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Early Improvement in Pain and Functional Outcome but Not Quality of Life After Surgery for Metastatic Long Bone Disease

Nooh, Anas MBBS; Goulding, Krista MD; Isler, Marc H. MD; Mottard, Sophie MD; Arteau, Annie MD; Dion, Norbert MD; Turcotte, Robert MD

Clinical Orthopaedics and Related Research®: March 2018 - Volume 476 - Issue 3 - p 535–545
doi: 10.1007/s11999.0000000000000065
2016 MUSCULOSKELETAL TUMOR SOCIETY PROCEEDINGS
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Background Bone metastases represent the most frequent cause of cancer-related pain, affecting health-related quality of life and creating a substantial burden on the healthcare system. Although most bony metastatic lesions can be managed nonoperatively, surgical management can help patients reduce severe pain, avoid impending fracture, and stabilize pathologic fractures. Studies have demonstrated functional improvement postoperatively as early as 6 weeks, but little data exist on the temporal progress of these improvements or on the changes in quality of life over time as a result of surgical intervention.

Questions/purposes (1) Do patients’ functional outcomes, pain, and quality of life improve after surgery for long bone metastases? (2) What is the temporal progress of these changes to 1 year after surgery or death? (3) What is the overall and 30-day rate of complications after surgery for long bone metastases? (4) What are the oncologic outcomes including overall survival and local disease recurrence for this patient population?

Methods A multicenter, prospective study from three orthopaedic oncology centers in Quebec, Canada, was conducted between 2008 and 2016 to examine the improvement in function and quality of life after surgery for patients with long bone metastases. During this time, 184 patients out of a total of 210 patients evaluated during this period were enrolled; of those, 141 (77%) had complete followup at a minimum of 2 weeks (mean, 23 weeks; range, 2-52 weeks) or until death, whereas another 35 (19%) were lost to followup but were not known to have died before the minimum followup interval was achieved. Pathologic fracture was present in 34% (48 of 141) of patients. The median Mirel’s score for those who underwent prophylactic surgery was 10 (interquartile range, 10-11). Surgical procedures included intramedullary nailing (55), endoprosthetic replacement (49), plate osteosynthesis (31), extended intralesional curettage (four), and allograft reconstruction (two). Seventy-seven percent (108 of 141) of patients received radiotherapy. The Musculoskeletal Tumor Society (MSTS), Toronto Extremity Salvage Score (TESS), Brief Pain Inventory (BPI) form, and Quality Of Life During Serious Illness (QOLLTI-P) form were administered pre- and postoperatively at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year. Analysis of variance followed by post hoc analysis was conducted to test for significance between pre- and postoperative scores. The Kaplan-Meier estimate was used to calculate overall survivorship and local recurrence-free survival. A p value of < 0.05 was considered statistically significant.

Results MSTS and BPI pain scores improved at 2 weeks when compared with preoperative scores (MSTS: 39% ± 24% pre- versus 62% ± 19% postoperative, mean difference [MD] 23, 95% confidence interval [CI], 16-32, p < 0.001; BPI: 52% ± 21% pre- versus 30% ± 21% postoperative, MD 22, 95% CI, 16-32, p < 0.001). Continuous and incremental improvement in TESS, MSTS, and BPI scores was observed temporally at 6 weeks, 3 months, 6 months, and 1 year; for example, the TESS score improved from 44% ± 24% to 73% ± 21% (MD 29, p < 0.001, 95% CI, 19-38) at 6 months. We did not detect a difference in quality of life as measured by the QOLLTI-P score (6 ± 1 pre- versus 7 ± 4 postoperative, MD 1, 95% CI, -0.4 to 3, p = 0.2). The overall and 30-day rates of systemic complications were 35% (49 of 141) and 14% (20 of 141), respectively. The Kaplan-Meier estimates for overall survival were 70% (95% CI, 62.4-78) at 6 months and 41% (95% CI, 33-49) at 1 year. Local recurrence-free survival was 17 weeks (95% CI, 11-24).

