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Metastatic Disease : Bone, Spinal Cord, Brain, Liver, and Lung
Local tumor control is now achieved with modern combined-modality therapy. Metastatic disease, therefore, dominates the survival outcomes of patients with cancer. Metastases to the bone, lung, liver, and brain cause organ dysfunction and pain, with substantial changes in quality of life. Metastases to any of these organs can lead to a shorter life. Although palliative care comprises a large part of the clinical practice of oncology, studies show that cancer pain is often inadequately managed.
Among painful metastases, osseous metastases remain the most common cause of intractable pain in patients with cancer. Bone is the third most common site of metastases after the lung and liver. Metastases usually become apparent after the diagnosis of the primary tumor, but in up to 23% of patients they are the presenting problem. Bone pain results in immobility, anxiety, and depression, severely impacting a patient's quality of life. Thus, adequate treatment of bone pain is a high priority.
The brain is a devastating site of metastatic disease. Most patients with brain metastases succumb to metastatic disease within a few months. Relatively few are candidates for open surgery, which can carry the risk of severe sequelae. The advent of radiosurgical techniques, intensity-modulated radiotherapy (IMRT), and high-quality magnetic resonance imaging (MRI) of the brain has greatly changed the outcomes for some patients with brain metastases. Patients can have improved duration of cognitive performance, with some enjoying prolonged survival. Among patients with lung cancer, the actuarial incidence of brain metastases can exceed 70%. Other cancers can also have high rates, including 19% of women with metastatic breast cancer. Local therapies, such as surgery or radiosurgery, are often used as well as the more global treatment of whole-brain irradiation.
Liver metastases are common in many cancers and, like brain metastases, are usually associated with a limited median survival. Liver metastases occur in 40% to 70% of patients with progressive colorectal cancer and in a similar range of patients with progressive breast cancer or progressive lung cancer. Treatment for liver disease, like pain, is often difficult and, therefore, inadequately managed. More recently, there has been an effort to treat liver metastases using localized therapies. These include stereotactic radiation techniques, radiofrequency ablation, hyperthermia, and transarterial embolic therapy (including bland embolization, chemoembolization and radioembolization) in addition to resection. There has been satisfactory success with many of these treatments, which appear to be improving patient outcomes. International consensus increasingly favors these local therapies depending on the specifics of the individual case for the treatment of liver metastases.
Bone Metastases
Table 29.1 shows the prevalence of skeletal metastases in several autopsy series. The marked variation may be attributed to differences in the thoroughness of the pathological examination of the skeleton. In general, bone scintigraphic surveys have reported higher rates of bone metastases. In a study by Tofe et al., bone scans of 1143 patients with a nonosseous primary tumor were examined; 61% of the patients had an abnormal bone scan finding, and 33% had breast, lung, or prostate primary cancer.
TABLE 29.1
Prevalence of Skeletal Metastases at Primary Site
Data from Galasko CSB. Incidence and distribution of skeletal metastases. Clin Orthop. 1986;210:14–22.
| Primary Site | Prevalence (%) |
|---|---|
| Breast | 47-85 |
| Prostate | 54-85 |
| Thyroid | 28-60 |
| Kidney | 33-40 |
| Bronchus | 32-40 |
| Esophagus | 5-7 |
| Other gastrointestinal | 3-11 |
| Rectum | 8-13 |
| Bladder | 42 |
| Cervix | 0 |
| Ovaries | 9 |
| Liver | 16 |
In a prospective series of hospital patients with bone metastases, the tumors carrying the highest risk of bone metastases were those originating in the prostate (32.4%), breast (21.9%), kidney (16.4%), thyroid (11.7%), lung (10.9%), and testes (10.2%). The incidence of patients developing bone metastases by primary site is shown in Table 29.2 .
