Assessment of the risk factors for impending fractures following radiotherapy for long bone metastases using CT scan-based virtual simulation: a retrospective study

The aim of extracorporeal radiotherapy of the long bones (RTLB) is to provide control of symptoms, destroy cancer cells in the treated area and prevent malignant disease-related fractures. The analgesic potential of RTLB has been demonstrated in numerous trials, with overall response rates of 60%, including 23–24% complete responses [1],[2]. Bone radiotherapy is also a useful means of halting tumor proliferation and then triggering osteoblastic activity with osteoproliferation [3]. Bone recalcification after RTLB has been observed in 70% of cases, particularly in the fractionated group [3]; recalcification commenced from the first month after RTLB and peaked at three months [4]. Nonetheless, RTLB does not entirely eliminate the risk of fracture [3], particularly in the three months immediately after radiotherapy. A pathologic fracture may occur during this time. While such fractures may be atraumatic, they can also considerably aggravate morbidity and mortality.

Prophylactic surgery (followed by RTLB) should be discussed for patients with a high risk of fracture. RTLB after surgery improves bone recalcification and guarantees the stability of the new bone [5],[6]. While the primary aim of fracture risk assessment is prevention, such an assessment also reduces the risk of surgical overtreatment in patients whose life expectancy is sometimes limited.

Numerous studies [1],[7] have explored the risk of fracture using radiographic images (standard x-rays) to determine predictive factors. Analysis of the dimensions of metastatic lesions, and especially any cortical involvement, on standard x-rays alone remains insufficiently predictive of the fracture risk. A three-dimensional CT study provides a more precise assessment of the risk of pathologic fracture, but is not always carried out when the pain is so great that radiotherapy is urgently required. CT scan-based virtual simulation is therefore a valuable tool for providing a precise analysis of tumor infiltration and osteolysis.

The aim of our study was to use CT scan-based virtual simulation to assess the risk of fracture and identify predictive factors with a view to offering prophylactic fixation to those most at risk.

Between September 2010 and February 2012, 37 patients with 47 lesions (28 femoral, 17 humeral and two tibial) underwent analgesic radiotherapy for long bone metastasis. The patients had been monitored for a minimum of four months. The male gender ratio was 0.59 and the mean age was 62.8 years (33–93). Cancer staging was I–II for 56.8% and II–III for 43.2%. The primary cancers were lung (35.1%), prostate (27%), breast (16.3%) and others (21.6%). There were 32 adenocarcinomas, two squamous-cell cancers and three other types. At the moment their painful long bone metastasis was discovered, 18 patients had been receiving treatment with bisphosphonates and 25 with chemotherapy. Surgery was not initially performed for a variety of reasons, including poor general patient health, increase in pain refractory to medical treatment requiring urgent radiotherapy and low risk of impending fracture. Twenty-two [22] of the 47 lesions received a single dose (7 to 8 Gy). The 25 other lesions received 15 to 30 Gy in three to ten sessions over three to 19 days. The radiation dose was delivered through hard X-ray energy (5.5 to 18 MV).

Ten of the 47 radiated lesions fractured during or after RTLB. When overall survival is taken into account, the incidence of fractures was 20% one month after RTLB and 25.9% at the end of the study. Two fractures occurred during RTLB, and another seven occurred in the first thirty days. The last fracture occurred at 6.6 months (Figure 2).

Our study showed that more than 25% of patients undergoing radiotherapy for metastases presented with a fracture. In the multivariate analysis, the only factor predictive of fractures identified during the CT-scan-based virtual simulation study was circumferential a CI ≥30%.

Several studies [1],[7] have explored risk factors for fractures using radiographic images (standard X-rays) to determine predictive factors. In general, high impending fracture risk lesions are lytic [8]-[17], proximal [10],[18],[19], large (>25 mm) [8]-[10] and femoral (Harrington criteria, [10],[25]). They trigger increasing pain [8]-[11],[13]-[15],[17],[20],[21], involve more than 50% of the cortex circumference [9],[10],[15]-[17],[21]-[23] with craniocaudal cortex involvement of over 30 mm [11],[22]-[24] and a Mirels score of ≥9 [21].

