Treating metastatic disease: Which survival model is best suited for the clinic?

BACKGROUND: To avoid complications associated with under- or overtreatment of patients with skeletal metastases, doctors need accurate survival estimates. Unfortunately, prognostic models for patients with skeletal metastases of the extremities are lacking, and physician-based estimates are generally inaccurate. QUESTIONS/PURPOSES: We developed three types of prognostic models and compared them using calibration plots, receiver operating characteristic (ROC) curves, and decision curve analysis to determine which one is best suited for clinical use. METHODS: A training set consisted of 189 patients who underwent surgery for skeletal metastases. We created models designed to predict 3- and 12-month survival using three methods: an Artificial Neural Network (ANN), a Bayesian Belief Network (BBN), and logistic regression. We then performed crossvalidation and compared the models in three ways: calibration plots plotting predicted against actual risk; area under the ROC curve (AUC) to discriminate the probability that a patient who died has a higher predicted probability of death compared to a patient who did not die; and decision curve analysis to quantify the clinical consequences of over- or undertreatment. RESULTS: All models appeared to be well calibrated, with the exception of the BBN, which underestimated 3-month survival at lower probability estimates. The ANN models had the highest discrimination, with an AUC of 0.89 and 0.93, respectively, for the 3- and 12-month models. Decision analysis revealed all models could be used clinically, but the ANN models consistently resulted in the highest net benefit, outperforming the BBN and logistic regression models. CONCLUSIONS: Our observations suggest use of the ANN model to aid decisions about surgery would lead to better patient outcomes than other alternative approaches to decision making. LEVEL OF EVIDENCE: Level II, prognostic study. See Instructions for Authors for a complete description of levels of evidence.

Which implant is best after failed treatment for pathologic femur fractures?

BACKGROUND: Successful treatment of pathologic femur fractures can preserve a patient's independence and quality of life. The choice of implant depends on several disease- and patient-specific variables; however, its durability must generally match the patient's estimated life expectancy. Failures do occur, however, it is unclear which implants are associated with greater risk of failure. QUESTIONS/PURPOSES: We evaluated patients with femoral metastases in whom implants failed to determine (1) the rate of reoperation; (2) the timing of and most common causes for failure; and (3) incidence of perioperative complications and death. METHODS: From a prospectively collected registry, we identified 93 patients operated on for failed treatment of femoral metastases from 1990 to 2010. We excluded five patients who subsequently underwent amputations leaving 88 who underwent salvage procedures. These included intramedullary nails (n = 11), endoprostheses (n = 61), and plate fixation (n = 16). The primary outcome was reoperation after salvage treatment. RESULTS: Seventeen of the 88 patients (19%) required subsequent reoperation a median of 10 months (interquartile range, 4-14) from the time of salvage surgery: 15 for material failure, one for local progression of tumor, and one for a combination of these. Five patients died within 4 weeks of surgery. Although perioperative complications were higher in the endoprosthesis group and dislocations occurred, overall treatment failures after salvage surgery were lower in the that group (four of 61) compared the group with plate fixation (eight of 16) and intramedullary nail groups (five of 11). CONCLUSIONS: Despite relatively common perioperative complications, salvage using endoprostheses may be associated with fewer treatment failures as compared with internal fixation. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

External validation of the Bayesian Estimated Tools for Survival (BETS) models in patients with surgically treated skeletal metastases.

BACKGROUND: We recently developed two Bayesian networks, referred to as the Bayesian-Estimated Tools for Survival (BETS) models, capable of estimating the likelihood of survival at 3 and 12 months following surgery for patients with operable skeletal metastases (BETS-3 and BETS-12, respectively). In this study, we attempted to externally validate the BETS-3 and BETS-12 models using an independent, international dataset. METHODS: Data were collected from the Scandinavian Skeletal Metastasis Registry for patients with extremity skeletal metastases surgically treated at eight major Scandinavian referral centers between 1999 and 2009. These data were applied to the BETS-3 and BETS-12 models, which generated a probability of survival at 3 and 12 months for each patient. Model robustness was assessed using the area under the receiver-operating characteristic curve (AUC). An analysis of incorrect estimations was also performed. RESULTS: Our dataset contained 815 records with adequate follow-up information to establish survival at 12 months. All records were missing data including the surgeon's estimate of survival, which was previously shown to be a first-degree associate of survival in both models. The AUCs for the BETS-3 and BETS-12 models were 0.79 and 0.76, respectively. Incorrect estimations by both models were more commonly optimistic than pessimistic. CONCLUSIONS: The BETS-3 and BETS-12 models were successfully validated using an independent dataset containing missing data. These models are the first validated tools for accurately estimating postoperative survival in patients with operable skeletal metastases of the extremities and can provide the surgeon with valuable information to support clinical decisions in this patient population.