Conclusions Surgical management of metastatic long bone disease substantially improves patients’ functional outcome and pain as early as 2 weeks postoperatively and should be considered for impending or pathologic fracture in patients whose survival is expected to be longer than 2 weeks provided that there are no immediate contraindications. Quality of life in this patient population did not improve, which may be a function of patient selection, concomitant chemoradiotherapy regimens, disease progression, or terminal illness, and this merits further investigation.

Level of Evidence Level II, therapeutic study.

A. Nooh, K. Goulding, R. Turcotte, Department of Orthopedic Surgery, McGill University Health Centre, Montreal, Quebec, Canada

M. H. Isler, S. Mottard, Division of Orthopedic Surgery, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada

A. Arteau, N. Dion, Department of Orthopaedic Surgery, CHU de Québec-Université Laval-Hôtel-Dieu, Quebec, Canada

K. Goulding, Montreal General Hospital, 1650 Cedar Avenue, T8-200, Montreal, QC H3G 1A4, Canada, email: krista.goulding@mcgill.ca

Each author certifies that neither he nor she, nor any member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Each author certifies that his or her institution approved for the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at McGill University Health Centre, Montreal, Quebec, Canada; Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada; and CHU de Québec-Université Laval-Hôtel-Dieu, Quebec, Canada.

Received January 01, 2017

Received in revised form May 22, 2017

Accepted November 15, 2017

Online date: February 05, 2018

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Introduction

Metastatic bone disease affects both the axial skeleton and long bones; as many as 70% of patients with a malignant neoplasm will develop bone metastases during the course of their disease [13]. Overall, one in five patients diagnosed with bone metastases will be symptomatic [19], but long bones are recognized as the most common cause of cancer-related pain in palliative settings [24]. Long bone metastasis is thus a major contributor to patients’ health-related quality of life; treatment of these lesions places a heavy burden on the healthcare system and potentially puts patients at risk from surgical procedures performed for attempted palliation.

The majority of metastatic bone disease can be managed adequately with nonoperative modalities including radiotherapy, chemotherapy, and antiresorptive agents such as bisphosphonates [13]. Surgical management is indicated in the presence of severe pain and impending or established pathologic fractures [8]. Benefits from surgery should reasonably occur within weeks of the intervention to justify the procedure’s invasiveness for individuals with limited life expectancy [26]. Short- and long-term effects of treatment on a patient’s functional capacity, pain level, and subjective experience of disease should therefore be at the forefront of our decisions around the most appropriate and predictable treatment strategies. This is especially true for the orthopaedic community, which is managing metastatic bone disease in a time of improved cancer survivorship and a focus on quality and value-based resources. Expected functional and quality-of-life outcome data would be useful for patients and surgeons when making the decision regarding surgical intervention. To our knowledge, few prospective studies have evaluated quality-of-life improvements in patients undergoing surgery for metastatic bone disease [9, 33], and there are no substantial prospective data confirming the temporal improvement in functional outcome in this population.

As a result, we sought to answer the following questions in this study: (1) Do patients’ functional outcome, pain, and quality of life improve after surgery for long bone metastases? (2) What is the temporal progress of these changes to 1 year after surgery or death? (3) What is the overall and 30-day rate of complications after surgery for long bone metastases? (4) What are the oncologic outcomes including overall survival and local disease recurrence?

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Patients and Methods

A multicenter study with prospective registration of patients was conducted between 2008 and 2016 across three orthopaedic oncology centers in Quebec, Canada, after approval by all institutions' research ethics boards.

All skeletally mature patients presenting to one of our three centers with a long bone metastasis and treated by surgical interventions were considered eligible for the study. Informed consent was obtained from all patients by the surgeon and research team before participation in the study. All patients had a recent bone scan or skeletal survey preoperatively to assess the integrity of the remaining skeleton and to avoid fracture of occult bone metastasis. Further local and systemic staging studies were completed as deemed necessary by the operating surgeon. Patients who presented with a suspected unknown primary malignancy with bony metastasis were enrolled in the study but only considered eligible once histopathologic confirmation of a metastatic lesion was available by pre- or intraoperative biopsy.

