
==== Front
J Am Acad Orthop Surg Glob Res Rev
J Am Acad Orthop Surg Glob Res Rev
JAAOS Glob Res Rev
JAAOS Glob Res Rev
JAAOS Global Research & Reviews
2474-7661
Wolters Kluwer Philadelphia, PA

39312687
JAAOSGlobal-D-24-00051
10.5435/JAAOSGlobal-D-24-00051
00012
3
007
Case Report
Treating Multilevel Cervical Degenerative Disk Disease in a Patient With Stage IV Lung Cancer With Notable Comorbidities Using a Drug Eluting Biomaterial: A Case Report
https://orcid.org/0000-0003-3473-9738
Margulies Bryan S. MS, PhD
Loy Joe C. BS, MBA
Thakur Nikhil MD
Sanz-Altamira Pedro MD
From Zetagen Therapeutics, Syracuse, NY (Dr. Margulies, Mr. Loy, and Dr. Thakur); the Department of Pathology, College of Medicine, Upstate Medical University, Syracuse, NY (Dr. Margulies); the Department Biological Sciences, University of Notre Dame, Notre Dame, IN (Dr. Margulies); the Mobility Bone and Joint Institute, Andover, MA (Dr. Thakur); and the Dana-Farber Cancer Institute, Boston, MA (Dr. Sanz-Altamira)
Correspondence to Dr. Margulies: bryan@zetagen.com
9 2024
20 9 2024
8 9 e24.0005106 2 2024
23 7 2024
27 7 2024
Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.
2024
American Academy of Orthopaedic Surgeons
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

A 64-year-old patient with stage IV non–small-cell lung carcinoma and several comorbidities, which include obesity and long-term smoking, was treated with N-allyl noroxymorphone eluting osteoinductive bone graft biomaterial. The patient had multilevel degenerative disk disease (DDD), which has a high rate of failure when osteoinductive bone grafts are not used. Infuse, the most widely administered osteoinductive bone graft, is contraindicated in the spine for patients with active tumor. As such, a novel drug eluting osteoinductive biomaterial was administered to this patient, for whom no other therapeutic options were available, to promote bone fusion in a three-level anterior cervical diskectomy and fusion as part of the Food and Drug Administration Expanded Access program. Despite patient comorbidities that are associated with poor bone physiology, confirmed radiographic fusion was achieved in all three cervical levels at 8 months.

National Cancer InstituteR43CA221553 Bryan Samuel MarguliesNational Cancer InstituteR44CA221553 Bryan Samuel MarguliesOPEN-ACCESSTRUE
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pmcThe nonunion rate for patients treated for a three-level anterior cervical diskectomy and fusion (ACDF) that includes the use of a bone graft and no comorbidities is 54%.1-3 However, patients with compromised bone physiology that results from their comorbidities often have a much higher rate of pseudarthroses, especially in the inferior level.4,5 For instance, morbidly obese patients have a 40% increased risk of nonunion after multilevel ACDF.6-8 In addition, previous long-term smokers have a 50% to 62% increased risk of complications that include nonunion.9,10 Finally, patients on long-term chemotherapy are at a much higher risk of nonunion because of the disruption of normal bone physiology,11,12 with a meta-analysis by Elder et al showing that chemotherapy increased the average time to fusion by 28.3%.11

Patients with active tumor have markedly compromised bone physiology and cannot be treated with an inductive bone graft (eg, either a synthetic graft or autograft). Iliac crest bone graft (ICBG) is a source of autograft often used to inductively promote bone growth. However, in patients with metastatic disease, there is a high risk of transplanting tumor cells from one site to another as well as an increased risk of infection for patients concurrently receiving chemotherapy. Infuse (Medtronic) is a growth factor-based inductive bone graft composed of a collagen sponge and the growth factor BMP-2 that has been used as an alternative to ICBG in spine fusion procedures. However, the BMP-2 contained in Infuse has been implicated in stimulating tumor growth.12 Infuse is also contraindicated for use in the cervical spine because of complications that have included death due to asphyxia that was the result of excessive edema.13-16 As such, Infuse has a ‘black-box’ warning from Food and Drug Administration (FDA) that restricts its use in the cervical spine.14