TABLE 29.2
Incidence of Bone Metastases According to Primary Site
Data from Tubiana-Hulin M. Incidence, prevalence and distribution of bone metastases. Bone . 1991;12:S9–S10.
| Primary Site | No. of Patients | Patients With Bone Metastases (%) |
|---|---|---|
| Breast | 6423 | 17 |
| Prostate | 144 | 16 |
| Esophagus | 451 | 6 |
| Lung | 589 | 5 |
| Bladder | 172 | 5 |
| Rectum | 274 | 4 |
| Thyroid | 107 | 4 |
| Uterine cervix | 1981 | 3 |
| Uterine corpus | 509 | 3 |
| Head and neck | 2860 | 2 |
| Ovaries | 586 | 1 |
| Colon | 153 | 1 |
| Stomach | 118 | 1 |
The distribution of skeletal metastases from breast cancer is shown in Table 29.3 . Similar distributions have been noted from prostate, lung, and breast primary cancers.
TABLE 29.3
Distribution of Skeletal Metastases in 212 Breast Cancer Patients
Data from Tubiana-Hulin M. Incidence, prevalence and distribution of bone metastases. Bone . 1991;12:S9–S10.
Pathophysiology
Tumor cells gain access to the systemic circulation primarily through the capillary system, but some gain access through the lymphatics; only a few of these cells are able to successfully establish a metastatic focus. Although circulating tumor cells are common, they do not reliably portend metastases and, when included in American Joint Committee on Cancer (AJCC) staging, are considered M0-like in choice of therapy. The process of developing a hematogenous metastasis from a primary tumor includes many steps, which are rarely achieved by any individual circulating tumor cell. The tumor must dissociate from the primary mass, gain access to the circulation, survive the immune system and circulatory shear forces, identify a host organ, and develop an exit passage to that organ. Once it enters an organ, it must retain reproductive potential, proliferate, generate a vasculature, and grow. The molecular expression profiles that dictate which tumor cells can produce a metastasis, at what frequency, and in which organs are of great research interest.
Cancer cells metastasize to bone mostly via hematogenous spread. Skeletal blood flow accounts for only 4% to 10% of the cardiac output, and some authors believe that the incidence of skeletal metastases is higher than expected based on perfusion alone. A mechanism explaining the high incidence has been described by Weiss. The microstructure of the hematopoietic marrow renders it particularly vulnerable to tumor cell accumulation and ultimate invasion. Nutrient arteries to the bone tend to subdivide into capillaries as they near the endosteal margin of the bone. These capillaries become continuous with a rich venous sinusoidal system, with a capacity six to eight times that of the osseous arterial system. More important, the circulation comes to a near standstill at this point, allowing tumor cells more time to invade the matrix.
To sustain growth, a colony of tumor cells needs to obtain its own vascular supply once it has been established. A hypothesis is that a tumor angiogenesis factor attracts endothelial cells to a small tumor colony that would otherwise be dependent on local tissue circulation and incapable of further invasion. The production of such tumor angiogenesis factor may be partly blocked by the immune responses, presumably mediated through lymphocytes. Therefore, an established micrometastasis may attract vasculature required for growth several years later. This theory may explain the late appearance of metastases long after definitive treatment of the primary tumor.
Some tumors, notably of the breast, prostate, lung, kidney, and thyroid, produce and secrete humeral mediators that stimulate osteoclast activity. These include transforming growth factor, platelet-derived growth factor, tumor necrosis factor, prostaglandins, procathepsin D, interleukins, parathyroid hormone-related protein, and granulocyte-macrophage colony-stimulating factors.
The distribution of metastases in the skeletal system is not uniform. Bone metastases tend to involve the axial skeleton more often than the appendicular skeleton. Considering the distribution of marrow in the axial and appendicular skeleton, this higher predilection argues for specific bone marrow–derived growth factors that fertilize the soil of the bone for tumor growth.
Diagnosis
Laboratory
The biochemical parameters include alkaline phosphatase, urinary hydroxyproline, and the urinary hydroxyproline-creatinine ratio. These parameters lack specificity, and are of no value in the diagnosis of skeletal metastases.
