survival in patients operated on for pathologic fracture: implications for end-of-life orthopedic...

Survival in Patients Operated on for Pathologic Fracture:Implications for End-of-Life Orthopedic CareSaminathan S. Nathan, John H. Healey, Danilo Mellano, Bang Hoang, Isobel Lewis, Carol D. Morris,Edward A. Athanasian, and Patrick J. Boland

A B S T R A C T

PurposeLife expectancy is routinely used as part of the decision-making process in deciding thevalue of surgery for the treatment of bone metastases. We sought to investigate thevalidity of frequently used indices in the prognostication of survival in patients withmetastatic bone disease.

MethodsThe study prospectively assessed 191 patients who underwent surgery for metastatic bonedisease. Diagnostic, staging, nutritional, and hematologic parameters cited to be related tolife expectancy were evaluated. Preoperatively, the surgeon recorded an estimate ofprojected life expectancy for each patient. The time until death was recorded.

ResultsKaplan-Meier survival analyses indicated that the survival estimate, primary diagnosis, use ofsystemic therapy, Eastern Cooperative Oncology Group (ECOG) performance status, num-ber of bone metastases, presence of visceral metastases, and serum hemoglobin, albumin,and lymphocyte counts were significant for predicting survival (P � .004). Cox regressionanalysis indicated that the independently significant predictors of survival were diagnosis(P � .006), ECOG performance status (P � .04), number of bone metastases (P � .008),presence of visceral metastases (P � .03), hemoglobin count (P � .009), and survivalestimate (P � .00005). Diagnosis, ECOG performance status, and visceral metastasescovaried with surgeon survival estimate. Linear regression and receiver-operator character-istic assessment confirmed that clinician estimation was the most accurate predictor ofsurvival, followed by hemoglobin count, number of visceral metastases, ECOG performancestatus, primary diagnosis, and number of bone metastases. Nevertheless, survival estimatewas accurate in predicting actual survival in only 33 (18%) of 181 patients.

ConclusionA better means of prognostication is needed. In this article, we present a sliding scale forthis purpose.

J Clin Oncol 23:6072-6082. © 2005 by American Society of Clinical Oncology

INTRODUCTION

Decisions regarding potential surgery for met-astatic disease require reliable data aboutpatient survival and quality of life. This inves-tigation evaluated factors that have been citedas important correlates to patient post-operative survival and compared them to sur-geon preoperative survival estimates.

This information is sought for manyreasons. It helps to set appropriate expecta-tions for the patient, family, and medicalstaff. Data about cost, risk, and quality of lifeare often conflicting, but if these data couldbe weighed properly, it would help to definethe most appropriate treatment for patientswith metastatic bone disease.1-7 Utilityanalysis is an effective method to evaluate

From the Orthopaedic Surgery Service,Department of Surgery, MemorialSloan-Kettering Cancer Center, NewYork; and Weill Medical College ofCornell University, Ithaca, NY.

Submitted August 17, 2004; acceptedApril 22, 2005.

Supported by grants from the BiometOncology Fellowship and the PearlmanLimb Preservation Fund.

Presented in part at the 12thInternational Symposium of LimbSalvage, Rio de Janeiro, Brazil,September 15-16, 2003.

This work is original and solely ownedby the authors and their institution.

Authors’ disclosures of potential con-flicts of interest are found at the end ofthis article.

Address reprint requests to Patrick J.Boland, MD, Memorial Sloan-KetteringCancer Center, 1275 York Ave, New York,NY 10021; e-mail: [email protected].

© 2005 by American Society of ClinicalOncology

0732-183X/05/2325-6072/$20.00

DOI: 10.1200/JCO.2005.08.104

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

VOLUME 23 � NUMBER 25 � SEPTEMBER 1 2005

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Downloaded from jco.ascopubs.org on February 13, 2016. For personal use only. No other uses without permission.Copyright © 2005 American Society of Clinical Oncology. All rights reserved.

complex problems like this and can guide decision mak-ing by the individual patient, other stake holders, andsociety in general. It depends on the accurate predictionof survival, among other factors. Unfortunately, littledata exist to inform these end-of-life decisions.8-18

The present study was designed to investigate the prog-nosis of patients with metastatic bone disease presenting tothe orthopedic surgeon in need of skeletal surgical stabili-zation. Often the decision to operate on a patient withmetastatic bone disease is strongly influenced by the ex-pected survival of the patient.1,2,4-7,17,18 Previous studiesfocusing on specific primary cancers have been conductedand remain valuable tools in this regard.5,6,10,19-21 However,these studies do not provide a general approach that may beapplied to this clinical scenario.

Much of the orthopedic literature on prognosticationis devoted to the definition of clinical, radiologic, and bio-logic markers of disease in the nonmetastatic patient popu-lation. It is assumed that the same parameters are applicableacross all stages of disease.17,18,21-26 The patients investi-gated in this series are, by definition, incurable, and manyare in the terminal stage of their disease. We sought toinvestigate some well-recognized prognostic parameters toassess their value in determining the survival of patientswho require treatment of metastatic disease to the bone.In addition, we sought to investigate how well theseparameters stacked up against the clinical judgment ofthe surgeon and to translate this clinical evaluation into areproducible format.11,17,18,27,28

METHODS

Between September 22, 1999 and March 13, 2003, all patients whowere operated on for pathologic fracture or related indicationswere entered into a prospective quality-control database. Survivaldata were determined at two time points (April 2003 and May2004). Approval for the use of clinical material was provided by theinstitutional review board.