In this report, we present data for a single patient with stage IV non–small-cell lung carcinoma (NSCLC), whose comorbidities include obesity and a history of long-term smoking. The patient was treated for DDD using a three-level ACDF procedure and a novel drug eluting biomaterial as a part of the FDA Expanded Access/Compassionate Use program. Infuse, the most widely used osteoinductive bone graft for use in the spine, is contraindicated for patients in need of spine fusion procedures that also have an active tumor because of its potential to stimulate latent micrometastases.12-16 Given the high risk of stimulating latent micrometastases, these patients are not good candidates for conventional bone graft products, such as Infuse. As such, the patient presented in this report was granted the option of being treated with a novel N-allyl noroxymorphone eluting biomaterial as a therapeutic intervention through the FDA's Expanded Access/Compassionate Use program, which provides a pathway through which serious or immediately life-threatening diseases or conditions can be treated with an investigational medical product outside of clinical trials when no comparable or satisfactory alternative therapeutic options are available.

Case Report

A 64-year-old male patient diagnosed with stage IV NSCLC was found to have cervical stenosis in 2022 at the C4-C7 cervical vertebral bodies, resulting in both cervical radiculopathy and cervical myelopathy. The patient previously worked as a custodian, is morbidly obese, and has high cholesterol but is not diabetic. The patient was a long-term smoker, having quit 6 years before the reported procedure. The patient was diagnosed with NSCLC in 2013 and treated with resection and four cycles of adjuvant cisplatin and pemetrexed therapy. In 2021, he progressed to stage IV disease with bilateral lung lesions and chest lymphadenopathy. Biopsy showed that the tumor was an adenocarcinoma, positive for napsin A1 and cytokeratin 7 (CK7) while staining negative for CK5 and p63. Furthermore, the patient's tumor was found to be positive for the Kirsten rat sarcoma virus g12C mutation. While patients with naspin A1/CK7-positive tumors and the Kirsten rat sarcoma virus g12C mutation generally have a poor prognosis, this patient is on cycle 42 of chemotherapy (ie, 3 years), which consists of pemetrexed (500 mg/m2) and pembrolizumab (200 mg) administered every 3 weeks. The patient has been taking 10-mg oxycodone every 4 hours as needed (ie, 30 mg total per day) to control pain from the tumor.

In 2022, the patient reported left arm pain and numbness due to a work-related accident, which resulted in degenerative changes to the neck while cervical stenosis was confirmed by MRI. The patient failed the nonsurgical standard-of-care treatments and was then considered a candidate for a C4-C7 ACDF procedure. During routine exposure of the cervical spine, the surgeon used fluoroscopy to confirm and identify the correct vertebral levels. Then, osteophytes and the degenerative disks were removed, the endplates were prepared according to convention, a foraminotomy was done to release the compressed nerves, and the posterior longitudinal ligament was released.

The titanium interbody cages (Cervical Spine Truss System; 4Web Medical) used during the ACDF procedure were filled with 2.5 cc of a novel drug eluting, osteoinductive biomaterial (ZetaFuse Bone Graft, Zetagen Therapeutics) under fluoroscopic guidance. It is a drug eluting biomaterial that uses N-allyl noroxymorphone hydrochloride dihydrate, to stimulate mesenchymal stem cells (MSCs) to become bone cells.17 The biomaterial is composed of calcium phosphate salts with type-I collagen, in which the small molecule N-allyl noroxymorphone hydrochloride dihydrate, C19H21NO4 · HCl · 2H2O (Mallinckrodt Pharmaceuticals; Chemical Abstract Service Number 51481-60-8), has been added. After implanting the interbody cage + drug eluting biomaterial, an anterior 3-level cervical plate (uNion Standard Cervical Plate, Ulrich Medical) and variable angled screws (Ulrich Medical) were used to provide biomechanical stability. After 8 months, there was definitive radiographic evidence of fusion across all treated levels (eg, the fourth (C4) through seventh (C7) cervical vertebral bodies). In addition, the patient reported a complete amelioration of pain and a return to normal physical activity.