During this time period, 210 patients with bone metastases were evaluated in our centers. A total of 184 patients were enrolled in the study. Of these, two patients died preoperatively and one operative procedure was cancelled because of rapid deterioration in the patient’s condition. One patient with a recent history of carcinoma presumed to have bony metastasis was excluded after being diagnosed with a localized primary bone sarcoma by intraoperative biopsy and frozen section. Four patients declined surgery after enrolling in the study. Of the 184 patients enrolled, 141 (77%) had complete followup at a minimum of 2 weeks (mean, 23 weeks; range, 2-52 weeks) or until death, whereas another 35 (19%) were lost to followup but were not known to have died before the minimum followup interval was achieved. There was no difference in patient demographics or surgical factors between the cohort lost to followup and those who completed the minimum followup.

Fifty-five (39%) patients were treated with intramedullary nailing, 49 (35%) with endoprosthetic replacement, 31 (22%) with plate osteosynthesis, four (3%) with extended intralesional curettage, and two (1%) with allograft reconstruction. All surgical procedures were performed by fellowship-trained orthopaedic oncologists.

Eighty-five (60%) patients were managed with postoperative radiotherapy, 17 (12%) with preoperative radiotherapy, and six (4%) with both. Systemic antiresorptive agents were used in 31 (22%) patients; of these, 27 patients received bisphosphonates and four patients received denosumab. Routine followup examinations were performed at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year. Charts and radiographs were available for review for all patients in this study.

The Musculoskeletal Tumor Society (MSTS) functional score, the Toronto Extremity Salvage Score (TESS), the Brief Pain Inventory (BPI) form, and the Quality Of Life During Serious Illness (QOLLTI-P) form were administered preoperatively and postoperatively at each followup (2 weeks, 6 weeks, 3 months, 6 months, and 1 year). The MSTS form utilizes six categories and was completed by clinicians (KG, MHI, SM, AA, ND, RT) to evaluate function based on pain, upper and lower extremity-specific function, and emotional acceptance [16]. The TESS is a validated measure developed by Davis et al. [14] to evaluate physical disability in patients treated with limb salvage surgery. It is a self-administered questionnaire that rates perceived difficulty in performing specified activities of daily life from the patient’s own perspective. The TESS includes items on activity limitations in daily life such as restrictions in body movement, mobility, self-care, and performance of daily tasks.

Pain was quantified using the Brief Pain Inventory Short Form (BPI-SF), a validated and self-reported measure [2] that requires patients to rate their pain intensity over the previous 24 hours with a focus on pain interference with sleep, mood, relationships, work, and general activity [10]. It has been widely used in several studies as an outcome measure to evaluate pain in patients with metastatic cancer.

Lastly, the QOLLTI-P questionnaire is a validated, patient-reported questionnaire designed to measure the quality of life in individuals with a life-threatening illness [32]. It has been adapted from the McGill Quality of Life Questionnaire [12, 32] and includes 27 items that address physical, psychologic, existential well-being, relationships, and quality of care. Extensively studied in Canada and widely used in our institution, the QOLLTI-P provides useful information in the setting of palliative cancer treatment specific to the Canadian cancer patient population [32].

Overall complications were defined as the occurrence of an adverse event at any time point during the 1-year study period and were reported as an event rate. We divided complications into intraoperative, systemic, or local complications. Intraoperative complications were recorded as neurovascular injury, iatrogenic fracture, massive blood loss (defined as > 2.5 L), and death. Systemic complications were defined as major adverse events occurring within 30 days of surgery including pneumonia, deep vein thrombosis (DVT), pulmonary embolism, cerebrovascular accident, fat embolism, and death. Local complications were defined as the rate of adverse events at the surgical site at any time postoperatively, including surgical site infection, wound dehiscence, implant failure, and dislocation.

Patients were censored at the study endpoint. The oncologic outcomes reported were overall survival and local disease recurrence, defined as clinical or radiographic evidence of disease recurrence at the surgical site.