Clinical parameters acquired included date of birth, sex, pri-mary diagnosis, site of surgery, use of systemic therapy, and East-ern Cooperative Oncology Group (ECOG) performance status.Age was divided for survivorship analysis into patients older than65 years and patients 65 years old and younger. For methodologicpurposes, the primary diagnosis was grouped into five broad cat-egories comprising lung cancer, breast cancer, prostate cancer,renal cancer, and other cancers. These categories represented themost prevalent of the diseases in this series. Site of surgery wasclassified into the upper extremity, the lower extremity, and thespine. Systemic therapy in the context of this study includes allforms of nonsurgical and nonradiotherapeutic adjuvants (eg, cy-totoxic, hormonal, immunologic, metabolic, and so on) adminis-tered before or after surgery. The ECOG performance status29 wasused as a clinical indicator of general functional condition. TheECOG performance status definitions are as follows: 0 for normalfunction, 1 for minimal functional impairment, 2 for impairmentamounting to spending less than 50% of time in bed, 3 for impair-

ment amounting to spending more than 50% of time in bed, and 4for being completely bed bound. The performance status wasmeasured at baseline as part of the standard evaluation of allpatients on our service.

The number of bone metastases was based on radiologicassessment and bone scans. For statistical assessment of survivor-ship analysis, metastasis was categorized into patients with a singlemetastatic focus and patients who had multiple bone metastases.The presence of visceral metastases was based on routine com-puted tomography scans of the chest, abdomen, and pelvis. Nodalinvolvement was categorized for methodologic purposes intopresence or absence of adenopathy and was assessed by physicalexamination and imaging studies of thoracic, abdominal, andpelvic cavities. Nodal involvement alone, independent of visceralinvolvement, was not classified as visceral metastases per se.

Blood investigations were based on the routine preoperativeassessment for surgery. Laboratory data acquired included serumalbumin and calcium, hemoglobin, and lymphocyte counts.10,21-27

For purposes of survivorship analysis, the following data weredivided into two groups: serum albumin, � 3.5 g/dL v greater than3.5 g/dL; serum calcium, � 9 mg/dL v greater than 9 mg/dL;hemoglobin, � 10 g/dL v greater than 10 g/dL; and lymphocytecount, � 500 cells/�L v greater than 500 cells/�L.

The authors’ service represents a specialized orthopaedic on-cology unit in a tertiary referral cancer center. Most patients weretreated by the senior author (P.J.B.) who has close to 30 years ofexperience in the field. All official consults are maintained in adepartment-owned database. This excludes informal consults forpatients who nevertheless may have had surgery and were in-cluded in this study. At the time of first consult, all patientsdeemed suitable for surgical stabilization were reviewed by thesurgeon who made an assessment of the expected survival of thepatient in months. This was recorded, and the patient wassubsequently observed. By definition, the prediction was accu-rate if the actual survival was within 20% of the surgeon esti-mate of expected survival.

Data on the occurrence of death was gleaned from aninstitution-owned patient management database (Disease Man-agement System version 5.2, 1996; Memorial Sloan-KetteringCancer Center, New York, NY). Data was maintained in hard copyand electronically in a spreadsheet in Microsoft Excel version 10for Windows NT (Microsoft, Redmond, WA). Unless otherwisestated, clinical parameters are presented as the mean � standarddeviation, and survival in months is presented as the median with95% CIs.

Statistical analysis was performed using SPSS version 11.5 forWindows NT (SPSS Inc, Chicago, IL). Univariate analysis usingthe Kaplan-Meier method with log-rank assessment was per-formed to assess prognostic significance of individual risk factors(Figs 1 to 6). Cox regression multivariate analysis of factors foundstatistically significant by univariate analysis was used to assess forthe independent prognostic value of risk factors. Comparisons ofvariables defined by means and standard deviations alone wereperformed with the Student’s two-tailed t test. Linear regressionanalysis and receiver-operator characteristic (ROC) curve assess-ment of independently prognostic variables were used to show therelative value of these factors in predicting survival (Fig 7). For theparameter of primary diagnosis, the hazard ratio was derived fromsurvival analysis and used as the independent variable in linearregression and ROC assessment. Statistical significance was de-fined as P � .05.

Survival in Patients With Pathologic Fracture

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Data from the parameters found to be statistically significantby multivariate analysis were consolidated in a sliding scale basedon median survival and 95% CI (Fig 8). To use the sliding scale, therelevant parameters were placed on the line representing the me-dian and 95% CI in order of chronologic clinical assessment (ie,diagnosis, ECOG performance status, bone metastasis, visceralmetastasis, and hemoglobin). When there was disparity betweenfactors (eg, a patient with low hemoglobin but single metastasis),the relative position of the other factors and their statistical signif-icance as well as the clinician estimate influenced placement.

RESULTS

Between September 22, 1999 and March 13, 2003, 191 pa-tients were entered onto the study. All patients underwentsurgical procedures pertaining to metastatic bone disease.The data were periodically updated during the 4 years of thestudy. The time of last accrual of data was May 19, 2004. Atthe time of last accrual, 50 patients remained alive, andthere had been 141 deaths. Survival estimates had beenprovided for 181 patients. Kaplan-Meier and Cox regres-sion analyses were performed on all 191 patients. Overall,

Fig 1. Primary diagnosis as a predictor of survival. Lung cancer patientsperformed poorly as opposed to renal cell carcinoma patients, who per-formed best. The patients with other cancers tended to cluster betweenthese two groups.

Fig 2. Systemic therapy as a prognostic indicator. Patients with a betterprognosis, like renal cell carcinoma, tended not to be candidates forsystemic therapy. Patients with poorer prognosis tended to be candidatesfor systemic therapy. Systemic therapy was not found to be an independentpredictor for survival.

Fig 3. Eastern Cooperative Oncology Group (ECOG) performance status asa predictor of survival. Patients with poorer ECOG performance status didprogressively worse. ECOG performance status was found to be indepen-dently predictive of survival and was also a covariate with the surgeon’sestimate of survival.