Imaging
Skeletal scintigraphy is usually the first-line imaging technique used for detecting skeletal metastases. A bone scan is more sensitive than plain radiographs and has the advantage of examining the entire skeleton. Most lesions evoke an osteoblastic response, which shows up as an increased tracer uptake. Occasionally, metastases may show up as areas of decreased uptake. This may be observed in rapidly growing lesions, when bone destruction far exceeds new bone formation, or secondary to an infarction. Highly vascular metastases, such as those from a primary cancer of the kidney, may be seen on the early vascular phase of the bone scan. Metastases not detected by a bone scan include tumors that do not evoke an osteoblastic response, such as myeloma, some lymphomas, and very small deposits.
Widespread metastatic disease may be misinterpreted as a normal scan with symmetrical uptake. In these situations, a reduction in urinary excretion of isotope and faint or absent renal uptake with decreased bladder activity are clues of an abnormal scan.
Most skeletal metastases develop in the medulla and involve the cortex later on; therefore, plain radiographs are generally insensitive. Within the spine, the vertebral body is affected first, although the radiological findings of pedicle destruction are noted first.
Computed tomography (CT) scanning has been found to differentiate between metastases and degenerative joint disease, even though the two coexist; the latter is a common cause of increased uptake on a bone scan. Muindi et al. reported that 50% of patients with breast cancer with a positive bone scan and a normal radiograph had obvious skeletal metastases on a CT scan, 25% had a benign cause, and 25% had a negative CT. None of the patients with a CT scan that was negative for metastases subsequently experienced metastases. CT scan is also valuable in evaluating soft-tissue involvement and can be combined with myelography for detecting extradural tumor spread in patients unable to undergo MRI.
More recently, MRI has been described as the method of choice for examining the spine. It is more sensitive than a bone scan for detecting early metastases within the medulla, but both T1- and T2-weighted images are required. It is the procedure of choice when neural compression is suspected because it is less invasive than CT myelography, and a small incidence of acute deterioration of neurological function has been reported by CT myelography. When cord impingement is suspected, imaging of the entire spine should be considered because approximately 10% of patients have multiple levels of cord impingement. It is also used in discriminating between benign and malignant vertebral collapse. In the future, whole-body MRI could emerge for metastasis screening. Disadvantages of an MRI include its high cost, exclusion of patients with metal implants, patients with severe claustrophobia, and inferior visualization of the cortex compared with a CT scan. Treatment response using MRI and CT can be difficult to evaluate.
Positron emission tomography (PET) with 18 F-fluoride or 2-fluoro-deoxy- d -glucose (FDG) is used for the initial staging of many malignancies and is helpful in the diagnosis of bony metastasis. 18 F-fluoride is a bone-imaging agent that forms fluoroapatite in osteoblastic cells. Uptake of 18 F-fluoride is higher than for 99Tc used for bone scintigraphy. This sensitivity can lead to inadvertant overdiagnosis of bone metastases but can be useful for diagnosis, tumor localization, and assessment of treatment response. FDG is a tumor-imaging agent that uses the higher glycolysis activity in the tumor cells. FDG-PET scan compared with bone scintigraphy shows a similar high sensitivity (range, 74%-95%) but a higher specificity (range, 90%-97%). Limitations include traumatic, infectious, and inflammatory processes that can also accumulate glucose. Accumulation of FDG requires the tumor to have an adequate metabolic rate. Neoplasms such as prostate adenocarcinoma are not consistently seen using PET scans. PET images provide poor anatomic imaging but are extremely useful when employed with a concurrent CT or fused MRI image.
Biopsy
Bone biopsy is not necessarily routine. It is helpful in patients with no history of malignancy, in patients with a solitary lesion (in whom a more aggressive treatment approach may be indicated), and in patients with more than one suspected primary lesion.
