IlluminOss^® Photodynamic Bone Stabilization System Improves Pain and Function After Treatment of Humeral Metastatic Disease

Abstract

Aims

The LightFix Trial was performed to evaluate clinical outcomes for one year after treatment of impending and completed pathological humerus fractures with the IlluminOss^® System (IS), and to analyze performance of this device.

Methods

Eighty-one patients suffering from impending or completed pathological fractures, with VAS Pain Scores > 60mm/100mm and Mirels’ Score ≥ 8, were enrolled in a multi-centre, open label single cohort study and treated with IS. VAS Pain, MSTS Upper Extremity Function, The European Organization for Research and Treatment of Cancer (EORTC) QoL Group Bone Metastases Module (QLQ-BM22) scores, all normalized to 100, and radiographs were obtained at baseline and 14, 30, 90, 180, and 360 days post-operatively.

Results

VAS pain scores decreased from 84/100 to 50, 38, 31, 31, and 21 between baseline and follow-up time points (p < 0.001). MSTS function scores increased from 27/100 to 52, 60, 67, 72, and 83 (p<0.0001). Pain and functional subscales of the QLQ-BM22 showed significant improvements at most time points. The unadjusted device fracture rate was 15%.

Conclusion

Stabilization with IS decreased pain and improved function with durable results out to one year. IS is a new, minimally invasive type of internal fixation. IS alone may be better for impending rather than completed pathological fractures, and may be better in completed fractures if an adjunctive plate or more than the usual number of locking screws is thought to be advantageous. Caution is warranted regarding its use alone in patients with completed pathological fractures due to the rate of implant breakage.

Introduction

Metastatic bone disease (MBD) adversely affects quality of life with an estimated prevalence of 0.1%^1,2. Prophylactic fixation of impending pathological fractures from MBD has demonstrated reduction of pain, improvement in activities of daily living, and better quality of life (QOL)³. The humerus is the second most affected appendicular bone, and its surgical treatment can be particularly challenging. Poor bone quality and extensive, progressive bone loss can limit the success or feasibility of internal fixation. The surgical options include intramedullary fixation, plating, open curettage with cementation or bone grafting, and resection with endoprosthetic reconstruction^3–8. Intramedullary fixation is the most commonly used⁹. Each technique has a wide range of failure rates which are related to the extent of disease, characteristics of the fixation, pace of disease progression, and patient comorbidities¹⁰. The IlluminOss^® System (IS), (IlluminOss^® Medical, Inc., East Providence, RI, USA) was developed as an alternative, minimally invasive, balloon catheter-based means of fixation that more effectively allows for the combination of intramedullary and extramedullary fixation. Here we report the results of the IlluminOss^® LightFix Trial. The objective was to determine one-year clinical outcomes and performance of the IS.

Materials and Methods

Trial Overview

Thirteen centres participated in an open label single cohort Phase II study with an accrual goal of 80 patients suffering from MBD (including myeloma and lymphoma) affecting the humerus to be treated with IS. The study was conducted under an Investigational Device Exemption (IDE) from the U.S. FDA, (ClinicalTrials.gov Identifier: NCT02338492). The trial was approved by each local institutional review board. Participants were recruited through the investigators’ clinical practices and all participants provided written informed consent.

Trial Design

Key eligibility criteria included a minimum age of 18; impending or completed pathological fracture of the humerus secondary to MBD; VAS Pain Score > 60mm on a 100mm scale; and Mirels Score ≥ 8 for impending fractures. Pain and function scores and radiographs were obtained at baseline and at follow-up times of 14, 30, 90, 180, and 360 days postoperatively. Data management and clinical monitoring was performed by ICON plc (Marlborough, MA), radiographs were reviewed by Medical Metrics, Inc (Houston, TX), and statistical analysis was performed by Biomedical Statistical Consulting (Wynnewood, PA) and Highlander Analytics (Prescott, AZ). Subjects were considered lost to follow-up if there was no response to two telephone calls and a certified letter.