Fig 4. Bony metastases as a predictor of survival. Multiple bone metastaseswere an independently significant poor prognostic factor. Multivariate analysiswith estimated survival did not change its significance. Hence, ironically, thismay not have been considered by the surgeon in deriving an estimate.

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median survival in the cohort was 8 months (95% CI, 5.4 to10.6 months).

There were 86 female patients (45%) and 105 malepatients (55%) in this series. Age was evenly distributedbetween the two groups (study population: mean age,61.8 � 13.6 years; mean for males, 61.6 � 13.5 years; meanfor females, 62.0 � 13.7 years). The most prevalent diagnos-tic groups included 39 patients (20%) with lung cancer, 37patients (19%) with breast cancer, 31 patients (16%) withrenal cancer, 15 patients (8%) with prostate cancer, and 69patients (36%) with other cancers (Table 1).

Within the stipulated time, there had been about 320official fracture-related consults on the service. Therefore,the operative rate was 60% (191 of 320 consults). Surgerywas performed on the spine in 34 patients (18%), on theupper extremity in 52 patients (27%), and on the lowerextremity in 105 patients (55%). The main indications forsurgery were fractures or impending fractures of bones ofthe extremity afflicted by metastatic disease. Impendingfractures in the extremities were assessed, as per publishedguidelines, to be at high risk for fracture and prophylacti-cally treated if they were osteolytic more than osteoblastic,were in the peritrochanteric area of the femur rather than innon–weight-bearing bones, involved more than half of thecircumference of a bone, and were associated with func-tional pain.9 Joint replacement surgery was performed forfractures in the hip, knee, shoulder, and elbow. Fracturestabilization using plates, screws, and rods supplementedwith cement was performed in long bones of the extremity.Spinal surgical decompression and stabilization were per-formed for neurologic compromise or potential neurologiccompromise in the spine, especially in radiation-resistant

tumors. Amputations were performed in patients with oth-erwise unmanageable limbs who were unsuitable for exten-sive surgery. Accordingly, joint replacement surgery was

Fig 5. Visceral metastases as a prognostic indicator. Although significanthere, visceral metastasis was not found to be independently predictive ofsurvival when considered with the surgeon’s estimate. This is probablybecause this factor was taken into consideration by the attending surgeonduring prognostication.

Fig 6. Hematologic markers as prognostic indicators. Of the markersreviewed, (A) hemoglobin level, (B) albumin, and (C) absolute lymphocytecount were found to be significant predictors of survival. Serum calcium wasnot significantly predictive. Only hemoglobin level was independently pre-dictive of survival on multivariate analysis.


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performed in 96 patients (50%), extremity fracture stabili-zation was performed in 59 patients (31%), spinal surgicaldecompression and stabilization were performed in 34 pa-tients (18%), and amputations were performed in two pa-tients (1%).

Twenty patients required reoperation. In general, thiswas a result of disease progression, which compromised theprevious construct. Two patients required surgery for infec-tion. Four patients had surgery for disease progression inthe form of excision of soft tissue masses, which did notcompromise previous constructs. Fracture stabilizationfailure was the most common indication for reoperation(seven patients). Other indications included five joint re-placement failures and two spinal instrumentation failures.

During the course of the study, 85 patients (45%) didnot receive systemic therapy, and 106 patients (55%) didreceive systemic therapy. ECOG performance status wasfavorable (0, 1, or 2) in 93 patients (49%) and unfavorable(3 and 4) in 93 patients (49%). ECOG performance status

was not available in five patients. Bone metastasis was singlein 55 patients (29%) and multiple in 136 patients (71%).Nonskeletal visceral metastases were present in 113 patients(59%) and absent in 78 patients (41%). Nodal involvementwas noted in 34 patients (18%) and absent in 157 patients(82%). The mean albumin level in the cohort was 3.9 � 0.6g/dL. The mean serum calcium measured 9.2 � 1.0 mg/dL.The mean hemoglobin level was 11.5 � 1.9 g/dL, and the meanabsolute lymphocyte count was 1,500 � 5,100 cells/�L.

Of the clinical parameters, only primary diagnosis, useof systemic therapy, and ECOG performance status werestatistically significant predictors of survival by Kaplan-Meier analysis. As defined, age older than or � 65 years wasnot found to be statistically significant for predicting sur-vival (P � .8). Sex (P � .4) and site of surgery (P � .8) weresimilarly unremarkable for predicting survival.

The primary histologic type was significant in predict-ing survival (P � .008). Lung cancer patients fared theworst, with a median survival (Table 2) from the time oforthopedic consult of 4 months (95% CI, 2.2 to 5.7months). Renal cell carcinoma patients fared the best, with amedian survival time of 20 months (95% CI, 15.2 to 24.8months). The median survivals of all other patients were clus-tered between the values for these two histologic types (Fig 1).

The use of systemic therapy (Fig 2) was a significantpredictor of survival (P � .0004). Systemic therapy use wasassociated with a poorer prognosis, with a median survivaltime of 5 months (95% CI, 3.3 to 6.7 months). Paradoxi-cally, patients who did not receive systemic therapy hadbetter prognoses (median survival time, 16 months; 95%CI, 5.7 to 26.3 months).

ECOG performance status (Fig 3) was significantlypredictive of survival (P � .0001). Median survival time forpatients with an ECOG performance status of 0, 1, or 2was 14 months (95% CI, 8.1 to 19.9 months), whichcontrasted strongly with patients with an ECOG perfor-mance status of 3 or 4 (median survival time, 5 months;95% CI, 2.8 to 7.2 months).