Postoperative Care, Clinical Evaluations, and Imaging

After recovering, the patient reported the following: minimal neck and left arm pain, decreased numbness, and improved strength relative to preprocedure levels. The patient was prescribed pain medicine after the surgery but declined to fill the prescription. Four weeks after the procedure, the patient's pain had decreased markedly, and his motor function had improved. On the day of surgery (day 0), the patient was administered two surveys: the Neurological Rating Scale (NRS) and the Short Form-12 (SF-12). The NRS is used to evaluate pain on a scale of 0 to 10 while the SF-12 is used to evaluate general measure of health. The SF-12 scoring yields two summary measures: the physical component summary (PCS) and the mental component summary. PCS and mental component summary scores are evaluated using a norm-based system, with a mean of 50 for the general population and a standard deviation of 10. The NRS scale showed a time-dependent decrease in the level of pain reported by the patient that reached 0 by 6 months (Table 1). The PCS score showed a 36% increase in reported physical well-being by the patient while the patient's reported mental wellness remained unchanged (Table 1).

Table 1 Patient-Reported Outcomes

Evaluation Time Points	NRS	Physical (PCS)	Mental (MCS)	
Surgery (day 0)	7/10	20.95	60.77	
3 wk (day 21)	7/10	21.25	55.73	
6 wk (day 42)	5/10	31.78	49.07	
3 mo (day 90)	4/10	30.29	55.67	
6 mo (day 180)	0/10	32.71	55.27	
MCS = mental component summary. NRS = Neurological Rating Scale, PCS = physical component summary

Cervical planar radiographs were used to assess postsurgical range of motion in the lateral plane and in flexion extension. AP planar radiographs demonstrated cervical implant alignment. CT images were acquired at 8 months postoperatively to assess fusion. Sagittal CT images showed that there was robust bone formation between the C4 through C7 vertebral bodies as well as within the cervical interbody devices (Figure 1). Dorsal-ventral CT images further demonstrate the fusion of the C4 through C7 vertebral bodies (Figure 2A). Axial CT images (Figure 2, B–E) demonstrated that there was no evidence of heterotopic bone within the spinal canal. Furthermore, the bone formation within the cervical interbody devices can also be observed in the axial CT images (Figure 2, C–E).

Figure 1 Sagittal CT images demonstrating C4 through C7 vertebral bones 6 months after the anterior cervical diskectomy and fusion (ACDF) procedure. Healthy intervertebral disks can be seen between C2/C3 and C3/C4 (yellow arrows). There is no evidence of adjacent disk disease. A, 3D reconstruction showing the fusion between C4 and C7 at the midpoint of the spine. Vertebral bones are highlighted (red dashed lines). B, Single CT image slice from the midpoint of the spine. This image clearly shows the bone growth throughout the interbody device.

Figure 2 Dorsal-ventral (A) and axial (B–E) CT images demonstrating C4 through C7 vertebral bones 6 months after the anterior cervical diskectomy and fusion (ACDF) procedure. There is no evidence of adjacent disk disease. A, Dorsal-ventral image of the C4 and C7 vertebral bones on the ventral side of the spine. The slice cuts through the vertebral body and shows the bone formation within the interbody device. B, Axial image (yellow box) of the cranial aspect of the C3 vertebral bone showing normal spinal canal anatomy. C, Axial image (red box) of the C4/C5 intervertebral disk space showing robust bone growth in the interbody device and normal spinal canal anatomy. D, Axial image (green box) of the C5/C6 intervertebral disk space showing robust bone growth in the interbody device and normal spinal canal anatomy. E, Axial image (purple box) of the C6/C7 intervertebral disk space showing robust bone growth in the interbody device and normal spinal canal anatomy.