A probabilistic analysis of completely excised high-grade soft tissue sarcomas of the extremity: an application of a Bayesian belief network.

BACKGROUND: It is important to understand the relative importance of prognostic variables in patients with soft tissue sarcomas. The purpose of this study was to describe the hierarchical relationships between features inherent to completely excised, localized high-grade soft tissue sarcomas of the extremity and compare the associations to those previously reported. METHODS: Data were collected from the Memorial Sloan-Kettering Cancer Center Sarcoma Database. All adult patients with high-grade extremity soft tissue sarcomas who underwent complete excision (R0 margins) at our institution between 1982 and 2010 were included in the analysis. Bayesian belief network (BBN) modeling software was used to develop a hierarchical network of features trained to estimate the likelihood of disease-specific survival. Important relationships depicted by the BBN model were compared to those previously reported. RESULTS: The records of 1318 consecutive patients met the inclusion criteria, and all were included in the analysis. First-degree associates of disease-specific survival were the primary tumor size; presence of and time to distant recurrence; and presence of and time to local recurrence. On cross-validation, the BBN model was sufficiently robust, with an area under the curve of 0.94 (95 % confidence interval 0.93-0.96). CONCLUSIONS: We successfully described the hierarchical relationships between features inherent to patients with completely excised high-grade soft tissue sarcomas of the extremity. The relationships defined by the BBN model were similar to those previously reported. Cross-validation results were encouraging, demonstrating that BBN modeling can be used to graphically illustrate the complex hierarchical relationships between prognostic features in this setting.

Estimating survival in patients with operable skeletal metastases: an application of a bayesian belief network.

BACKGROUND: Accurate estimations of life expectancy are important in the management of patients with metastatic cancer affecting the extremities, and help set patient, family, and physician expectations. Clinically, the decision whether to operate on patients with skeletal metastases, as well as the choice of surgical procedure, are predicated on an individual patient's estimated survival. Currently, there are no reliable methods for estimating survival in this patient population. Bayesian classification, which includes bayesian belief network (BBN) modeling, is a statistical method that explores conditional, probabilistic relationships between variables to estimate the likelihood of an outcome using observed data. Thus, BBN models are being used with increasing frequency in a variety of diagnoses to codify complex clinical data into prognostic models. The purpose of this study was to determine the feasibility of developing bayesian classifiers to estimate survival in patients undergoing surgery for metastases of the axial and appendicular skeleton. METHODS: We searched an institution-owned patient management database for all patients who underwent surgery for skeletal metastases between 1999 and 2003. We then developed and trained a machine-learned BBN model to estimate survival in months using candidate features based on historical data. Ten-fold cross-validation and receiver operating characteristic (ROC) curve analysis were performed to evaluate the BNN model's accuracy and robustness. RESULTS: A total of 189 consecutive patients were included. First-degree predictors of survival differed between the 3-month and 12-month models. Following cross validation, the area under the ROC curve was 0.85 (95% CI: 0.80-0.93) for 3-month probability of survival and 0.83 (95% CI: 0.77-0.90) for 12-month probability of survival. CONCLUSIONS: A robust, accurate, probabilistic naïve BBN model was successfully developed using observed clinical data to estimate individualized survival in patients with operable skeletal metastases. This method warrants further development and must be externally validated in other patient populations.

Diagnosis and management of chronic infection.