Both the presence of visceral metastases and the num-ber of bones involved by metastatic disease were significantpredictors of survival. Patients with single bony metastasis(Fig 4) did significantly better than patients with multiplebony metastases (P � .00001). Median survival time was24.7 months (95% CI, 17.5 to 32 months) for patients withsingle bony metastasis compared with 6 months (95% CI,3.6 to 8.4 months) for patients with multiple bony metasta-ses. Nodal involvement was not a significant predictor ofsurvival (P � .08). Patients with visceral metastases (Fig 5)did significantly worse than patients without visceral metas-tases (P � .00001), with median survival times of 6 months(95% CI, 4 to 8 months) versus 24.7 months (95% CI, 15.2to 34 months), respectively.

Several of the blood test results correlated with sur-vival. Hemoglobin (Fig 6A) was a significant predictor of

Fig 7. Survival estimate was the most accurate prognostic parameter on(A) linear regression and (B) receiver-operator characteristic curve analysis.On the graph (A), the boxed areas represent areas that would correspondto short, intermediate, and long actual and estimated survivals as defined inthe text. Short- and intermediate-term survivors were overestimated,and long-term survivors were underestimated. ECOG, Eastern CooperativeOncology Group.

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survival (P � .0001). Patients with a low hemoglobin levelhad a median survival time of 3 months (95% CI, 1.3 to 4.7months), whereas patients with higher levels survivedlonger (median survival time, 10.3 months; 95% CI, 5.5 to15.2 months). Albumin level (Fig 6B) had a significantprognostic value (P � .004). Patients with low albumin hada median survival time of 5.6 months (95% CI, 2.6 to 8.6months), whereas patients with normal albumin fared bet-ter (median survival time, 10.3 months; 95% CI, 5 to 15.7

months). Absolute lymphocyte counts (Fig 6C) were signif-icantly predictive of survival (P � .0003). The median sur-vival time in patients with low lymphocyte counts was 3.2months (95% CI, 2.3 to 4.1 months) compared with 10.3months (95% CI, 6.4 to 14.3 months) in patients withhigher counts. Serum calcium was not a significant predic-tor of survival (P � .8).

The parameters found to be significant by Kaplan-Meier univariate analysis were assessed for independent

Fig 8. Graphical representation of datalisted in Table 2. (A) In this sliding scale, thecircles represent the medians, and the ar-rows represent the 95% CIs. (B) The bandsrepresent the values of parameters of twopatients presented in Table 3 (see text fordetails). The P value should influence judg-ment, as should the clinician estimate. ECOG,Eastern Cooperative Oncology Group.


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prognostic value using Cox regression multivariate analysis.The results of the analysis for the parameters of primarydiagnosis, systemic therapy, ECOG performance status,bone metastases, visceral metastases, hemoglobin level, se-rum albumin level, and absolute lymphocyte count arelisted in Table 2. In addition, estimated survival was in-cluded in a second multivariate analysis.

The six parameters found to be independently sig-nificant in predicting survival were primary diagnosis(P � .006), ECOG performance status (P � .04), number ofbone metastases (P � .008), presence of visceral metastases(P � .03), hemoglobin level (P � .009), and survival esti-mate (P � .00005). Survival estimate was found to be acovariate with diagnosis, ECOG performance status, andvisceral metastases. The trend 1 year later was similar, ex-cept that multiplicity of bone metastases became less signif-icant (P � .05) and presence of visceral metastases becamemuch more significant (P � .00003).

These six parameters were assessed using linear regres-sion and ROC curve assessment (Fig 7). Linear regressionanalysis (graphs not shown) revealed a squared correlationvalue (R2) that was highest for estimated survival(R2 � 0.33), followed by hemoglobin (R2 � 0.15), visceralmetastases (R2 � 0.11), ECOG performance status(R2 � 0.06), primary diagnosis (R2 � 0.05), and bonemetastases (R2 � 0.05). Linear regression analysis (Fig 7A)of estimated survival within 20% of the actual estimate

reduced the R2 value to 0.30, suggesting that the clinician’sestimate could not be further optimized by simply increas-ing its tolerance. ROC curve assessment (Fig 7B) of survivalas the state variable showed that the area under the curveand, thus, prognostic value were greatest for estimated sur-vival, followed by visceral metastases, hemoglobin level,bone metastases, diagnosis, and ECOG performance status.

At final analysis, the survival estimate with a 20% mar-gin of error was accurate in predicting actual survival in33 (18%) of 181 patients. Of the remaining 148 patients, 78(43%) were underestimated and 70 (39%) were overestimatedin terms of duration of expected survival. There did not seemto be a systematic error in over- or underestimating survival.From a practical standpoint, it is often necessary to give aminimum survival estimate (ie, the minimum duration thatthe patient is at least likely to survive). Analysis with a 20%margin of error showed that the survival estimate was able topredict the minimum survival of 111 (61%) of 181 patients.There was no tendency towards over- or underestimation inmen versus women or in patients older versus younger than 65years. When corrected for diagnosis, the numbers in eachcomparison group were considerably reduced. In the majordiagnostic groups, however, there was no significant trendtowards over- or underestimation with respect to sex or age.

When the patients were categorized into groups ofsurvivors, namely short (survival for � 3 months), interme-diate (survival � 3 and � 9 months), and long (� 9months), the data indicates that, although the clinicianestimate is the most accurate prognostic parameter, it isapparently miscalibrated. Defined in this manner, 34 (64%)of 53 short survivors, 22 (53%) of 41 intermediate survi-vors, and 56 (64%) of 87 long survivors were categorizedaccurately (Fig 7A). In the short survival group, actualsurvival (1.4 � 1.1 months) was significantly lower(P � .000001) than the surgeon estimate (4.5 � 3.9months). In the intermediate survival group, actual survival(5.9 � 1.7 months) was also significantly lower than thesurgeon estimate, which was 8.1 � 5.7 months (P � .02). Inthe long survival group, actual survival (24.9 � 10.4months) was significantly longer than the surgeon estimate,which was 14.8 � 9.3 months (P � .000001). Hence, shortand intermediate survivors were overestimated and longsurvivors were underestimated in terms of expected dura-tion of survival.