End-Point Measures and Safety Assessments

The primary endpoints were change in VAS pain and MSTS Upper Extremity Function scores from baseline compared to follow-up times after surgery. The VAS pain is a single-item scale with a range from 0–100mm: 0 means “no pain” and 100 means “pain as bad as it could be” or “worst imaginable pain.” The MSTS Upper Extremity score was normalized to a 0–100 range with higher scores indicating better function.

Secondary endpoints were The European Organization for Research and Treatment of Cancer (EORTC) QoL Group Bone Metastases Module (QLQ-BM22) scores and The Composite Safety Success (CSS) of the IS, both of which were also assessed at all follow-up times. QLQ-BM22 was standardized to a 0–100 range, higher scores for the symptom scales represent a higher level of symptomatology, higher scores for the functional scales represent a higher level of functioning. CSS is defined as no serious device related complications, additional surgical interventions, or device breakage, migration, mal-alignment or loss of reduction or fixation on follow-up radiographs. Survival and CSS were determined for all subjects until one year after enrolment of the last patient (500 days after enrolment of the first patient). The surgical time, blood loss, and systemic complications were recorded.

Statistical Analysis

Changes in VAS and MSTS scores between baseline and each follow-up time point were analysed with one-sample t-tests to test the null hypothesis of no difference in change from baseline at a two-sided 0.05 level of significance. Post-hoc Bonferroni correction was applied to account for multiple comparisons. Survival was analysed with the Kaplan-Meier method. Competing risk analysis of safety failure (1-CSS) for surviving patients adjusted for the risk of death was performed¹¹. A sample size of 80 was chosen based on pain relief in prior studies of MBD treatment^4,7,12,13. Data are presented as means with 95% confidence intervals. (SAS software, version 9.2, Cary, NC).

Device Description and Surgical Technique

To insert the IS, an incision is made on the shoulder over the greater tuberosity and an entry portal is made lateral to the rotator cuff insertion. After intramedullary reaming, the sheath and polyethylene terephthalate (PET; Dacron^™) balloon are placed in the intramedullary canal over a guide wire, the sheath and wire are removed, and the balloon is filled with methacrylate monomer under fluoroscopic guidance. The filled balloon conforms to the geometry of the intramedullary canal. A preloaded fiberoptic cable (Dymax Corp., Torrington, CT) is used to deliver light to polymerize the cement in situ (Fig. 1). The polymerized cement stabilizes the bone and can be drilled for additional fixation with screws alone or with plates, which surgeons used at their discretion at the time of primary or secondary salvage procedures.

Figure 1.

The IlluminOss^® System is shown in vitro in two different sizes (left), one with supplemental screws (arrows), and in a postoperative AP radiograph of a patient with myeloma and a dialysis shunt (arrow) (right).

Source of Funding:

IlluminOss^® Medical, Inc., East Providence, RI USA.

Results

Trial Participants

Clinical information is provided about the eighty-one enrolled patients in Table I. Seventy-nine patients were treated with the IS device. One was not treated because the investigator was unable to adequately reduce the fracture and the second due to balloon leakage. No ancillary hardware was used in 58, supplemental screws were used in 17, plate and screws were used in 4. Thirty-three patients received postoperative radiation therapy. The average VAS at baseline was 84, 4 patients were enrolled with VAS less than 60, the least being 42. Table II lists the number of patients and data available at 90 and 360 days.

Table 1:

Baseline Demographics

Age (Mean (SD))	64	11.91
VAS (pre-op) (Mean (SD))	84	15.05
Sex (n (%))
Male	42	51.9%
Female	39	48.1%
Ethnicity (n (%))
Hispanic	1	1.2%
Not Hispanic	78	96.3%
Unknown	2	2.5%
Race (n (%))
Asian	1	1.2%
Black	9	11.1%
White	68	84.0%
Multiple	1	1.2%
Other	2	2.5%
Work Status (n (%))
Full Time	13	16.0%
Part Time	4	4.9%
Restricted	3	3.7%
Other	44	54.3%
Unknown	2	2.5%
N/A	15	18.5%
Occupation Type (n (%))
Sedentary	15	18.5%
Active	13	16.0%
N/A	53	65.4%
Smoking History (n (%))
Current	11	13.6%
Former	33	40.7%
Non-smoker	37	45.7%
Hand Dominance (n (%))
Right	76	93.8%
Left	5	6.2%
Primary Cancer Type (n (%))
Breast	14	17.3%
Thyroid	2	2.5%
Gastrointestinal	5	6.2%
Lymphoma	2	2.4%
Myeloma	18	22.2%
Renal cell carcinoma	15	18.5%
Prostate carcinoma	2	2.5%
Lung carcinoma	16	19.8%
Melanoma	3	3.7%
Soft tissue sarcoma	2	2.5%
Miscellaneous and site unspecified	2	2.5%
Fracture or Impending Fracture (n (%))
Fracture	49	60.5%
Impending Fracture	32	39.5%
Fracture – Humerus Location* (n (%))
Left	24	49.0%
Right	25	51.0%
Proximal	25	51.0%
Diaphyseal	20	40.8%
Distal	4	8.2%
Impeding Fracture – Humerus Location* (n (%))
Left	14	43.8%
Right	18	56.3%
Proximal	22	68.8%
Diaphyseal	9	28.1%
Distal	1	3.1%
AO Classification* (n (%))
11-A1	1	2.0%
11-A2	6	12.2%
11-A3	5	10.2%
12-A1	7	14.3%
12-A2	12	24.5%
12-A3	5	10.2%
12-B1	3	6.1%
12-B2	7	14.3%
12-C3	1	2.0%
II-A3	1	2.0%
Missing	1	2.0%
Gustilo Grading of Soft Tissue* (n (%))
Closed Fracture	46	93.9%
Type I	3	6.1%
Type II	0	0.0%
Type III A	0	0.0%
Type III B	0	0.0%
Type III C	0	0.0%

^*Among those with Fracture

Table 2:

Patient Accounting

Follow-up Interval	90 days	1 year
Enrolled	81	81
Device Implanted	79	79
Death	17	32
Lost to Follow-up	6	12
VAS, MSTS	56, 52	35, 33

Primary Endpoints Analysis

VAS pain scores decreased from 84/100 to 50, 38, 31, 31, and 21 between baseline and follow-up times (p < 0.001) (Fig. 2). MSTS function scores increased from 27/100 to 52, 60, 67, 72, and 83 (p<0.0001) (Fig. 3).

Figure 2.

VAS pain scores were less at all time points compared to baseline through 360 days (p < 0.001, 95% CI). * = 7 to 14 days.

Figure 3.

MSTS Upper Extremity Function scores improved at all time points compared to baseline (p < 0.0001, 95% CI). * = 7 to 14 days.

Secondary Endpoints Analysis

The Pain Characteristics, Painful Sites, and the Functional Interference subscales of the QLQ-BM22 showed significant improvements at most time points out to one year, which meet the criteria for minimal clinically important differences (MCID) (Fig. 4). The Psychosocial Aspects subscale did not show improvement.

Figure 4a-c.

The two pain and function subscales of The European Organization for Research and Treatment of Cancer (EORTC) QoL Group Bone Metastases Module (QLQ-BM22) are shown. Nonoverlapping confidence intervals indicate nominal statistical significance. * = 7 to 14 days.

The CSS was 82.7% at one year. 14 subjects were considered study failures: 12 because of device breakage and 2 for malalignments. The 2 malalignments were not clinically significant. All of the device breakages occurred in patients with completed rather than impending fractures. Three devices broke by day 90, 10 by day 180, 12 by day 360. Five had myeloma, four renal cell carcinoma, one leiomyosarcoma, one adenocarcinoma of unknown primary, and one melanoma; seven had received radiation therapy. Seven of the twelve had a second surgery so that the reoperation rate was 9% (7/79). The second surgeries were fixation with plate and screws, which is one of the advantages of IS since screws can be anchored into the rod. Figure 5 shows a radiograph of a broken IS in a patient with myeloma that was treated with additional fixation using a plate and screws. The unadjusted device breakage rate is 15% (12 of the 79 subjects who received the device) and 24% in patients with completed fractures (12 of 49). The cumulative risk of device breakage with death as a competing risk for all patients is 10.2% (95% CI 4.7% to 18.2%) at six months, and 15.6% (95% CI 8.5% to 24.7%) at one year (Fig. 6).