High-energy penetrating extremity injuries are often associated with severe open fractures that have varying degrees of soft-tissue contamination and tenuous soft-tissue coverage. The result is a relatively high prevalence of chronic osteomyelitis compared with that in civilian trauma patients. Diagnosing chronic osteomyelitis requires a careful history and thorough physical and radiographic examinations. Cross-sectional imaging can help delineate the extent of bony involvement, and scintigraphy can be used as a diagnostic tool and to gauge response to treatment. Clinical staging also directs surgical management. Adequacy of débridement remains the most important clinical predictor of success; thus, adopting an oncologic approach to complete (ie, wide) excision is important. Reconstruction can be safely performed by a variety of methods; however, proper staging and patient selection remain critical to a successful outcome. Although systemic and depot delivery of antibiotics plays a supporting role in the treatment of chronic osteomyelitis, the ideal dosing regimens, and the duration of treatment, remain controversial.

Lower extremity combat-related amputations.

Since the onset of combat activity in Iraq and Afghanistan, there have been over 1100 major limb amputations among United States service members. With a sustained military presence in the Middle East, continued severe lower extremity trauma is inevitable. For this reason, combat surgeons must understand the various amputation levels as well as the anatomic and technical details that enable an optimal functional outcome. These amputations are unique and usually result from blast mechanisms and are complicated by broad zones of injury with severe contamination and ongoing infection. The combat servicemen are young, previously healthy, and have the promising potential to rehabilitate to very high levels of activity. Therefore, every practical effort should be made to perform sound initial and definitive trauma-related amputations so that these casualties may return to their highest possible level of function.

Heterotopic ossification in wartime wounds.

Heterotopic ossification (HO) refers to the formation of mature lamellar bone in nonosseous tissue. In the setting of high-energy wartime extremity wounds, HO is expected to complicate up to 64% of patients, has a predilection for the residual limbs of amputees, and remains a significant source of disability. Although the inciting events and the definitive cell(s) of origin continue to remain elusive, animal models and human histology samples suggest that HO formation follows a predictable sequence of events culminating in endochondral ossification. Primary prophylaxis is not medically or logistically practical in most cases because patients have generally sustained massive wounds and are undergoing serial debridements during an intercontinental aeromedical evacuation. Surgical excision of symptomatic lesions is warranted only after an appropriate trial of conservative measures and is associated with low recurrence rates in appropriately selected patients. Future research regarding prognostication and defining the early molecular biology of ectopic bone may permit individualized prophylaxis and development of novel targeted therapies.

Heterotopic ossification in high-energy wartime extremity injuries: prevalence and risk factors.

BACKGROUND: Heterotopic ossification in the extremities remains a common complication in the setting of high-energy wartime trauma, particularly in blast-injured amputees and in those in whom the definitive amputation was performed within the zone of injury. The purposes of this cohort study were to report the experience of one major military medical center with high-energy wartime extremity wounds, to define the prevalence of heterotopic ossification in these patients, and to explore the relationship between heterotopic ossification and other potential independent predictors. METHODS: We retrospectively reviewed the records and radiographs of all combat-wounded patients admitted to this institution between March 1, 2003, and December 31, 2006. Patients with a minimum of two months of radiographic follow-up who underwent at least one orthopaedic procedure on an extremity constituted our study group; those who underwent at least one orthopaedic procedure but had not had heterotopic ossification develop constituted the control group. Variables recorded for each study subject included age and sex, location and mechanism of injury, method(s) of fracture fixation, number of débridement procedures, duration of negative pressure therapy, location of heterotopic ossification, presence and severity of traumatic brain injury, and Injury Severity Scores. RESULTS: During the study period, 1213 war-wounded patients were admitted. Of those patients, 243 (157 in the heterotopic ossification group and eighty-six controls) met the inclusion criteria. The observed rate of heterotopic ossification was 64.6%. A significant relationship was detected between heterotopic ossification and the presence (p = 0.006) and severity (p = 0.003) of a traumatic brain injury. Risk factors for the development of heterotopic ossification were found to be an age of less than thirty years (p = 0.007, odds ratio = 3.0), an amputation (p = 0.048, odds ratio = 2.9), multiple extremity injuries (p = 0.002, odds ratio = 3.9), and an Injury Severity Score of >or=16 (p = 0.02, odds ratio = 2.2). CONCLUSIONS: The prevalence of heterotopic ossification in war-wounded patients is higher than that in civilian trauma. Although trends associated with local wound conditions were identified, the risk factors for the development of heterotopic ossification found in this study suggest that systemic causes predominate.