By considering all significant factors listed in Table 2, asliding scale may be constructed (Fig 8). To test this scale,five subsequent patients not in this study were gleaned froma department-owned database, and their parameters werecompared with the chart (Table 3). Figure 8B illustratestwo patients from Table 3 mapped onto the chart as bands.Patient 1, who had a diagnosis in the other category andan ECOG performance status of 3, had visceral metasta-ses, multiple bony metastases, and a hemoglobin level ofmore than 10 g/dL. The intersection of all these values was

Table 1. Major Histologic Diagnosis of Patients With Metastasesto the Bones

Primary Diagnosis�

No. ofPatients

Lung 39Breast 37Renal 31Prostate 15Myeloma 11Colorectal 11Melanoma 10Lymphoma 7Bladder 7Unknown primary 6Uterine leiomyosarcoma 3Sarcoma 3Thyroid 2Pancreas 2Hepatocellular 2Esophagus 2Trachea 1Squamous cell carcinoma, tongue 1Cholangiocarcinoma 1

NOTE. The diagnoses follow the general epidemiologic pattern of moststudies on the subject.

�For methodologic purposes, the first four most prevalent cancers wereassessed individually in survivorship analysis, whereas the remainderwas grouped as others.

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ultimately dictated by the upper limit of the range repre-senting ECOG performance status and the lower limit of therange representing the hemoglobin level, yielding an esti-mated survival of 6 to 7 months. The actual survival was 7months. Patient 3, who had a diagnosis in the other categoryand an ECOG performance status of 4, had visceral metas-tases, multiple bony metastases, and a hemoglobin level ofless than 10 g/dL. In contrast, the intersection of all thesevalues corresponded to the upper limit of the range repre-senting the hemoglobin level and the lower limit of therange representing the presence of visceral metastases. Thisyielded a survival estimate of 4 months, which corre-sponded to the actual survival. As shown from these results,patients with poor prognostic factors are reasonably pre-dicted to have poor survival. Patients who die prematurely

from nononcologic underlying medical problems and pa-tients with discordant prognostic factors are less accuratelypredicted, although this difference is small (2 months inpatient 4 in our example). In patients with discordant fac-tors, the clinician estimate is used as an additional parame-ter to guide placement on the scale.

DISCUSSION

This article attempts to answer a difficult question. What isthe expected survival in patients presenting with metastaticbone disease? In their early description of treatment for thiscondition, Beals et al8 stated that the indication for surgery wasthat these “fractures were predictable.” The idea that there

Table 2. Median Survival of Log-Rank–Derived Significant Prognostic Groups and Levels of Significance as Derived by Cox RegressionMultivariate Analysis

ParameterKaplan-MeierAnalysis (P )

Cox Regression(P )

Cox Regressionon Data 1 Year

Later� (P )

Cox RegressionWith SurvivalEstimate† (P )

Median Survival(months)

95% CI forMedian Survival

(months)

ClinicalPrimary diagnosis .008 .006‡ .001 .43

Renal cell carcinoma 20 15.2 to 24.8Breast cancer 13.5 7.5 to 19.4Prostate cancer 10 0 to 23.6Lung cancer 4 2.2 to 5.7Other cancers 7 3.1 to 10.9

Systemic therapy .0004 .31 .18 .47No 16 5.7 to 26.3Yes 5 3.3 to 6.7

ECOG performance status .0001 .04‡ .03 .760, 1, and 2 14 8.1 to 19.93 and 4 5 2.8 to 7.2

RadiologicBone metastases .00001 .008‡ .05 .03

Single 24.7 17.5 to 32Multiple 6 3.6 to 8.4

Visceral metastases .00001 .03‡ .00003 .71Absent 24.7 15.2 to 34Present 6 4 to 8

HematologicHemoglobin, g/dL .0001 .009‡ .009 .01

� 10 10.3 5.5 to 15.2� 10 3 1.3 to 4.7

Albumin, g/dL .004 .23 .17 .40� 3.5 10.3 5 to 15.7� 3.5 5.6 2.6 to 8.6

Lymphocyte count, cells/�L .0003 .97 .94 .89� 500 10.3 6.4 to 14.3� 500 3.2 2.3 to 4.1

Abbreviation: ECOG, Eastern Cooperative Oncology Group.�The same data set was reviewed 1 year later. Overall trends were similar except for one obvious difference; multiplicity of bone metastases became less

significant as a predictor of survival, whereas presence of visceral metastases became more significant, which may be a reflection of progression of diseaserendering the patients terminal.†When survival estimate was included in the Cox regression analysis, primary diagnosis, ECOG performance status, and visceral metastases were all

rendered insignificant. This suggests that these three parameters were intuitively considered at some level by the attending surgeon in deriving a survivalestimate. The survival estimate was the most significant predictor of survival in this study (P � .00005).‡These parameters and the survival estimate represent the six factors that were independently predictive of prognosis.