Figure 5a-c.

Anterior-posterior radiographs of a humerus affected by myeloma, (a) postoperative after stabilization with IS, (b) broken IS 3 months postoperative, (c) 8 months after supplemental fixation with plate and screws.

Figure 6.

Kaplan-Meier survival analysis (upper) and cumulative incidence of device breakage with death as a competing risk are shown (lower), (95% CI).

The median surgical time was 1:19 (first and third quartiles: 1:01, 1:47); median blood loss was 50 ml (20, 200); there were no deep infections, one superficial infection, one radial nerve palsy, and no systemic complications. The radial nerve palsy fully recovered by 11 months postoperative.

Discussion

The LightFix Trial is the largest prospective clinical trial for treatment of impending or completed humeral fractures affected by MBD. Ninety-day follow-up was available for 90% of surviving patients and for 74% at 1 year. Pain and functional improvements were durable to one year. Stabilization with IS was feasible, failures and reoperation rates were within the range reported for other techniques, device breakage was more common than for metal rods, and there were no systemic adverse events¹⁰. This is the longest follow-up of published prospective studies for this problem and this information will be useful in counselling patients. Smaller retrospective studies utilizing IS in the upper extremity showed encouraging results, one of which has 24 month follow-up^14–16.

Impending and completed pathologic fractures of the humerus adversely affect QOL. The major goals in the treatment of extremity MBD are improvement of functional status through pain relief and treatment or prevention of fractures. Our data indicate that stabilization of the humerus with IS improved QLQ-BM22 pain measures and decreased VAS pain scores from 84 (severe) to mild (< 40) at all time points beginning at 30 days, all clinically important differences. In cancer patients, a patient whose worst pain decreased from moderate or severe (50 or greater out of 100) to none or mild (0–40) was defined as a responder (clinically significant) since patients who report pain of 50 or more have greater pain-related interference with function than those with mild or no pain^17–20. Pain relief was similar to prior studies. The difference in VAS pain scores between baseline and one year in this study was 63 compared to 66 at various time points ranging from 1 month to 1 year in the prior studies used for the power analysis (N = 54)^4,7,12,13.

Patients in this report had an increase in functional status. MSTS scores were 60, 67, and 83 at 30, 90, and 360 days compared to 27/100 at baseline and the Functional Interference subscale of the QLQ-BM22 showed an improvement out to one year (Figs. 3 and 4c). Our results are similar to prior studies in which mean MSTS scores were 60 in 15 patients after 3 days⁷, 64 in 20 patients after two months²¹, 69 in 25 patients after six months⁵, and 79 in 55 patients after eight months⁶. Based on the current and previous studies, patients can be reassured that pain and function can be improved with surgical stabilization of the humerus affected by MBD.

Twelve of the 79 subjects experienced a device breakage, all in patients with completed fractures. Cumulative risk of device breakage accounting for death as a competing risk is 10.2% (95% CI 4.7% to 18.2%) at six months, and 15.6% (95% CI 8.5% to 24.7%) at one year. The goal in surgical treatment of MBD is to have one operation that stabilizes a bone for the duration of the patients’ lives^22,23. Although the failure and reoperation rates in this study are within the range of those reported in the literature (0–25%), the number of devices that broke compared to metal rods is higher^10,15. Device failure can be related to disease progression. In conventional fracture treatment, implants only need to function until the fracture has healed. In MBD, implants need longer fatigue life since the affected bone rarely, if ever, returns to normal strength. One benefit of IS is that if it breaks, fixation can be supplemented with plate and screws anchored into the IS as was performed in seven patients (9%), although this violates the goal of one operation per bone. This reoperation rate of 9% is consistent with reoperation rates of 0–10% previously reported¹⁰. In vitro biomechanical testing of IS in a Sawbones defect model has shown fatigue life of over one million cycles, so the number of device failures in this study was surprising and warrants further analysis.²⁴ Some of the failures could be due to technical issues such as inadequate filling of the balloon at the fracture site or motion during the curing process. This trial reports the initial experience with a new device and there may be a learning curve such that results may improve with additional experience and refined indications. Its use in patients with completed fractures may require use of an adjunctive plate, although this would no longer be less invasive than a metal rod. Photodynamic nails are now being used for other oncologic and non-oncologic indications as surgeons gain more experience with this device.^25,26