Correlation of procalcitonin and cytokine expression with dehiscence of wartime extremity wounds.

BACKGROUND: Despite technological advances in the treatment of severe extremity trauma, the timing of wound closure remains the subjective clinical decision of the treating surgeon. Traditional serum markers are poor predictors of wound-healing. The objective of this study was to evaluate the cytokine and chemokine profiles of severe extremity wounds prior to closure to determine if wound effluent markers can be used to predict healing. METHODS: Serum and effluent (exudate) samples were collected prospectively from adult volunteers with multiple high-energy penetrating extremity wounds sustained during military combat. Samples were collected prior to definitive wound closure or flap coverage. Wounds were followed clinically for six weeks. The primary clinical outcome measures were wound-healing and dehiscence. Control serum samples were collected from normal age and sex-matched adult volunteers. All samples were analyzed for the following cytokines and chemokines: procalcitonin; eotaxin; granulocyte macrophage colony stimulating factor; interferon (IFN)-gamma; interleukin (IL)-1 through 8, 10, 12, 13, and 15; IFN-gamma inducible protein-10; monocyte chemotactic protein-1; macrophage inflammatory protein-1alpha; the protein regulated on activation, normal T expressed and secreted (RANTES); and tumor necrosis factor (TNF)-alpha. RESULTS: Fifty wounds were analyzed in twenty patients. Four of the fifty wounds dehisced. An increased rate of wound dehiscence was observed in patients with a concomitant closed head injury as well as in those with an associated arterial injury of the affected limb (p < 0.05). Among the serum chemokines and cytokines, only serum procalcitonin levels correlated with wound dehiscence (p < 0.05). Effluent analysis showed that, compared with wounds that healed, wounds that dehisced were associated with elevated procalcitonin, decreased RANTES protein, and decreased IL-13 concentrations (p < 0.05). No wound with an effluent procalcitonin concentration of <220 pg/mL, an IL-13 concentration of >12 pg/mL, or a RANTES protein concentration of >1000 pg/mL failed to heal. CONCLUSIONS: Effluent procalcitonin, IL-13, and RANTES protein levels as well as serum procalcitonin levels correlate with wound dehiscence following closure of severe open extremity wounds. These preliminary results indicate that effluent biomarker analysis may be an objective means of determining the timing of traumatic wound closure.

Chronic lateral ankle instability and associated conditions: a rationale for treatment.

BACKGROUND: Ankle sprains have a high incidence of associated injuries and conditions that may be unrecognized at the initial time of injury. Failure to treat these conditions at the index surgery may compromise outcomes and delay recovery. The purpose of this study was to determine the type and frequency of associated injuries and conditions in military patients with chronic lateral ankle instability. METHODS: Between 1996 and 2002, 160 patients had 180 modified Broström-Gould lateral ankle ligament reconstructions for chronic ankle instability. A retrospective review of the clinical history, physical examination, radiographs, and intraoperative findings was conducted. RESULTS: The overall incidence of associated extra-articular conditions and injuries found in this study was 64%; 115 conditions were identified in 180 ankles. Peroneal tendon injuries occurred with the highest frequency (28%), followed by os trigonum lesions (13%), lateral gutter ossicles (10%), hindfoot varus alignment (8%), anterior tibial spurs (3%), and tarsal coalitions (2%). Twenty revision lateral ankle ligament reconstructions were required for either persistent pain or recurrent instability. The most common associated conditions were undiagnosed hindfoot varus alignment abnormalities (28%) followed by untreated peroneal injuries (25%). CONCLUSIONS: This study confirms the frequency of conditions associated with lateral ankle instability and emphasizes several conditions that have received little attention in the literature. Identifying these associated conditions before surgery enables the surgeon to treat all conditions at one operation, returning the patient to full activity sooner. Guidelines are presented to assist clinicians in screening patients for these associated conditions.