Long bone, spinal metastasis often the initial presentation of unknown cancer

In a demographic where clinicians already see high rates of osteoporosis leading to bone loss and fracture, orthopaedic surgeons are often required to diagnose patients with metastatic disease to the bones in an emergency setting due to pathological fracture. They face challenges of beginning the diagnosis before the optimal situation of having an oncological team in place.

“There is no doubt that modern multi-modal therapy leads to excellent results in terms of survival and overall control in cancer today. However, bone remains the third most common site of metastases and is a significant cause of morbidity,” Stephen R. Cannon, MA, MCh(Orth), FRCS, FRCS(Ed), an orthopaedic surgeon at Spire Bushey Hospital, Bushey, Hertfordshire, England, and member of the Orthopaedics Today Europe Editorial Board, said.

“Cancers that commonly metastasize to bone are breast, prostate, lung, thyroid and kidney. These etiologies account for far more than 75% of all metastatic lesions in bone,” Enric Càceres Palou, MD, PhD, FRC, head of orthopaedics, Vall d’Hebron University Hospital, Barcelona, Spain, chair of Autonomous University in Barcelona, said.

Many of these metastatic lesions lead to fractures and bone complications.

“Twenty percent of the skeletal metastases lead to pathological fractures. It is a huge task for the profession,” Miklós Szendri, PhD, DSc, head of department of orthopaedics, Semmelweis University, in Budapest, Hungary, told Orthopaedics Today Europe.

Reducing bone complications

According to the Scandinavian Sarcoma Group data, the incidence of cancer has increased by 18% during the last decade, yet the mortality rate has remained almost the same, Szendri said. “That means that due to the more effective personalized multimodality therapy patients survive longer, often for several years even with their metastases,” he said.

Advances in cancer treatment have also led to a reduction of bone complications and pain. This is in part due to the use of multidisciplinary oncology teams, according to the sources for this story.

Oncological centers throughout the world should use multidisciplinary oncology teams, and orthopaedic surgeons need to be part of that team, Péter Pál Varga, MD, an orthopaedic tumor surgeon at the Buda Health Center, in Budapest, Hungary, and director of the National Center for Spinal Disorders, Budapest, Hungary, noted.

“I think it is important in terms of survival of the metastatic patients that they are treated in centers where orthopaedic surgeons work close together with medical oncologists, radiation oncologists, musculoskeletal radiologists, experienced pathologists in an oncoteam,” Szendri added.

Diagnosing tumor, finding the source

Patients with bone metastasis typically come to the orthopaedic surgeon in two ways. They may be referred by the oncologist or the patients may present in an emergency with a fracture with unknown cancer etiology.

The orthopaedic surgeons we spoke with agreed that patients already under longitudinal care of an oncologist have the optimal situation.

“In this situation, according to the primary histology of the primary tumor and according to the different treatment options, the team could decide on the proper treatment, such as radiosurgery, conventional oncology techniques such as chemotherapy, or additional hormone therapy, bisphosphonates, or surgery,” Varga told Orthopaedics Today Europe.

“Surgery is certainly required where there is a pathological fracture and where there is impending fracture in the major weight bearing bones as outlined by Mirels’ scoring system from 1989. There is also undoubtedly a role for specific excision of solitary metastatic lesions where the primary tumor has a good prognosis and the interval between diagnosis of the primary tumor and the occurrence of the metastasis is a significant period of time, perhaps two to three years. These excisions should follow the principles developed in the management of primary bone tumors,” Cannon said.

Addressing the patient with an acute pathological fracture and unknown primary cancer may be far more complicated.

Varga said sometimes the first sign of an oncological disease is a pathologic fracture. “The most common sites of this undiscovered metastasis are spine, humerus or femoral neck. Femoral neck fracture, humerus fractures and compression fractures are the three types of fractures where we have to consider pathologic origin, which is very clear even during the emergency hours — even the very first X-ray may show special diagnostic characteristics of a tumor,” he said.

According to Càceres, the most common sites of involvement he sees as well are the axial skeleton and proximal end of long bones. The spine and pelvis are the most irrigated zones in adult people and distal to knee and elbow metastases are rare sites.

“The first challenge for the surgeon is to make the right diagnosis,” Szendri said.