There are some limitations to our study. Similar to prior series, there was no control group, so we are only able to compare the results to baseline scores. We do not know how much improvement in pain and function there would be with systemic treatment and or radiation therapy and splinting alone, or from stabilization with other types of implants. We do not know how many patients met inclusion criteria but were not enrolled. Although this may result in selection bias, more patients had completed as opposed to impending fractures, and the distribution of primary cancers was similar to previous studies. The inclusion criteria for patients with impending fractures were those commonly used by clinicians including a Mirels score > 8, significant cortical erosion, and pain. Therefore, this cohort is representative of MBD patients. There may be variation in the results related to the number of centres involved, however, this increases the generalizability of the results.

Some additional observations are worth noting since this is a new category of device. The median operative time of 1:19 is comparable to conventional IM nailing¹⁵. However, an advantage of IS compared to a conventional nail is that insertion of IS can avoid disruption of the rotator cuff. A conventional nail requires either splitting the rotator cuff or detaching and then repairing the rotator cuff to the greater tuberosity. Since IS is flexible at the time of insertion, the entry point can be lateral to the rotator cuff footprint allowing the device to be inserted without disruption of the rotator cuff, which may allow for a quicker recovery and better function. A potential disadvantage is that removal of the device could require osteotomy of the humerus.

Blood loss was minimal (median 50 ml) and similar to a report of 165 ml²⁷. Because the diameter of the IS is up to 22mm, after inflation there is a tamponade effect that could lessen blood loss. This is helpful for highly vascularized tumours such as renal cell carcinoma and may obviate the need for preoperative embolization.²⁸

Conventional humeral nails have 2–4 locking screws proximally and distally. When there are large metaphyseal metastatic deposits, proximal fixation is potentially better with IS since the proximal diameter is up to 22mm which allows for increased proximal fill and fixation with a larger number of locking screws as well as a plate. IS provides a better purchase for the screws than bone that has been compromised by metastatic disease. If distal locking is desired, screws can be placed away from the radial nerve. The reported incidence of radial nerve palsy after conventional nailing ranges from 0% to 14% and with plating 0–18%^10,29,30. There was one radial nerve palsy in this cohort which fully recovered.

A theoretical advantage of IS is that unlike a metal rod, there would be no effect of the polymer on blocking or distorting the radiotherapy field, which is typically used in treatment of MBD³¹. Also, postoperative imaging is improved without the presence of a metal rod allowing for more accurate monitoring of the diseased bone. Whether any of these potential benefits warrant utilization of this new technology is subject to debate³².

In conclusion, stabilization with IS improves pain and function in patients with MBD affecting the humerus. The results improve with time and are durable out to one year. Careful clinical decision making about which type of procedure should be performed is critical. If intramedullary fixation is chosen, IS may have a role in some MBD patients instead of a metal rod. When an adjunctive plate should be used prophylactically cannot be definitively determined from this trial and requires further study. IS alone may be better for impending rather than completed pathological fractures, and may be better in completed fractures if an adjunctive plate or more than the usual number of locking screws is thought to be advantageous. Caution is warranted regarding its use alone in patients with completed pathological fractures due to the rate of implant breakage.

Figure 7.

Cumulative incidence with 95% CIs of device breakage with death as a competing risk.

• Clinical results after stabilization of humeri with IS affected by metastatic bone disease are similar to stabilization with traditional implants.

• Device breakage in patients with completed pathological fractures warrants concern but can be addressed with prophylactic or subsequent adjunctive fixation.