Discussion

This report describes the outcomes for a single patient in need of a 3-level ACDF who successfully fused in 8 months using a novel N-allyl noroxymorphone eluting osteoinductive bone graft. This single result is promising and sets the foundation of further studies. Previous work demonstrated that the N-allyl noroxymorphone eluting osteoinductive biomaterial stimulates osteogenesis through a p21-dependent/SMAD1-dependent pathway that causes MSCs to differentiate into osteoblasts.17

Several studies have previously reported that fusion rates for a three-level ACDF is <50% by 18 months.2,3 Interpretation of the results presented in this report when viewed in the context of other studies is limited by the poor quality of the scientific literature. For instance, in a meta-analysis by Wang et al,18 these authors found very few high-quality studies that compared multilevel ACDF procedures in which the number of treated levels is notable (eg, typically < 50 patients) and no randomized clinical trials. A systematic review of the criteria used to determine radiographic fusion by Oshina et al also noted that the literature was limited by the quality of the studies,19 although they did report that there was a large range of radiographic fusion outcomes for the studies they reviewed that ranged from 60% to 100% at the 2-year follow-up. This does not seem inconsistent with the observations of Guo et al2 and Swank et al3 who found radiographic fusion rates below 50% for 3-level ACDF.

A titanium cage with plates was used in this study. Titanium implants are known to be osteoconductive.20 In a systematic review completed by Goldberg et al,21 they compared fusion rates for titanium cages versus PEEK cages or structural allograft and found that they were comparable. Specifically, they found that titanium cages had a fusion rate between 82%-100% while PEEK cages had a fusion rate of 62.2% to 100% and structural allograft had a fusion rate of 82% to 100%. Importantly, most of the procedures reported in the review by Goldberg et al were for single-level ACDF. By contrast, Chou et al22 found markedly different fusion rates for a titanium cage at 6 months, which was 37.21% versus 93.3% for PEEK cages and 84.85% for ICBG. At 12 months, fusion rates were 46.51% for titanium, 100% for PEEK, and 100% for ICBG. Nevertheless, it is possible to discern from these studies that the success rate in multilevel ACDF is low in general and would be even lower for patients with notable comorbidities that include obesity, smoking, and chemotherapy due to active tumor.4-12

The patient in this study was administered pembrolizumab for approximately 3 years, the administration of which would further complicate the patient's ability to heal after an orthopedic procedure. Pembrolizumab is a human monoclonal antibody to PD-1.23 The PD-1 inhibitors have been associated with decreased bone health, inhibition of bone healing, and increased likelihood of fracture.24-26 PD-1 inhibitors (eg, pembrolizumab, nivolumab, and cemiplimab) and PD-1 ligand (PD-1L) inhibitors (eg, atezolizumab, avelumab, and durvalumab) are currently approved by the FDA for use in cancers that result in painful bone metastases such as NSCLC, breast carcinoma, renal carcinoma, and melanoma.27 Pharmacovigilance studies have identified an increased risk of fracture in patients treated with PD-1 or PD-1L inhibitors.20,27-30 Specifically, these studies identified that patients who had experienced a PD-1/PD-1L related fracture also had osteoporotic bone. By contrast, studies in PD-1−/− mice have demonstrated that a loss of PD-1 expression leads to a loss in osteoclastic bone reabsorption and increased bone mass.31,32 Specifically, Wang et al31 demonstrated that PD-1−/− mice whose femurs were inoculated with Lewis lung cancer cells had less tumor-mediated bone destruction and less bone pain relative to wild-type control mice.

PD-1 and PD-1L were originally identified as immune signaling proteins, associated with T-cell lymphocytes and macrophages. Their role in bone biology has only recently been identified as a part of the new field of osteoimmunology, which has provided a biological connection between inflammatory conditions and osteologic conditions such as osteoporosis.33-35 A clinical study by Cai et al recently demonstrated that increased PD-1 expression was highly correlated with a postmenopausal state in women with osteoporosis.27 In addition, several recent studies have shown that PD-1/PD-1L signaling between MSC and osteoblasts regulates normal osteogenesis.36-39