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should be a reasonable life expectancy before consideringsurgery is a relatively recent suggestion.1,2,4-7 In addition,being able to predict the expected survival of a patient hasfundamental implications on the kind of reconstructionused. Patients with a prolonged life expectancy should re-ceive an appropriately durable reconstruction, as opposedto the individual with a short life expectancy for whom anexpedient method may be preferable.3,10

The present study has one major limitation; all patientsconsidered for surgery had been physician selected to be inan ill-defined group with an expected survival reasonableenough to benefit from surgery. Also, issues of comorbidityare undoubtedly important but were not considered in ourstudy. Recent work suggests that these issues should receivecloser scrutiny.30 Hence, this data may not be applicable topatients who are not deemed reasonable surgical candidatesor who refused surgery. Terminally ill patients with less than a1-month prognosis were not operated on because they had aprohibitive operative risk. The main value of this analysis is inpredicting survival in all other patients who were at least sur-gical candidates at the outset, which is the more commonclinical scenario for the orthopedic surgeon.11,27,28

The main parameters assessed were gleaned from pre-vious studies that have looked at prognostic factors in anumber of conditions.10,19-22,25,31-33 The clinical parame-ters of age and sex were not expected to be of prognosticsignificance because these two parameters were evenly dis-tributed among the good and bad performers. Perhaps sur-prisingly, the site of surgery was not predictive of survival.3

This has interesting implications. Spine surgery, for exam-ple, has been regarded as high-risk surgery that should bejustified by an adequate estimated survival.7 Our findingssuggest that this concept is misleading. The other interpre-tation of this data is that the successful surgical treatment ofthe patient’s metastatic disease may improve survival to thepoint that the actual region involved becomes immaterial.34

Primary site was found to be a significant predictorof survival. The four most prevalent diagnostic groups

(lung, breast, renal cell, and prostate cancer) are represen-tative of most series on the subject.9,21 Patients with lungcancer fared the worst, and patients with renal cancer faredthe best, as shown in Figure 1 and Table 2. Diagnosis wasfound to be independently predictive of survival on multi-variate analysis.17,18

Systemic therapy use was found to be a poor prognosticindicator for survival. This should not be taken to mean thatsystemic therapy is contraindicated in this condition. Be-cause of the complex combinations of different forms ofsystemic therapy in patients with prostate, breast, and lungcancer, it is difficult to interpret the meaning of this result.In this series, systemic therapy use was unevenly distributedbetween the primary diagnostic categories. Of the fourcommon diagnoses, systemic therapy was predominantlyused in breast and prostate patients. In lung cancer patientsand all other patients (the patients with the worst prog-noses), systemic therapy was used in approximately half ofthe patients. The overwhelming majority of renal cancerpatients (the patients with the best survival) did not receivesystemic therapy. This selection bias accounted for the poorprognosis associated with systemic therapy.

The ECOG performance status was found to be a sig-nificant prognostic factor. This has similarly been found tobe a useful prognostic indicator in other studies. Further-more, it’s simplicity of use and reproducibility makes it avaluable index for prognostication.29,35-37

Bone metastases were found to be independently pre-dictive of survival.4 The concept of polyostotic metastasesbeing poorly prognostic has important implications. Atleast part of the morbidity and mortality that result frompathologic fractures is the predisposition to infirmity andimmobility,34 which are readily amenable to improvementby surgical intervention. This would be a strong justifica-tion for surgical intervention in these patients as a means ofprolonging life and not just palliation alone.

Hematologic markers have been used in various studiesas prognostic indicators.21-27 Surprisingly, serum calcium was

Table 3. Predictive Value of Sliding Scale Presented in Figure 8

Patient No. Primary DiagnosisECOG

PSBone

MetastasesVisceral

MetastasesHemoglobin Level

(g/dL)

ScaleEstimation(months)

ActualSurvival(months)

1 Other 3 Multiple Present 13.8 6-7 72 Other 3 Multiple Present 9.4 4 43 Other 4 Multiple Present 9.5 4 44 Lung cancer 4 Single Absent 12.0 6-7† 45 Other 3 Multiple Present 12.9 6-7 1‡

Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status.�Five patients with complete data are presented here. The scale was found to be relatively accurate in predicting survival. The caveats are patients who have

discordant parameters (patient 4) and patients who have unexpected early death (patient 5).†This patient had two poor (diagnosis and ECOG performance status) and three good (hemoglobin and bone and visceral metastases) parameters.‡This patient had multiple medical problems and died soon after surgery.

Nathan et al



not found to be a significant predictor of survival both byunivariate Kaplan-Meier and t test analyses. Hypercalcemiais a problem that is actively pursued and treated in thisinstitution; hence, it may not have become a clinically ap-parent problem. This is supported by the absence of hyper-calcemia seen in this series; the levels in survivors (9.27 �0.86 mg/dL) were not significantly different from levels innonsurvivors (9.23 � 1.03 mg/dL). Historically, this factormay have been important, but modern oncologic practiceincluding bisphosphonate treatment may have neutralizedthis prognostic factor. Serum albumin, lymphocyte counts,and hemoglobin level were all found to be significant pre-dictors of survival. However, only hemoglobin level wasfound to be an independent predictor of survival.17,18,22-25,27

Diagnosis, ECOG performance status, number of bonemetastases, presence of visceral metastases, hemoglobinlevel, and survival estimate were independent predictors ofsurvival.4-6,10,17-19,27,36,37 The trend 1 year later was similar,except that multiplicity of bone metastases became lesssignificant (P � .05) and presence of visceral metastasesbecame much more significant (P � .00003); this is likely areflection of disease progression and increased tumor load.In general, it was found that patients with an unfavorableprimary diagnosis, poor ECOG performance status, multi-ple bone and visceral metastases, and low hemoglobin levelsurvived half as long as patients with favorable parameters(Fig 8). Linear regression (Fig 7A) and ROC curve assess-ment (Fig 7B) suggest that the predictive values of theseparameters for survival were low, accounting for between5% and 15% of the variance in the data (R2 � 0.05 to 0.15).This weak correlation implies that these parameters are notas clinically useful as commonly assumed. The attendingsurgeon’s prediction (R2 � 0.33) was clearly superior to anyof these parameters; this may be attributed to their extensiveexperience in the field.11,27,28 Conversely, by consider-ing hemoglobin level (R2 � 0.15), visceral metastases(R2 � 0.11), ECOG performance status (R2 � 0.06),primary diagnosis (R2 � 0.05), and bone metastases(R2 � 0.05), 42% (the sum of R2) predictability of survival ispossible from an objective standpoint. This may be superiorto that offered by experience alone.

