With the available numbers, we could not demonstrate a difference in the proportion of patients who developed local disease progression after orthopaedic reconstruction or fixation of a femoral metastasis. Among the 41 patients with tumors responsive to biologics, three patients (7.3%) developed local disease progression, diagnosed either symptomatically or radiographically. This progression was noted at a mean of 424 days from the index surgery. Among the 52 patients with tumors that did not respond to biologic therapy, two patients (3.5%) demonstrated progression of disease at a mean of 476 days from surgery. In one of the 51 patients (1.6%) in the chemotherapy group, the disease progressed locally 106 days after femoral surgery.
With the available numbers and the low overall incidence of revision surgery, we could not demonstrate a difference in implant survival based on the type of systemic treatment used or whether a patient’s disease responded to biologic therapy. In total, there were four patients who underwent revision surgery as a result of local progression of disease; all had originally undergone internal fixation procedures. No revisions of endoprosthetic replacements were performed in the time period of this study. Three of these patients who underwent revision had received biologic treatment and their tumors responded, yet local tumor progression developed at the femoral site of metastasis causing pain, bone resorption around the hardware, and loosening. There were two patients in the group whose disease did not respond to chemotherapy or biologics and who developed local progression radiographically, but neither of them underwent revision surgery because they were too medically ill to sustain it.
Femoral metastases are a common cause of morbidity among patients with adenocarcinoma of the lung and kidney [4, 10]. Recent development of biologic treatments has prolonged survival considerably for certain patients with these diseases when compared with traditional chemotherapy options [9, 12, 15, 19]. This has not been shown specifically in patients undergoing internal fixation or endoprosthetic reconstruction for pathologic fracture, and it is unclear whether improved survival afforded by biologic agents impacts local tumor recurrence or need for revision. Our analysis demonstrates a measurable impact of biologic treatments on survival in some patients who undergo internal fixation or prosthetic replacement to manage femoral metastases. The improved survival is exhibited by patients who respond viscerally to the biologic agent. Those who do not have a visceral response exhibit the same survival as those treated only with traditional chemotherapy. With the numbers available, we could not demonstrate a difference in either the local tumor recurrence rate or implant survival as a result of systemic treatment.
There were several limitations to our study. First, because it was a retrospective and nonrandomized study, there exists potential for selection bias. In determining eligibility for biologic therapy, oncologists are more likely to select the strongest patients who meet strict physiological and functional criteria; those deemed too sick for biologic agents by the oncologist were not offered that treatment, but may have received chemotherapy. This difference in patient status could have biased our survival analysis. However, criteria for initiating biologic treatment also included progressive disease burden, partly mitigating this selection bias. Further bias was introduced by not utilizing an independent objective measure of visceral tumor response to systemic treatment such as RECIST , but we attempted to standardize the delineation of patients responding or not responding to biologic treatment by using documentation of stability or regression over a 6-month period. A more formal method of quantifying response using objective criteria would have been ideal but was not available.
An important source of bias was introduced by our decanting of patients who did not respond to biologic treatment from the overall biologics group during the analysis. We identified and designated the strongest patients who responded to the best systemic treatment and compared them with a combined group of patients who received only chemotherapy plus those who did not respond to biologics; this design inflated the apparent survival benefit of biologic agents. The rationale for this decision was our intent to investigate orthopaedic implant survival among the class of patients with the best overall prognosis among the metastatic lung/renal cell carcinoma population and compare this with a class of patients whose disease continues to progress despite the best available medical management. The authors recognize the significant bias that this methodology introduces into the survival analysis and for this reason, these results must be considered preliminary. Future randomized controlled trials with clear criteria and intent-to-treat analysis will further elucidate the true survival impact these drugs have on patients and their orthopaedic implants.
Our analysis was also hampered by the small sample size and low incidence of events, because mechanical failure or revision of any type of orthopaedic construct is a relatively rare occurrence. Because we divided the patients by both systemic treatment and response to treatment, the resultant groups were small and this made comparison of recurrence and revision rates between individual groups difficult. Therefore, our finding of no difference in risk of revision should be interpreted with caution, because a true difference may exist but has gone undetected here as a result of the insufficient sample size. Lastly, although postoperative radiation was performed in some patients, detailed data on radiation therapy were not available, and it is beyond the scope of this project to investigate the potential impact radiotherapy had on the local recurrence rate. The authors recognize that failure to include radiation status is a confounding factor when analyzing tumor recurrence rate, although we do not believe it introduces systematic bias into the survival analysis.