Two important observations can be made from a synthesis of these studies. First, PD-1 and PD-1L inhibitors are likely inhibiting osteogenesis by a reduction in MSC differentiation into osteoblasts, which results in a loss of accumulating bone mass that results in osteoporosis or increases the likelihood of pathologic fracture in patients with bone metastases. Second, the increasing use of PD-1 and PD-1L inhibitors for cancers that preferentially metastasize to bone, such breast or lung cancers, may lead to an increase in the incidence of pathologic fracture, particularly for postmenopausal women with osteopenia or osteoporosis. Finally, we hypothesize that the ability of the drug eluting biomaterial to stimulate bone formation in a complicated clinical situation, as we report here, may be due to how the small molecule N-allyl noroxymorphone hydrochloride component stimulates osteogenesis, which is through the upregulation of the p21/SMAD1 signaling in MSCs that results in their differentiation into osteoblasts.17

In addition to treatment with the PD-1 inhibitor pembrolizumab, the patient was administered several cycles of both cisplatin and carboplatin. Although, both cytotoxic therapies were administered approximately 3 years ago, the effects of platinum-containing chemotherapies can have deleterious effects on bone health long after their original administration.40

Patients with active tumor are not good candidates for treatment with ICBG autograft or bone grafts that incorporate a growth factor, such as Infuse. This is unfortunate, given the already low success rates for these patients when treated with a multilevel ACDF. While the patient in this study did not have observable bone metastases by imaging, cancer is considered a systemic disease and the apparent presence or absence of metastatic lesions on imaging does not preclude the presence of micrometastases.41 This is of particular concern because spine is one of the most common sites for metastases in general42 and patients with NSCLC have a 35% to 60% incidence of spinal metastases during their disease.43 The potential for micrometastases to manifest in the spine is problematic since patients with spinal metastases also have a 45% incidence of skeletal related events (eg, fracture, nerve compression, or pain) that results in a decrease in median overall survival to 7 months.42-44

The successful multilevel cervical fusion observed for this single patient, especially with respect to the inferior level, at 8 months postoperatively is exciting when viewed in the aggregate, that is, the patient's comorbidities, the failure rate for multilevel ACDF in healthy patients, and the potential negative effects that pembrolizumab has on bone health.

There are several limitations to these results. First, this is a report of a single patient, which can add notable bias to the interpretation of the results and makes it impossible to know if the effects of treatment are better or worse than existing therapies without a control group. Not having a control group also presents a limitation because the incidence of adverse events cannot be assessed directly, which could be very different in a fully powered study. Second, patients treated through Expanded Access/Compassionate Use have failed conventional therapy and may have notable comorbidities that could confound the interpretation of the results. Nevertheless, treating a patient using Compassionate Use provided notable insights into where in the treatment continuum the N-allyl noroxymorphone eluting biomaterial could be effective. Additional studies are needed to define the utility of this product in the management of spinal fusions.

In conclusion, this case report demonstrates the first successful treatment of a patient with this novel drug delivery bone graft substitute intended to treat patients with multilevel DDD and notable comorbidities, such as stage IV NSCLC. Further testing is currently being conducted as part of a pilot clinical trial presently enrolling for patients with DDD in need of a two-level ACDF (ClinicalTrials.gov: NCT05971329).

Research reported in this publication was supported, in part, by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under awards R43CA221553 (Margulies) and R44CA221553 (Margulies).

The authors state that they have obtained appropriate institutional review board (IRB) approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. Furthermore, studies were conducted consistent with the principles outlined in the National Institutes of Health (NIH) guidelines on the ethical conduct of research.

Dr. Margulies or an immediate family member has stock or stock options held in Zetagen Therapeutics. Mr. Loy or an immediate family member has stock or stock options held in Zetagen Therapeutics. Dr. Thakur or an immediate family member has stock or stock options held in Zetagen Therapeutics. Dr. Sanz-Altamira s an advisor for Zetagen on studies unrelated to the current report.

The procedure was reviewed and approved by Western IRB (Seattle WA; IRB# 20230724).

All the data generated or analyzed during this study are included in this published article.
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