Interestingly, within specific survival groups, thenumbers of short and intermediate survivors were over-estimated and the number of long survivors was under-estimated in terms of duration of survival. This providessome insight into conflicting literature that, for the mostpart, shows that survival estimates tend to be overoptimisticbut has occasionally reported the reverse. Furthermore, ithas been shown that, when clinical prediction of survivalincreased, variability in actual survival also increased.11 The

accuracy of survival estimation for the surgical patients inthis series illustrates this point well.

One possible explanation in this study for why diagno-sis, ECOG performance status, and visceral metastasis wereall significant predictors rendered insignificant by multivar-iate analysis is that these parameters covaried with the sur-geon’s estimate or that the surgeon already considered allthese factors at some level in deriving a conclusion. Yet thesurgeon’s estimate alone was inaccurate as a predictor ofsurvival. Perhaps the determinant is an ambiguous combi-nation of factors that has, to date, not been determined. Itmay be that the patient’s cognitive state, demeanor, drive,general state, or other factors together with the more tradi-tional parameters should all be considered in the prognos-tication of these patients.11,18,27,28,38,39

The suggestion that the clinician estimate is accuratebut miscalibrated has been described.11,18 This may be cap-italized on by getting the treating clinician to suggest aprognostic category (eg, short, intermediate, or long sur-vival) and support this estimate using the data presented inTable 2 and Figure 8. It would prove to be a more objectiveundertaking than suggesting an actual number, which israrely helpful. Such a model of assessment would be auseful adjunct to the graphical system proposed. Graphicalmethods of prognostication are admittedly cumber-some.4,9,11,27,28,35,40,41 The proposed sliding scale systemhas the benefit of allowing for the influence of the clinicianestimate, which, as we and others have described, is the mostaccurate tool in prognostication.11,17,18,28 We believe that theclinician estimate should be considered as one of a few impor-tant criteria rather than as a unique criterion in choosingtherapeutic interventions.38,39 To that end, a future study willbe conducted to validate this prognostic model.

In summary, this study shows that the only indepen-dent predictors of survival in the patient with bone metas-tases are diagnosis, ECOG performance status, number ofbone metastases, presence of visceral metastases, and hemo-globin level. These parameters distinguish, with an accuracyof 5% to 15%, the ability of patients to survive less than 6months when these parameters are unfavorable and morethan 12 months when they are favorable. An assessment bya senior surgeon independent of these factors is far moreaccurate at 33%. This is a wake-up call to the community atlarge. Justification of surgery on the basis of survival prog-nostication is dangerously inaccurate. There is a need tocreate a more accurate prognostic index for patients under-going orthopedic surgery for bone metastases.

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www.jco.org 6081


Authors’ Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author or immediate family members indicateda financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of theinvestigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interestpolicy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section inInformation for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other

Saminathan S.Nathan

Biomet OncologyFellowship (B);Pearlman Limb

Preservation Fund(B)

Dollar Amount Codes (A) � $10,000 (B) $10,000-99,999 (C) � $100,000 (N/R) Not Required

REFERENCES

1. Harrington KD: Introduction, in: Orthopae-dic Management of Metastatic Bone Disease (ed1). St Louis, MO, Mosby, 1988, pp 1-14

2. Coleman RE, Rubens RD: Bone metasta-ses, in: Abeloff MD, Armitage JO, Lichter AS, etal (eds): Clinical Oncology (ed 2). New York, NY,Churchill-Livingstone, 2004, pp 836-871

3. Bohm P, Huber J: The surgical treatmentof bony metastases of the spine and limbs.J Bone Joint Surg Br 84:521-529, 2002

4. Tokuhashi Y, Matsuzaki H, Toriyama S, etal: Scoring system for the preoperative evalua-tion of metastatic spine tumor prognosis. Spine15:1110-1113, 1990

5. James JJ, Evans AJ, Pinder SE, et al:Bone metastases from breast carcinoma:Histopathological-radiological correlations andprognostic features. Br J Cancer 89:660-665, 2003

6. Pietropaoli MP, Damron TA, Vermont AI:Bone metastases from squamous cell carcinoma ofthe head and neck. J Surg Oncol 75:136-141, 2000

7. Cohen DB, Riley LH: Management of met-astatic carcinoma to the spine: Surgical treatment,in: Sim FH, Menendez LR (eds): Orthopedic Knowl-edge Update: Musculoskeletal Tumors (ed 1).Rosemont, IL, American Academy of OrthopedicSurgeons, 2002, pp 331-348

8. Beals RK, Lawton GD, Snell WE: Prophy-lactic internal fixation of the femur in metastaticbreast cancer. Cancer 28:1350-1354, 1971

9. Mirels H: Metastatic disease in longbones: A proposed scoring system for diagnos-ing impending pathologic fractures. Clin OrthopRelat Res 249:256-264, 1989

10. Wedin R: Surgical treatment for pathologicfracture. Acta Orthop Scand Suppl 72:1-29, 2001

11. Glare P, Virik K, Jones M, et al: A system-atic review of physicians’ survival predictions interminally ill cancer patients. BMJ 327:195, 2003