“Many other lesions in the bone, such as much more infrequent primary bone tumors, simple cysts, tumor-like lesions, but more often osteoporosis, can lead to pathologic fracture, which needs a different treatment strategy,” he said. “Consultation with an experienced radiologist, further examinations, use of other imaging techniques, and evaluation of laboratory tests are often essential.”

The orthopaedic surgeon must be familiar with the indications for intervention and the most optimal implants for fixation or replacement of the defect in the case of resection, Szendri said.

“Simple and permanent solutions are preferred, such as long intramedullary nails for the lower extremities. This allows immediate weight-bearing and rehabilitation time is short. The use of short plates should be avoided, as the progression of the metastasis often leads to a re-fracture of the bone and a second operation is demanding for a patient whose general condition is deteriorating. Finding the right indication for surgery in the spine is challenging. In most cases surgery is not the first option as the lesions are usually multiple and good results may be accomplished by other treatment modules, such as radiotherapy and chemotherapy. Pain, impending fracture, instability of the vertebrae or pathological fractures associated with a neurological deficit are the right indications for decompression and fixation,” he said.

A pathologic fracture of the long bone gives the orthopaedic surgeon more time to prepare, according to Varga. “These patients may not need immediate surgical intervention,” he said. “In the spine, however, compression fractures require immediate intervention.”

Càceres discussed a workup for suspected metastatic disease to bone and noted it should include studies to localize the primary tumor and estimate the local and distant extent of the disease.

“CT of chest, abdomen and pelvis could be included, tumor markers and PET scans to assess the extension of the disease. The local bone lesion could be intently studied by long radiology, and MRI to assess the presence of skipped metastases. The main indications for nonsurgical treatment includes no displaced fractures in non-weight bearing bones especially in patients with poor medical health and shortened lifespan. Medical adjuvant therapy is based in chemotherapy and hormonal treatment,” Càceres said.

Treatment challenges

Treatment of bone metastasis, which often involves surgery or radiation therapy, has varying success rates. Patient life spans may be limited following a diagnosis, so physicians told Orthopaedics Today Europe there is the need to concentrate on stopping further bone destruction, reducing pain and returning as much function and quality of life as possible for the patient.

“The main goal of the intervention is to diminish the pain, restore patient mobility, to improve quality of life until the end of life,” said Szendri.

However, much of this depends on the primary tumor and the stage of the disease. The primary oncological treatment determines the fate of the patient. Metastatic surgery is always palliative surgery, according to Varga.

“After the conventional X-ray, CT and MRI are the next logical steps. However, in an emergency, a local hospital may not have CT or MRI available during night. Especially in countries where economic possibilities are less favorable, many hospitals and orthopaedic colleagues work without MRI or CT support in the emergency. In this situation X-ray is an important tool, but there is no possibility to search for other metastases or primary tumor,” Varga said.

According to Szendri, “The effectiveness of treatment may be monitored by the number of reoperations, improvement in quality of life and survival of patients. The prevalence of reoperations due to complications varies from 10% to 25% in the literature depending on the applied method and general condition of the patient. Quality of life is improved not only by fixation of the fractures, and the use of minimally invasive techniques, but also by using tumor endoprostheses which allow the patient to retain or regain joint function in the hip, knee or shoulder.”

Spine metastasis considerations

The incidence of spinal metastasis with cord compression is lower than without such compression, Càceres said. He said this accounts for about 5% of all metastatic disease to the spine.

If the metastasis is in the spine, even without pathological fracture, surgery may be indicated. The tumor could extend into the spinal canal compressing the nerve roots of the spinal cord, and as a result, neurological deficits would develop,” Varga said.

Radiation therapy in the spine has recently improved in its effects.

“Advances in imaging technology and computerized treatment planning have allowed the safe delivery of high-dose radiation (spinal radiosurgery),” Càceres said.

In an evidence-based medicine update about the effectiveness of radiosurgery (CyberKnife Robotic Radiosurgery System; Accuray Inc., Switzerland) at the EuroSpine meeting in Warsaw in 2009, Càceres and colleagues conveyed a strong recommendation that radiosurgery should be considered over radiotherapy for spinal metastasis in the setting of oligometastatic disease and/or radioresistant histology with no relative contraindication.

Càceres told Orthopaedics Today Europe external beam radiation is indicated in painful lesions, impeding fractures and when there are initial neurological symptoms. It should be used for patients with radiosensitive tumors of the spine who have pain or tumor progression without instability or myelopathy, he said. The usual dose Càceres suggested is 30 Gy in 10 fractions to bone lesion and he found this delivered pain relief in more than 70% of his patients.