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Statistical Analysis

All statistical analyses were conducted using SPSS Version 21 (IBM Corp, Armonk, NY, USA). Analysis of variance followed by post hoc analysis was conducted to test for significance between pre- and postoperative scores, and 95% confidence intervals (CIs) were calculated for differences between two means. Repeated-measures two-way analysis of variance with interactions was used to test the difference in the functional scores; chi-square tests were conducted to test for differences in complication rates between patients with or without pathologic fracture. The Kaplan-Meier estimate was used to calculate overall survivorship and local recurrence-free survival. A p value of < 0.05 was considered statistically significant.

The mean age of our population was 61 years (range, 50-72 years), of whom 53% were men. The most prevalent histopathologic diagnoses were lung adenocarcinoma (28%), breast adenocarcinoma (19%), and renal cell carcinoma (18%) (Fig. 1). The most commonly involved site of metastasis was the femur (89) followed by the humerus (38), tibia (10), ulna (three), and radius (one). Diaphyseal lesions accounted for 45% (64) of all tumor sites followed by metaphyseal (44%) and epiphyseal lesions (11%). Pathologic fractures were present in 34% (48) of patients (Table 1). The median Mirel’s score for those who underwent prophylactic surgery was 10 (interquartile range, 10-11). Overall, 26% patients completed the 1-year followup.

Fig. 1

Fig. 1

Table 1

Table 1

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Results

The MSTS scores demonstrated an improvement 2 weeks after surgery (63% ± 19%) as compared with preoperative scores (39% ± 24%, mean difference [MD] 23, 95% CI, 16-32, p < 0.001). This improvement continued to improve over the course of the study at 6 weeks (66% ± 21%, MD 27, 95% CI, 20-36, p < 0.001), 3 months (71% ± 20%, MD 32, 95% CI, 25-41, p < 0.001), 6 months (72% ± 21%, MD 33, 95% CI, 24-43, p < 0.001), and 1 year (74% ± 24%, MD 35, 95% CI, 25-46, p < 0.001; Fig. 2A). There was no difference in MSTS scores in patients with or without pathologic fracture (p = 0.4) (Fig. 2B).

Fig. 2 A-B

Fig. 2 A-B

There was no difference in TESS scores at 2 weeks postoperatively (50% ± 24% post- versus 44% ± 24 preoperative, MD 6, 95% CI, -2 to 14, p = 0.2). Nevertheless, TESS scores improved at 6 weeks (64% ± 22%, MD 19, 95% CI, 11-28, p < 0.001), 3 months (73% ± 22%, MD 29, 95% CI, 20-37, p < 0.001), 6 months (73% ± 21%, MD 29, p < 0.001, 95% CI, 19-38), and 1 year (75% ± 27%, MD 31, 95% CI, 20-42, p < 0.001) when compared with the preoperative scores (Fig. 3A). Similar to the MSTS scores, there was no difference in the TESS in patients with or without fracture (p = 0.4) (Fig. 3B).

Fig. 3 A-B

Fig. 3 A-B

With regard to pain relief, the BPI demonstrated a reduction in pain scores at 2 weeks postoperatively when compared with the preoperative scores (30% ± 21% post- versus 52% ± 21% preoperative, MD 22, 95% CI, 16-32, p < 0.001). Furthermore, BPI scores improved at 6 weeks (26% ± 21%, MD 26, 95% CI, 20-36, p < 0.001), 3 months (25% ± 24%, MD 27, 95% CI, 25-41, p < 0.001), 6 months (26% ± 24%, MD 25, 95% CI, 24-43, p < 0.001), and 1 year (17% ± 20%, MD 35, 95% CI, 25-46, p < 0.001; Fig. 4). We did not detect an improvement in the QOLLTI-P scores postoperatively when compared with the preoperative scores (6 ± 1 pre- versus 7 ± 4 postoperative, MD 1, 95% CI, -0.4 to 3, p = 0.2; Fig. 5).

Fig. 4

Fig. 4

Fig. 5

Fig. 5

Over the study period, 49 (35%) complications occurred in 36 patients. The 30-day rate of systemic complications was 14% (19), the most prevalent being DVT (seven of 141 [5%]). The 30-day mortality rate was 1% (two of 141) with no intraoperative deaths, two deaths within 30 days, and two deaths preoperatively that were excluded from the analysis. Additionally, 23 (16%) local complications occurred during the study period. Surgical site infection occurred in six patients, four (3%) of whom required reoperation. There was no difference in complication rates in those with and without pathologic fracture (Table 2).