Treatment
The primary goal of therapy in metastases is to improve quality of life. To achieve this goal, we need to decrease or eliminate pain and improve or maintain skeletal function. The complexity, duration, and cost of therapy should be low, and complications should be avoided.
Treatment recommendations must be individualized. A key consideration is the patient's overall prognosis. This assessment should be based on an understanding of the natural course of the specific disease. Although the survival of patients with bone metastases is generally poor, potential long-term survivors must be identified. Long-term survivors require a more durable relief of pain, but they are also at more risk for a late, treatment-related complication. A Radiation Therapy Oncology Group (RTOG) trial studied longevity among patients with bone metastases. The median survival in patients with solitary and multiple bone metastases was 36 and 24 weeks, respectively. Patients with breast and prostate primaries survived significantly longer (30-73 weeks), whereas patients with lung cancer died within a median of 12 to 14 weeks. Patients with renal cell carcinoma with solitary metastasis are also likely to be long-term survivors. Kjaer monitored 25 such patients for 10 to 14 years. The median survival was 4.3 years, with a 5-year overall survival (OS) of 36% and 10-year OS of 16%.
Pharmacological Treatment
Systemic and immunotherapy remain the mainstay of treatment for metastatic disease, including bone metastases. For asymptomatic bone metastases not at immediate risk of fracture, disease-appropriate systemic therapy—including chemotherapy, hormonal therapy, and biological therapy—is indicated. Patients may also benefit from bisphosphonate therapy.
Bisphosphonates and denosumab.
The discovery of compounds inhibiting calcium phosphate precipitation in plasma and urine led to an interest in the use of bisphosphonates as therapeutic agents. The inhibitory activity was attributed to inorganic pyrophosphate, but the use of this agent was limited because of its rapid hydrolysis when given parenterally. Subsequent research led to the development of pyrophosphate analogs resistant to endogenous phosphatases, now known as bisphosphonates.
Bisphosphonates inhibit osteoclast-mediated bone resorption. The exact mechanism is likely multifactorial, including direct biochemical effects on the osteoclast, prevention of osteoclast attachment to the bone matrix, and inhibition of differentiation of osteoclast precursors and recruitment.
Four Phase II trials of intravenous pamidronate every 2 to 4 weeks as the sole treatment of osteolytic bone metastases in breast cancer reported similar results. Relief of pain was noted in approximately 50% of patients, and approximately 25% showed radiographic evidence of bone healing. Similar results for bone pain have also been reported in patients with prostate cancer.
In more recent studies, one Phase II and one Phase III trial showed equivalence between zoledronic acid and pamidronate. Rosen et al. conducted a three-arm study for patients with bone lytic or mixed disease from either breast cancer or multiple myeloma. A total of 1648 patients received intravenous pamidronate 90-mg zoledronate in 4 mg or 8 mg doses every 3 weeks for 13 months. The primary endpoint was the incidence of a skeletal event, and secondary endpoints were pain relief and performance status (Eastern Cooperative Oncology Group [ECOG]). All treatment groups showed equivalence with a similar frequency of skeletal events at 12 months and with pain scores decreased by an average of 0.5 on a scale of 5. This randomized trial led to modification of the American Society of Clinical Oncology (ASCO) 2003 and the Cochcrane Breast Cancer Review Group update recommendations on the use of bisphosphonates in breast cancer. Both boards now recommend either pamidronate 90 mg intravenously (IV) over 2 hours or zoledronate acid 4 mg IV over 15 minutes for patients with an abnormal bone scan and abnormal imaging by plain radiographs on CT scan or MRI. Bisphosphonates have not yet been formally tested in patients with early asymptomatic bone metastasis.
Zoledronic acid has also been used in prostate cancer to treat blastic metastasis. Saad et al. randomized 643 patients to placebo or to zoledronic acid 4 or 8 mg IV infusion every 3 weeks for 15 months. Results show a reduction in skeletal-related events from 44% to 33% with a significant p value of 0.021. Pathological fractures were reduced from 22% to 13% ( p = 0.015). Onset of the events occurred at a median time of >420 days (median not reached) in the group receiving zoledronic acid and at 321 days in the placebo group. Time to disease progression or survival was similar in both groups. The need for local-field radiation was not significantly different in the two groups.