Another area in development for spine treatment that Varga and other spine surgeons perform is surgical resection of the metastatic vertebral segment as a whole using an en bloc technique. However, he said it is technically demanding and not performed at all centers.

“To perform en bloc resection (which we do routinely for resection of primary spine tumors) for spinal metastasis highly depends on the particular case and generally on the philosophy of the center where the patient is treated. In a monotopic vertebral manifestation and good general health, the en bloc resection makes sense, especially in renal cell carcinoma, where the possibilities of other treatment options are limited. For the quality of life of such a patient, this technique offers excellent outcomes, while the effect on the survival is not supported yet by evidence-based literature,” Varga said.

Cannon discussed the use of cementoma in the treatment of spinal metastasis.

“Where the vertebral fracture or compression of cord is impending, the indications for surgery as opposed to other methods of treatment are extremely complex. Considerable work has been done over recent years in the use of a ‘cementoma,’ which involves percutaneous injection of polymethylmethacrylate to stabilize the skeletal system and provide pain relief. This stabilization will prevent further collapse and mitigate stresses across the vertebra,” Cannon said.

The technique used can either be a vertebroplasty, accepting the collapse of the vertebra that may be present, or kyphoplasty which involves a degree of correction of the deformity, he said.

“This has proved to be effective in pain relief in a great number of patients and may prevent more extensive spinal surgery in many patients,” Cannon said.

Bone metastasis: new treatments

Càceres discussed areas of advancement that are influencing practice today.

“Advances in imaging and pathologic diagnostic techniques will enable better and more precise diagnosis of different subtypes of tumors, especially predicting tumor necrosis in patients treated with neoadjuvant chemotherapy,” he said. “Significant improvements have been made with the development of targeted radiation delivery systems, CyberKnife, and the role of chemotherapy in soft-tissue tumors continues to evolve.”

Varga said, “I think these are the times when the radiosurgery expansion is characteristic. Image modulated radiotherapy today is booming.”

Regardless of approach, each patient requires individualization in treatment mechanism.

“Although the traditional modalities of treatment are surgery, radiation and chemotherapy, newer techniques such as bisphosphonates, drugs which alter RANK ligand inhibition, and cryotherapy, together with radiofrequency ablation are becoming increasingly important,” Cannon said. “In recent years considerable interest has also been given to the drug denosumab (Prolia; Amgen Inc.), a human monoclonal antibody, which is well recognized to inhibit osteoclast formation, function and survival by attacking the RANK ligand.”

Szendri explained more about the role of this medication.

“The inhibition of RANK ligand activity suppresses osteoclast formation, function and survival; therefore, it can be used in bone metastases successfully. It reduces skeletal related events like pathologic fractures and bone loss,” he said.

Bisphosphonates as an option

Bisphosphonates have been one the most significant advances in the treatment of metastatic disease, and it has significantly decreased the number of pathologic fractures, according to Càceres.

In a recent systematic literature review in Anticancer Research, Maria Tolia, MD, Msc, PhD, from the University Hospital Athens, and colleagues, wrote in their study results “bisphosphonates can reduce, delay and prevent complications related to bone metastasis.”

The risks with bisphosphonate use, however, include osteonecrosis of the jaw and atypical femoral fractures.

“Bisphosphonates play an important role in the multidisciplinary management of metastatic bone disease and represent the standard of care for the prevention and treatment of skeletal-related complications from metastatic bone disease. It is important to note bisphosphonates, by reducing the reabsorption of bone, are able to reduce pain in osteolytic bone metastases. The ongoing trials for the prevention of bone metastases and treatment-related bone loss in cancer patients suggest that we can open a new window in this exciting and intriguing area,” Càceres said. – by Suzanne Bryla Reist

• References:
• Mirels H. Clin Orthop Relat Res. 1989;249:256-64.
• Tolia M. Anticancer Res. 2014;34:23-38.
• For more information:
• Enric Càceres Palou, MD, PhD, FRC, can be reached at Passeig Vall d’Hebron, 119-129, 08035 Barcelona, Spain; email: ecaceres@vhebron.net.
• Stephen R. Cannon, MA, MCh(Orth), FRCS, FRCS(Ed), can be reached at Spire Bushey Hospital, Heathbourne Road, Bushey Hertfordshire, WD23 1RD, England; email: cannon.frcs@gmail.com.
• Miklós Szendri, PhD, DSc, can be reached at Semmelweis University, H-1113 Budapest, Karolina 27. Hungary; email: szenmik@orto.sote.hu.
• Péter Pál Varga, MD, can be reached at Buda Health Center, Budapest, Hungary; email: vpp@bhc.hu.