As in other studies, we found that the other radiological parameters predictive of fracture were a lytic, diffuse, poorly circumscribed appearance and cortical involvement (30% circumferential, 45 mm height and 100% thickness). In our study, ≥30 mm femoral craniocaudal cortical involvement was a significant predictor of fracture risk in the univariate analysis, but this consideration could have led to 14 unnecessary surgical procedures (37.8% false positive rate).

In our series, a composite Mirels score of ≥9 was also predictive of fracture. However, while this score has the advantage of being very sensitive, it lacks specificity [7],[23],[24]. Therefore, in our study this score was ≥9 in 100% of the fracture cases, but there were 14 false positives (37.8%). The three-dimensional study clearly provides a more precise assessment of the risk of pathologic fracture. Measuring circumferential cortical involvement enhances this assessment: primary surgical fixation should be considered in patients with circumferential cortical involvement ≥30%.

Our study was representative and comparable with those reported in other series in the literature in terms of age, gender, primary cancer type, performance status and fracture rates [6],[15],[24],[26]-[28]. In our series, radiotherapy procedures and fractionation did not affect the fracture incidence and the data in the literature are discordant on this point [26],[28]. Furthermore, in our population, bisphosphonate administration did not influence the risk of bone fractures.

Nevertheless, our study has several limitations:

It is retrospective in design and our population was very small. However, all the patients treated with RTLB were enrolled and none were lost to follow-up, which represents a real-life experience.

The four-month follow-up period could also be seen as a limitation of our study. However, 90% of the fractures occurred in the month following RTLB and it has been shown that bone recalcification is obtained three months after RTLB, after which time the risk of fractures is very low [4].

While our scan images were read by a radiotherapist and an oncologist rather than a radiologist, these are the healthcare professionals who are required to assess fracture risk in patients with painful bone metastases on a daily basis. Our patients were oriented directly for urgent analgesic radiation and a CT scan was performed promptly for the virtual simulation (without evaluation by a radiologist). At the same time, we recorded bone scan parameters for this study.

Due to the retrospective nature of the study, some risk factors for fracture could not be included, such as assist devices, weight-bearing status, bone density status, smoking status and osteoporosis comorbidity.

Our data must be confirmed in a prospective study including a much larger series of patients, since it is important to precisely establish when prophylactic fixation is required to reduce morbidity and mortality [5],[6],[10],[15]. The development of an instrument that identifies patients who have a relatively high risk of developing such a fracture and therefore should be considered candidates for surgical stabilization is helpful. This strategy could optimize the management of fragile metastatic patients. Elective surgery in patients in good general health is simpler and less risky than an emergency procedure, with more rapid relief of pain and recovery of mobility [29],[30]. Surgical overtreatment also unnecessarily increases morbidity (e.g., hospitalization, general anesthetics and complications arising from a forced supine position) in patients whose life expectancy is limited. The appropriate management of palliative patients and cost-effective proactive approaches may offer more clinical benefit and value for carefully selected patients.

This study analyzes the risk of fractures following radiation for bone metastasis and attempts to determine which patient population would benefit from prophylactic surgery. Circumferential cortical involvement is easy to measure and should be systematic during CT scan-based virtual simulation prior to radiotherapy.

ZT participated to study design, analysed CT images and participated in the sequence alignment and drafted the manuscript. MS participated in the sequence alignment and drafted the manuscript. AFD participated in the sequence alignment and the reviewing of the manuscript. PV participated in the sequence alignment and the reviewing of the manuscript. SB participated in the sequence alignment and the reviewing of the manuscript. ML participated to study design, analysed CT images and participated in the sequence alignment and drafted the manuscript. All authors read and approved the final manuscript.