have a large gain in their conditional survival probability over time.
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Acknowledgments
The collection of cancer incidence data used in this study was supported by the California Department of Health Services (CADHS) as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institutes (NCI) Surveillance, Epidemiology and End Results Program under contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute (PHI); and the Centers for Disease Control and Prevention’s (CDC) National Program of Cancer Registries, under agreement #U55/CCR921930-02 awarded to the PHI. The ideas and opinions expressed herein are those of the authors and endorsement by the CADHS, the NCI, and the CDC or their contractors and subcontractors is not intended nor should be inferred.
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Tsao-Wei, D.D., Hu, J., Groshen, S.G. et al. Conditional survival of high-grade glioma in Los Angeles County during the year 1990–2000. J Neurooncol 110, 145–152 (2012). https://doi.org/10.1007/s11060-012-0949-6
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DOI: https://doi.org/10.1007/s11060-012-0949-6