Disclosures: Càceres, Cannon, Szendri and Varga have no relevant financial disclosures.

Are bone-targeted agents useful in patients with metastatic bone cancer?

May improve survival

New effective adjuvants make treatment increasingly complex for patients with disseminated cancer to the bones. Oncological adjuvants are improving and bone-targeted agents may reduce growth of bone metastases. Bisphosphonates are embedded in the bone and released at bone resorption where they inhibit the resorptive processes. A number of randomized trials, especially in breast cancer patients, have documented reductions in skeletal complications (fractures, spinal cord compression, etc.) and thereby they are improving survival. They also seem to reduce skeletal complications in osteosclerotic metastases in castrate-resistant prostate cancer patients.

Denosumab is a newer synthetic antibody which inhibits the osteoclastic activity. The final impact on bone resorption for the two principles of treatment seems comparable, although most studies have been performed with bisphosphonates. The drugs are widely tolerated in patients with normal renal function, but both drugs may cause necrosis of the jaw. In patients with reduced renal function denosumab is better tolerated. Due to the high price, bisphosphonates are probably the first choice in most cases. The bone-targeted agents are recommended as soon bone metastases are diagnosed. The duration of treatment is still questionable, but should probably be continued for at least 2 years. In selected patients bone-targeted treatment may also prevent bone metastases.

The treatment possibilities of advanced cancer are changing in these years making it important for a close collaboration between the orthopaedic surgeons and oncologists.

• Reference:
• Coleman R. Ann Oncol. 2014. doi:10.1093/annonc/mdu103.

Johnny Keller, DMSc, MD, is associate professor at Sarcoma Center in the Department of Orthopedics at Aarhus University Hospital, in Aarhus, Denmark.
Disclosure: Keller has no relevant financial disclosures.

Inhibits bone resorption

Bone-targeted agents inhibit osteoclast-mediated bone resorption. Bone metastases can lead to serious skeletal-related events, including pathologic fracture, radiation or surgery to bone, and spinal cord compression. The bone microenvironment makes it especially conducive to the development of metastatic lesions, such as the release of growth factors from the bone matrix through osteoclast-mediated bone resorption. In osteolytic lesions, factors secreted by cancer cells induce osteoclast recruitment and activation leading to increased osteolysis. Bone resorption also releases growth factors that stimulate tumor growth and increase secretion of osteoclast-stimulating factors. Although bone destruction may be more apparent in osteolytic lesions, osteoblastic lesions also contain a strong osteolytic component. Moreover, cancer cells activate osteoblasts to increase the production of the receptor activator for nuclear factor-B ligand (RANKL). RANKL interacts with RANK and promotes differentiation into mature osteoclasts.

Two types of bone-targeted agents are generally used in the treatment of metastatic bone cancer. Bisphosphonates are synthetic analogs of pyrophosphate that bind to hydroxyapatite and are taken up by osteoclasts, inducing apoptosis of the osteoclasts. The nitrogen- containing bisphosphonates (e.g., pamidronate and zoledronic acid) inhibit the activity of farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. They stop the transmission of the cellular signal at the level of small signaling proteins, which are essential for cellular function and survival in osteoclasts. RANKL inhibitor (denosumab) is a human monoclonal antibody that binds to RANKL, thereby inhibiting osteoclast function and preventing generalized bone resorption and local bone destruction.

Although anti-tumor activity of bisphosphonates and denosumab is mainly attributed to their ability to inhibit osteoclast-mediated bone resorption, several preclinical studies also suggest a possible direct anticancer effect of these bone-targeted agents.

Shoji Shimose, MD, PhD, is associate professor in the Department of Orthopaedic Surgery, Integrated Health Sciences, Institute of Biomedical & Health Sciences at Hiroshima University, in Hiroshima, Japan.
Disclosure: Shimose has no relevant financial disclosures.