12. Fidler M: Prophylactic internal fixation ofsecondary neoplastic deposits in long bones. BrMed J 1:341-343, 1973

13. The Breast Specialty Group of the BritishAssociation of Surgical Oncology: British Associ-ation of Surgical Oncology Guidelines: The man-agement of metastatic bone disease in theUnited Kingdom. Eur J Surg Oncol 25:3-23, 1999

14. Zhou Z, Redaelli A, Johnell O, et al: Aretrospective analysis of health care costs forbone fractures in women with early-stage breastcarcinoma. Cancer 100:507-517, 2004

15. Hansen BH, Keller J, Laitinen M, et al: TheScandinavian Sarcoma Group Skeletal Metasta-sis Register: Survival after surgery for bonemetastases in the pelvis and extremities. ActaOrthop Scand Suppl 75:11-15, 2004

16. Miner TJ, Jaques DP, Shriver CD: A pro-spective evaluation of patients undergoing surgeryfor the palliation of an advanced malignancy. AnnSurg Oncol 9:696-703, 2002

17. Vigano A, Bruera E, Jhangri GS, et al: Clinicalsurvival predictors in patients with advanced can-cer. Arch Intern Med 160:861-868, 2000

18. Vigano A, Dorgan M, Buckingham J, et al:Survival prediction in terminal cancer patients: Asystematic review of the medical literature. Pal-liat Med 14:363-374, 2000

19. Yamashita K, Koyama H, Inaji H: Prognos-tic significance of bone metastasis from breastcancer. Clin Orthop Relat Res 312:89-94, 1995

20. Rana A, Chisholm GD, Khan M, et al:Patterns of bone metastasis and their prognosticsignificance in patients with carcinoma of theprostate. Br J Urol 72:933-936, 1993

21. Coleman RE: Skeletal complications ofmalignancy. Cancer 80:1588-1594, 1997

22. Conlan DP: Value of lymphocyte counts asa prognostic index of survival following femoralneck fractures. Injury 20:352-354, 1989

23. Carson JL, Terrin ML, Barton FB, et al: Apilot randomized trial comparing symptomaticvs. hemoglobin-level-driven red blood cell trans-fusions following hip fracture. Transfusion 38:522-529, 1998

24. Gruson KI, Aharonoff GB, Egol KA, et al:The relationship between admission hemoglobinlevel and outcome after hip fracture. J OrthopTrauma 16:39-44, 2002

25. Koval KJ, Maurer SG, Su ET, et al: Theeffects of nutritional status on outcome after hipfracture. J Orthop Trauma 13:164-169, 1999

26. Walls J, Bundred N, Howell A: Hypercal-cemia and bone resorption in malignancy. ClinOrthop Relat Res 312:51-63, 1995

27. Muers MF, Shevlin P, Brown J: Prognosisin lung cancer: Physicians’ opinions comparedwith outcome and a predictive model. Thorax51:894-902, 1996

28. Vigano A, Dorgan M, Bruera E, et al: Therelative accuracy of the clinical estimation of theduration of life for patients with end of life cancer.Cancer 86:170-176, 1999

29. Oken MM, Creech RH, Tormey DC, et al:Toxicity and response criteria of the Eastern

Cooperative Oncology Group. Am J Clin Oncol5:649-655, 1982

30. Piccirillo JF, Tierney RM, Costas I, et al:Prognostic importance of comorbidity in ahospital-based cancer registry. JAMA 291:2441-2447, 2004

31. Jensen JS, Tondevold E: Mortality after hipfractures. Acta Orthop Scand 50:161-167, 1979

32. Kyo T, Takaoka K, Ono K: Femoral neckfracture: Factors related to ambulation and prog-nosis. Clin Orthop Relat Res 292:215-222, 1993

33. Townsend PW, Rosenthal HG, SmalleySR, et al: Impact of postoperative radiation ther-apy and other perioperative factors on outcomeafter orthopedic stabilization of impending orpathologic fractures due to metastatic disease.J Clin Oncol 12:2345-2350, 1994

34. Nozue M, Oshiro Y, Kurata M, et al: Treat-ment and prognosis in colorectal cancer patientswith bone metastasis. Oncol Rep 9:109-112, 2002

35. Blay JY, Lasset C, Carrie C, et al: Multivar-iate analysis of prognostic factors in patientswith non HIV-related primary cerebral lympho-ma: A proposal for a prognostic scoring. Br JCancer 67:1136-1141, 1993

36. Masutani M, Tsujino I, Fujie T, et al: Moder-ate dose-intensive chemotherapy for patients withnon-small cell lung cancer: Randomized trial, can itimprove survival of patients with good perfor-mance status? Oncol Rep 6:1045-1050, 1999

37. Mani S, Todd MB, Katz K, et al: Prognosticfactors for survival in patients with metastaticrenal cancer treated with biological responsemodifiers. J Urol 154:35-40, 1995

38. Pirovano M, Maltoni M, Nanni O, et al: Anew palliative prognostic score: A first step for thestaging of terminally ill cancer patients—ItalianMulticenter and Study Group on Palliative Care.J Pain Symptom Manage 17:231-239, 1999

39. Maltoni M, Nanni O, Pirovano M, et al:Successful validation of the palliative prognosticscore in terminally ill cancer patients: ItalianMulticenter Study Group on Palliative Care.J Pain Symptom Manage 17:240-247, 1999

40. Culine S, Kramar A, Saghatchian M, et al:Development and validation of a prognosticmodel to predict the length of survival in patientswith carcinomas of an unknown primary site.J Clin Oncol 20:4679-4683, 2002

41. Hess KR, Abbruzzese MC, Lenzi R, et al:Classification and regression tree analysis of 1000consecutive patients with unknown primary carci-noma. Clin Cancer Res 5:3403-3410, 1999

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survival in patients operated on for pathologic fracture: implications for end-of-life orthopedic...

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