Zoledronic acid has also been evaluated for the treatment of bone metastases from other disease sites; 773 patients with lung, renal, head and neck, thyroid, and unknown primaries received either a placebo or zoledronic acid 4 or 8 mg. Skeletal events, including hypercalcemia, were significantly reduced from 47% to 38% ( p = 0.039), and the median time to the first event was longer in the zoledronic acid group (225 vs. 155 days, p = 0.023).
Although zoledronic acid is well tolerated, the treating physician is advised to monitor serum creatinine before each administration. Caution is also advised for patients receiving concomitant aminoglycoside or loop diuretic because of an increased risk of hypocalcemia. Ruggiero et al. published a retrospective review of 63 patients on bisphosphonates who suffered osteonecrosis of the jaw ; 57% received pamidronate and 21% zoledronic acid. Surgical treatment was required. Oral agents, such as clodronate, have low bioavailability (2%) and produce gastrointestinal side effects.
Denosumab is a well-tolerated monoclonal antibody to the receptor activator of nuclear factor kappa-Β ligand (RANKL), which mitigates osteoclastic activity. In a randomized trial comparing denosumab and zolendronic acid in patients with metastatic breast or prostate cancer, denosumab significantly reduced skeletal events.
Analgesics.
The optimal management of pain begins with careful assessment of the degree of pain, site, functional limitations, and concurrent neurological symptoms. The World Health Organization (WHO) analgesic ladder for cancer pain management provides guidelines for analgesic use.
-
Step I. Nonopioid with or without adjuvant therapy
-
Step II. Opioid for mild to moderate pain plus nonopioid with or without adjuvant therapy
-
Step III. Opioid for moderate to severe pain with or without nonopioid with or without adjuvant therapy
Step I nonopioid analgesics include acetaminophen, aspirin, and other nonsteroidal antiinflammatory drugs (NSAIDs). The dose of acetaminophen should not exceed 4 g/day. Step II opioids include codeine, dihydrocodeine, hydrocodone, oxycodone, and propoxyphene. Step III opioids include morphine, oxycodone, hydromorphone, and fentanyl.
Attention should be paid to selecting the appropriate analgesic, dose, route, and schedule. Continuous, slow-release medications are generally preferred over short-acting medications. The latter can be used effectively for breakthrough pain. Allowing pain to recur between doses causes unnecessary suffering and may allow tolerance to develop. When prescribing oral opioids, the dose is about two times that of the subcutaneous dose and three times that of the intravenous dose. For patients unable to take oral medications, suppositories and transdermal patches are good options. When combining drugs, it is important to use drugs that act at different levels of the pain pathway ( Fig. 29.1 ). The combined effect can be additive and, at times, synergistic.
The pain of bone metastases is generally only partially responsive to opioids. Many osseous metastases produce prostaglandins that induce osteolysis. NSAIDs alleviate pain by inhibiting the synthesis of prostaglandins. Corticosteroids prevent the formation of arachidonic acid (the precursor of prostaglandins) from cell membrane phospholipids. The use of NSAIDs or corticosteroids combined with morphine is usually effective.
Corticosteroids can be used when pain is caused by nerve compression. They decrease edema and reduce the pressure on the nerve. Pain relief can be achieved within 48 hours. Corticosteroids can be used as a temporary measure before a more definitive decompression is achieved with radiotherapy or surgery.
Side effects associated with the use of opioids include nausea, vomiting, constipation, urinary retention, dysphoria, mental clouding, tolerance, and addiction. Nausea and vomiting are usually self-limiting and resolve during the first week. Side effects should be anticipated, prevented, and managed aggressively.