The first conclusion from our analysis is that patients who receive biologics and experience a visceral response can survive longer than those who do not exhibit a visceral response to them or who are treated only with chemotherapy. This survival benefit associated with biologic agents has been shown in large studies in the medical oncology literature [9, 12, 19, 22] but not specifically in patients with Stage IV disease undergoing fixation or endoprostheses for impending or pathologic fractures. Only a subset of those patients who receive a biologic agent will respond to it; Motzer et al.  demonstrated an objective response rate (partial plus complete response) of 44% with an additional 22% of their cohort experiencing stable disease for at least 3 months among their cohort of 105 patients who received sunitinib for second-line treatment of metastatic RCC. Our analysis demonstrates a similar response rate despite slightly different criteria used to define response; 41 of our 97 (42%) patients who received a biologic agent experienced stable or regressive visceral disease over at least 6 months. Those who fell into this category demonstrated prolonged overall survival. It is critical to note, however, that 58% of the patients who received a biologic agent did not respond to it, and these patients’ survival was not longer than the survival of those who only receive chemotherapy. It is critical to understand that the difference in survival observed between the 97 patients who received biologics and the 51 who received chemotherapy is driven by the minority who respond to the biologic agent, raising the overall mean for the biologics group.
With the available numbers, we could not demonstrate a difference in the proportion of patients who developed local disease progression after orthopaedic surgery for femoral metastasis. Seven percent of patients responding to biologics experienced local progression of tumor in their femur as compared with 3.5% of those in the nonresponders group and 2% in the chemotherapy group. Small sample size and low incidence of events could have contributed to a lack of statistical power to detect a difference, if one truly exists in this comparison. In terms of time to local recurrence, recurrence was noted at nearly the same time from index surgery among patients who both responded and did not respond to biologic treatment. These findings suggest that despite the positive impact that biologics can have on visceral disease, these agents may not postpone skeletal progression of disease, but because it is often more difficult to discern response in a bone compared with viscera, we cannot be sure. Further large studies investigating this relationship are needed, because the impact of biologic therapy on bony metastases is not well described in the literature to date.
With the available numbers and the low overall incidence of revision surgery, we could not demonstrate a difference in implant survival based on the type of systemic treatment used or whether a patient responded to biologic therapy. We did observe that all four revisions were performed in patients who had initially undergone internal fixation, which is consistent with multiple reports that demonstrate increased mechanical failure rates after internal fixation of femoral metastases compared with endoprosthetic replacement [11, 23]. Three of the four were among the group who responded to biologic treatment. Two patients in the nonresponder group developed local progression radiographically, but neither of them underwent revision surgery to address this because they were too medically ill to undergo surgery. Although the numbers are not large enough to explicitly identify a difference, these data may reflect orthopaedic decision-making regarding two classes of patients: a surgeon may be more aggressive in revising a painful nonunion or local recurrence in patients who are viscerally responding to systemic treatment and may be less apt to reoperate on patients who are in decline despite the best treatment available. The former group is physiologically more fit to undergo, and recover from, revision surgery; patients with extremely poor prognoses are often treated with palliative, nonoperative measures .
Improved survival among patients with RCC and lung cancer associated with biologic treatment has been well described [3, 9, 12, 19, 21], and our study has found that a subset of patients with lung or renal cancer undergoing femoral surgery who receive and respond to biologic treatment can experience prolonged survival. A much higher proportion of patients who responded to biologics were alive 1 year after surgery compared with those who did not receive, or did not respond to, biologics (61% versus 10% and 20%, respectively). There are no validated nomograms or biomarkers of response to help the surgeon determine how to treat an impending or established pathologic fracture .
This comparison may be particularly relevant when selecting an orthopaedic implant. Those patients who live longer because of their response to these agents and who undergo internal fixation might be at a higher risk of implant failure based on previous data published on the association between overall survival and revision rates . Unfortunately, we cannot currently predict who will or will not respond to the biologics when planning the operation. To reduce the likelihood of revision surgery, it is critical that a patient’s first surgery be the most appropriate procedure for his or her clinical circumstances. The orthopaedic surgeon has always weighed the recovery time needed against the desire to provide a durable surgical treatment, and reconciliation of these potentially competing concepts hinges on a thorough and patient-specific understanding of the overall prognosis. We have shown that the use of biologic therapies prolongs the survival of some patients who receive them. This introduces another variable for the surgeon to consider when deciding how to treat a patient with a fracture or impending fracture of the femur. Should he or she internally fix the lesion or resect and reconstruct with an endoprosthesis? Currently, we cannot predict who will respond to biologics, but what we have shown is that some patients treated with biologics will respond, so this potential should be considered when making the decision. Larger, prospective studies will be needed to determine if the patients who respond are indeed at higher risk for implant failure related to their prolonged survival.