Table 2

Table 2

The Kaplan-Meier estimates for overall survival were 70% (95% CI, 62.4-78) at 6 months and 41% (95% CI, 33-49) at 1 year. A total of 63 (45%) patients died within 1 year of surgery with a mean overall survival of 7 months (95% CI, 6-8). The Kaplan-Meier estimate for local recurrence-free survival was 17 weeks (95% CI, 11-24). Clinical and radiographic signs of local recurrence were observed in 19 (14%) patients. There was no difference in local recurrence rates between patients who had a fracture and those who did not (p = 0.2).

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Discussion

Surgical management of bone metastasis aims to preserve patient independence and quality of life, but studying outcomes in this population can be quite difficult as a result of variability in cancer biology, differing treatment regimens, and disparate life expectancies. Bone metastasis in itself is a marker of advanced disease, and the challenge for the orthopaedic surgeon is to identify those patients who will benefit from surgery given the substantial risk of complications. Few studies prospectively report the temporal progress of functional outcome and quality of life of patients over different time points postoperatively [9, 33], and none to our knowledge has reported functional improvements earlier than 6 weeks, both of which are the aims of this study.

We acknowledge several limitations of the study. First, attrition of the study population from either death or loss to followup is a well-known but considerable study limitation and highlights the difficulty of studying this patient population. The surgical outcome is unknown in the group lost to followup and may lead us to overestimate the benefit of surgery, especially early in the postoperative course. It is possible that these patients represent the group with more aggressive biology and a higher disease burden and subsequently experienced worse outcomes than those completing the study followup. Many of our patients received their oncologic treatment in other centers at some distance from our site and did not return for further followup for unknown reasons (death or complications managed at other centers, intensive adjuvant treatments, did not wish to travel, or other reasons). To better understand this issue, we compared the demographics and preoperative scores of those lost to followup with the cohort with minimum followup and found that they were not different. The surgical outcomes of the former group are, nonetheless, unknown. Attrition of the eligible cohort was also an issue in our study as a result of death and other complications precluding routine followup over the course of the year and does affect the precision of our estimate of treatment effect later in the course of followup. Second, selection bias is a limitation in this prospective study. We did not collect outcomes for patients with metastatic lesions who did not undergo surgery and, as such, we are not able to comment on the decision-making process in determining the need for surgical intervention. These patients were managed by a group of orthopaedic oncologists with a significant proportion requiring endoprosthetic replacement, and this may indicate a more advanced disease state in this cohort. Third, although we limited the cohort to include long bone metastasis alone, there remains heterogeneity in tumor origin, location, size, and biologic aggressiveness, not to mention surgical technique and adjuvant therapy. This in itself makes interpretation of confounding factors difficult but does reflect the clinical reality in orthopaedic oncology. Lastly, quality of life can be difficult to quantify and our cohort has a uniquely Canadian experience, which may limit its generalizability to other populations with different subjective cultural experience of disease. Furthermore, quality of life is affected not only by the long bone metastases and operative procedures that these patients endured, but other comorbidities and adjunctive treatments, which may have limited the ability to detect differences in quality of life resulting from our surgical procedures. We had insufficient numbers of patients to study whether one type of surgical fixation technique might be different from another.