Surgery
Surgery should be considered for patients with pathological fractures or impending fractures ( Fig. 29.2 ). In the former situation, fixation can reduce pain and expedite healing. In the latter, prophylactic fixation may prevent a fracture, thereby eliminating the functional loss and reducing the risk of nonunion of a fracture.
To understand the role of surgery better, we need first to elaborate on the biomechanics of pathological fractures. Cortical defects weaken bone, especially in the setting of torsional stress. The two general categories of cortical defects are (1) the stress riser, a defect with dimensions less than the diameter of the bone; and (2) the open-section defect, a discontinuity of dimensions greater than the diameter of the bone. By creating a nonuniform distribution of stresses in bone, stress risers can decrease bone strength by 60% to 70%. An open-section defect has a greater impact on decreasing shear and torque-loading resistance. The volume of bone able to resist the load is significantly decreased compared with a closed section. A 90% reduction in load to failure and energy storage to failure is noted in torsion testing of the human adult tibia with open section. Torsional or rotational forces occur in various daily movements, such as getting out of a chair. Bone is weakest during torsion. A single quarter-inch hole made for a bone biopsy can decrease torsional strength by 50%.
The nature of the metastatic lesion affects overall bone strength. Both lytic and blastic lesions dramatically alter bone elasticity; lytic lesions reduce bone strength more than blastic lesions. Irregular lesions are not necessarily more detrimental to the bone than smooth lesions, but elongated lesions drastically reduce bone strength.
The distribution of pathological fractures is shown in Table 29.4 . Several series have examined various criteria predicting the risk of a pathological fracture. Keene et al. evaluated 2673 patients with breast cancer in an attempt to predict pathological fracture of the femur using clinical and radiological criteria. Only 26 (13%) of 203 patients with evaluable proximal femur metastasis had pathological fractures. They were unable to correlate lesion size and risk of pathological fracture. No other risk factor was identified. The authors concluded that plain radiographs are insufficient diagnostic tools for identifying high-risk lesions. Of note is that this study was limited to single anteroposterior (AP) films.
TABLE 29.4
Distribution of Pathological Fractures
From Mirels H. Metastatic disease in long bones: A proposed scoring system. Clin Orthop . 1989;249:256-264.
| Location | No. | % |
|---|---|---|
| Femur Femoral neck Peritrochanteric Subtrochanteric Femoral shaft Supracondylar | 2586950843817 | 65.017.013.021.010.04.0 |
| Acetabulum | 34 | 8.5 |
| Tibia | 31 | 7.5 |
| Humerus | 68 | 17.0 |
| Forearm | 8 | 2.0 |
| Total | 399 | 100.00 |
Mirels designed a scoring system to predict the risk of a pathological fracture ( Tables 29.5 and 29.6 ). Of 78 patients, 51 experienced a fracture and 27 did not. The mean score for the nonfracture group was 7 versus 10 for the fracture group. This system provides a useful tool to evaluate patients for prophylactic fixation. Patients with a score of 10 to 12 should undergo surgery. Patients with scores of 7 or less are not likely to benefit from such therapy. In patients with a “gray-zone” score, the status of surrounding bone and lifestyle (old, osteoporotic woman vs. young athlete) should be considered.
TABLE 29.5
Scoring System by Mirels
From Mirels H. Metastatic disease in long bones: A proposed scoring system. Clin Orthop . 1989;249:256-264.
| Variable | POINTS | ||
|---|---|---|---|
| 1 | 2 | 3 | |
| Site | Upper extremity | Lower extremity | Peritrochanteric |
| Pain | Mild | Moderate | Mechanical |
| Radiograph | Blastic | Mixed | Lytic |
| Size (% of shaft) | 0-3 | 34-67 | 68-100 |
TABLE 29.6
Pathological Fracture Rate
From Mirels H. Metastatic disease in long bones: A proposed scoring system. Clin Orthop . 1989;249:256-264.
| Score | No. of Patients | Fracture Rate (%) |
|---|---|---|
| 0-6 | 11 | 0 |
| 7 | 19 | 5 |
| 8 | 12 | 33 |
| 9 | 7 | 57 |
| 10-12 | 18 | 100 |
The following guidelines may help with decision-making regarding prophylactic fixation. Because each patient has unique circumstances, these guidelines cannot replace sound clinical judgment on the part of the attending physician.