We thank Drs Carol Morris, Daniel Prince, and Edward Athanasian for their contribution of patients to our longitudinally maintained institutional database.
1. Bauer HC. Controversies in the surgical management of skeletal metastases. J Bone Joint Surg Br. 2005;87:608–617.
2. Bong MR, Kummer FJ, Koval KJ, Egol KA. Intramedullary nailing of the lower extremity: biomechanics and biology. J Am Acad Orthop Surg. 2007;15:97–106.
3. Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer. 1987;55:61–66.
4. DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles & Practice of Oncology. 10th
ed. Philadelphia, PA, USA: Lippincott Williams & Wilkins; 2005.
5. Dijstra S, Wiggers T, van Geel BN, Boxma H. Impending and actual pathological fractures in patients with bone metastases of the long bones. A retrospective study of 233 surgically treated fractures. Eur J Surg. 1994;160:535–542.
6. Eastley N, Newey M, Ashford RU. Skeletal metastases–the role of the orthopaedic and spinal surgeon. Surg Oncol. 2012;21:216–222.
7. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247.
8. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, D'Amico TA, DeCamp MM, Dilling TJ, Dobelbower M, Doebele RC, Govindan R, Gubens MA, Hennon M, Horn L, Komaki R, Lackner RP, Lanuti M, Leal TA, Leisch LJ, Lilenbaum R, Lin J, Loo BW, Martins R, Otterson GA, Reckamp K, Riely GJ, Schild SE, Shapiro TA, Stevenson J, Swanson SJ, Tauer K, Yang SC, Gregory K, Hughes M. Non-small cell lung cancer, version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:504–535.
9. Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, McDermott DF, Pardoll DM, Sankar V, Ahlers CM, Salvati M, Wigginton JM, Hellmann MD, Kollia GD, Gupta AK, Brahmer JR. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33:2004–2012.
10. Hage WD, Aboulafia AJ, Aboulafia DM. Incidence, location, and diagnostic evaluation of metastatic bone disease. Orthop Clin North Am. 2000;31:515–528, vii.
11. Harvey N, Ahlmann ER, Allison DC, Wang L, Menendez LR. Endoprostheses last longer than intramedullary devices in proximal femur metastases. Clin Orthop Relat Res. 2012;470:684–691.
12. Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK. External validation and comparison with other models of the international metastatic renal-cell carcinoma database consortium prognostic model: a population-based study. Lancet Oncol. 2013;14:141–148.
13. Jacofsky DJ, Haidukewych GJ, Zhang H, Sim FH. Complications and results of arthroplasty for salvage of failed treatment of malignant pathologic fractures of the hip. Clin Orthop Relat Res. 2004;427:52–56.
14. Marcove RC, Yang DJ. Survival times after treatment of pathologic fractures. Cancer. 1967;20:2154–2158.
15. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–640.
16. Motzer RJ, Bukowski RM, Figlin RA, Hutson TE, Michaelson MD, Kim ST, Baum CM, Kattan MW. Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2008;113:1552–1558.
17. Motzer RJ, Jonasch E, Agarwal N, Bhayani S, Bro WP, Chang SS, Choueiri TK, Costello BA, Derweesh IH, Fishman M, Gallagher TH, Gore JL, Hancock SL, Harrison MR, Kim W, Kyriakopoulos C, LaGrange C, Lam ET, Lau C, Michaelson MD, Olencki T, Pierorazio PM, Plimack ER, Redman BG, Shuch B, Somer B, Sonpavde G, Sosman J, Dwyer M, Kumar R. Kidney Cancer, version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:804–834.
18. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295:2516–2524.
19. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33:1430–1437.
20. Nathan SS, Healey JH, Mellano D, Hoang B, Lewis I, Morris CD, Athanasian EA, Boland PJ. Survival in patients operated on for pathologic fracture: implications for end-of-life orthopaedic care. J Clin Oncol. 2005;23:6072–6082.
21. Ohmori K, Matsui H, Yasuda T, Kanamori M, Yudoh K, Seto H, Tsuji H. Evaluation of the prognosis of cancer patients with metastatic bone tumors based on serial bone scintigrams. Jpn J Clin Oncol. 1997;27:263–267.
22. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–125.
23. Steensma M, Boland PJ, Morris CD, Athanasian E, Healey JH. Endoprosthetic treatment is more durable for pathologic proximal femur fractures. Clin Orthop Relat Res. 2012;470:920–926.