In this cohort, we demonstrated improvement in pain relief and function as early as 2 weeks postoperatively, which increased temporally during the study period. Conversely, quality of life did not improve after surgery. Functional improvement after surgery for long bone metastases has been established by others and previously quantified using the MSTS and TESS scores [5, 18, 29, 33] (Table 3). However, the vast majority of these studies has been of a retrospective nature in an already difficult to study patient population [1, 5, 18, 25, 27-29, 31]. Previously, our group demonstrated that functional improvement occurs as early as 6 weeks postoperatively, which echoes other studies’ findings [33]. Pain is a crucial contributor to patient function and quality of life and represents a possible confounder when evaluating these outcomes. Other studies have analyzed pain using analgesia intake or the pain category of the MSTS, and the results after operative fixation have been mixed [23, 31, 33]. We utilized the validated BPI-SF tool at each followup visit and were able to show improved pain relief as early as 2 weeks after surgery. Quality of life was evaluated using a validated tool for the Canadian population developed at the institution of the senior author (KG). It includes 27 items on physical, psychologic, and existential well-being submeasures. Also, it addresses aspects of relationships, quality of care, and environment. Our results did not show an improvement in QOLLTI-P after surgery. Results of other studies have varied depending on the tools used to quantify quality of life [22, 33], and it may be that other factors such as concomitant chemoradiotherapy regimens, other procedures for primary disease, multiple appointments in followup, and terminal illness confound this relationship. Another important factor is patient expectations; for instance, a patient who is functional at baseline and has slightly higher MSTS scores will not report a significant change in his or her quality of life. Further development of a musculoskeletal-based quality-of-life measurement tool will certainly help to assess the concerted effect of the surgical management on quality of life in this population.

Table 3

Table 3

The temporal progress in both patient-reported and clinician-measured functional outcome up to 1 year after surgery for long bone metastases is a substantial finding of this study (Figs. 2A, 3A). Previously, our group has reported progressive functional improvement at 6 and 12 weeks postoperatively in a similar patient population [33]. To our knowledge, no other studies have evaluated functional improvement in a temporal fashion. Furthermore, a similar trend in pain relief was also observed up to 1 year after surgery (Fig. 4). Other studies have demonstrated good pain control up to 6 weeks after surgery using nonvalidated measures [11, 33]. However, pain status after 6 weeks was not explored. Knowing how these outcomes change over time will help surgeons plan surgical treatment and manage patient expectations.

In our study, the overall complication rate was 35%. Complications after surgery for long bone metastases are prevalent with reported rates ranging from 17% to 38% [4, 17, 35]. The most common complication in our cohort was DVT, which affected 5% of the cohort despite prophylactic anticoagulation. Jenkinson et al. [21] also reported a 4.9% rate of DVT after surgical stabilization of a femoral metastatic lesion. Similar to our previous study, we did not encounter any patients who developed fat or tumor embolism, which has been reported in up to 26% after intramedullary nail fixation [3]. Surgical site infection requiring reoperation occurred in 3% of the cohort. Infection was more prevalent in patients with endoprosthetic replacement, whereas fixation failure was more prevalent in those with plate fixation, which is consistent with other reports [15, 20, 36]. Our rate of dislocation was 2% as compared with other reports of proximal femur reconstruction, which range from 0% to 22% [6, 20, 29]. Previously, pathologic fractures have been reported to lead to worse overall morbidity and mortality [34], but our results do not corroborate this (Figs. 2B, 3B). We did not detect a difference in complication rates when comparing patients with and without pathologic fracture. Jenkinson et al. [21] and Bauer [4] similarly found no difference in complications but did demonstrate higher mortality rates in patients with pathologic fracture. Thirty-five percent of our cohort were treated with endoprosthetic replacement for bone metastases, indicating advanced disease at the time of surgery, and this may account for the failure to show a difference in surgical outcomes in those with pathologic fracture.

The estimated overall survival in our cohort was 70% at 6 months and 41% at 1 year with a mean survival of 7 months. Survival in patient with bone metastases is variable and mainly associated with primary tumor biology as well as disease stage at presentation [7]. Reported 1-year survival in the literature ranges from 0% to 62% [20]. Local tumor recurrence occurred in 14% of our cohort; however, only 5% developed implant failure requiring reoperation. Reports of local recurrence after surgical management in the literature range from 0% to 48% [25, 30]. Adjuvant postoperative radiotherapy was used in 61% of our patients, and we did not find any association between radiation and local control. Chandrasekar et al. [9] observed higher rates of local recurrence with pathologic fractures (17% versus 4%); however, our findings did not corroborate this association.

Surgical management of metastatic long bone disease substantially improves patients’ functional outcome and pain as early as 2 weeks postoperatively and should be considered for impending or pathologic fracture in patients with expected short-term survival. The presence of pathologic fracture did not appear to worsen function or increase complication rates. Quality of life in this patient population did not improve, which merits further investigation.

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