- 1.
Life expectancy is longer than 3 months.
- 2.
Patient is medically fit to tolerate major surgery.
- 3.
Procedure planned is expected to expedite mobilization.
- 4.
Quality of bone both proximal and distal to the lesion is adequate to support any fixation device.
- 5.
There is cortical bone destruction of 50% or more.
- 6.
Lesion measuring 2.5 cm or larger is located in the proximal femur.
- 7.
There is pathological avulsion fracture of the lesser trochanter.
- 8.
Stress pain persists after irradiation.
The following principles govern the surgery of impending fractures:
- 1.
Maximum effort is made to avoid disrupting the surrounding soft tissue to preserve the periosteal blood supply. This is of particular importance in these patients because the endosteal circulation has usually been disrupted by the metastatic deposits.
- 2.
Highly vascular lesions (e.g., metastasis from renal cell carcinoma) should be considered for possible embolization before open curettage.
- 3.
Defects that include the entire circumference of the cortex should be plugged by acrylic cement at fixation to reduce the biomechanical risks associated with stress risers or open-section defects.
- 4.
When large, thin-walled lesions exist, intramedullary nailing techniques should be augmented by direct reinforcement of the lesion using methyl methacrylate. This will enhance fixation of the distal long bone, particularly with regard to torsional stability, and will prevent shortening of the bone.
Pathological fractures of the humerus commonly occur in the diaphysis, followed by the proximal humerus. Fractures of the diaphysis can be fixed using an intramedullary interlocking device, such as a Brooker-Wills nail, which provides excellent strength and effective resistance against varus, torque, and distraction forces. Proximal humerus fractures commonly require a prosthesis. These patients usually achieve a limited flexion and abduction of about 90 to 100 degrees and enjoy good overall function, joint stability, and pain relief.
Fixation of the femoral neck–intertrochanteric area can be achieved with the use of a compression hip screw and side plate. Fractures involving the femoral neck may be better treated with prosthetic replacement because they are rarely amenable to internal fixation. Subtrochanteric, femoral shaft, and supracondylar femoral lesions are amenable to internal fixation, but large cortical lesions may benefit from an intramedullary acrylic cement filling.
The common problem encountered in acetabular lesions is the failure to appreciate the extent of bone lysis radiographically. Extensive destruction of bone may render efforts to reinforce such lesions with bone graft fruitless. Pathological fractures of the acetabulum should be managed by total hip arthroplasty.
The spine is the most common site of skeletal metastases. The vertebral body is typically affected first, although pedicle destruction is noted first radiographically. In the absence of a blastic lesion, 30% to 50% of the vertebral body needs to be destroyed before any destruction can be noted on a radiograph. Vertebral metastases are often asymptomatic. Symptoms are usually a result of one of the following: (1) an enlarging mass within the vertebral body that breaks through the cortex and invades the paravertebral soft tissues; (2) a mass compressing or invading local nerve roots; (3) a pathological fracture; (4) spinal instability secondary to a pathological fracture, in particular, when the posterior elements are involved; and (5) spinal cord compression.
An aggressive surgical approach to spine metastases is usually not warranted. Spinal stabilization is a major surgery involving multiple risks and prolonged recovery. Most patients with spinal metastases do not have progressive spinal instability or neurological involvement and can be treated with radiation, hormones, chemotherapy, or temporary bracing. Even patients with vertebral body compression fractures can be treated with temporary bed rest and soft bracing. Indications for surgical intervention include (1) progressive spinal canal impingement and cord compression by a radioresistant tumor or a recurrence after maximum tolerable dose (MTD) of radiation to the intended area; (2) bone or soft-tissue detritus extruded into the canal as a result of progressive spinal deformity, with or without spinal instability; (3) progressive spinal deformity; (4) progressive kyphotic deformity associated with posterior disruption and shear deformity; and (5) solitary metastases of a histology that is unlikely to be controlled long term with tolerable doses of irradiation.
Vertebroplasty of bone metastasis was first described in 1987 and consists of direct injection of the affected vertebra with cement. Polymethylmethacrylate (PMMA) is active through several pathways and produces pain relief in 80% of the patients. The procedure is done under intravenous sedation or general anesthesia. Pain-receptor destruction is achieved with exothermic reaction of the polymonomer and compressive effect on small nerves. Vertebroplasty effects are not modified by external-beam radiotherapy (EBRT), and PMMA conserves its properties despite radiation. Vertebroplasty and radiation are complementary, both providing pain relief—the former providing more structural benefit of weak bones and the latter offering more durable tumor control of larger tumors.
Radiotherapy
Local-field radiotherapy.
The vast majority of patients can be managed successfully with EBRT. A large body of clinical evidence documents the effectiveness of such therapy. The optimal dose and fractionation schedule is still not resolved. A summary of the major prospective clinical trials that have addressed these issues is provided in Table 29.7 . The results of these studies should be interpreted with caution because the inherent heterogeneity within the randomization groups may have precluded detection of significant differences even when such differences could have existed. The use of different pain scoring systems (physician based vs. patient based) and different handling of concomitant use of analgesics, chemotherapy, or hormonal therapy precludes meaningful comparison of the results of these studies.
TABLE 29.7
Summary of Prospective Clinical Trials of Radiotherapy for Painful Osseous Metastases
| Study | No. of Patients | Total Dose (Gy) | No. of Fractions | Overall Response (%) | Complete Response (%) |
|---|---|---|---|---|---|
| Tong et al. | 1016 | 40.520.030.015.020.025.0 | 15510555 | 858287858378 | 615357495649 |
| Price et al. | 288 | 8.030.0 | 110 | 8271 | 4528 |
| Hoskin et al. | 270 | 4.08.0 | 11 | 4469 | 3639 |
| Okawa et al. | 92 | 30.022.520.0 | 15510 (bid) | 767578 | ——— |
| Madsen | 57 | 24.020.0 | 62 | 4748 | —— |
| Steenland et al. | 1157 | 8.024.0 | 16 | 71 | —— |
| Sze et al. (review) | 3621 | Varies | 1>1 | 6090 | 3432 |
Between 1974 and 1980, the RTOG conducted a large national study to determine the effectiveness of five different dose fractionation schedules. A total of 1016 patients were entered, 266 into a solitary metastasis stratum and 750 into a multiple metastasis stratum. The former were randomly assigned to treatment with 40.5 Gy in 15 fractions or 20 Gy in 5 fractions. The latter were assigned to 30 Gy in 10 fractions, 15 Gy in 5 fractions, 20 Gy in 5 fractions, or 25 Gy in 5 fractions. A quantitative measure of pain, based on severity and frequency of pain and the type and frequency of pain medications used, was devised to evaluate response. Overall, 89% of patients experienced at least minimal relief, 83% achieved partial relief, and 54% obtained complete relief. There were no significant differences between the treatment arms in both strata. The initial pain score was found to be a useful predictor; patients with high scores were less likely to respond and less likely to experience a complete response. Patients with breast or prostate cancer were significantly more likely to respond than those with lung or other primary lesions. Patients completing their treatment as planned had a significantly higher rate of complete response than those who did not. Although some pain relief was experienced almost invariably within the first 4 weeks, complete relief was first reported later than 4 weeks after the start of treatment in about 50% of patients. The median duration of minimal and complete pain relief was 20 and 12 weeks, respectively. There were no significant differences in the duration of pain relief between the different arms. The authors concluded that all treatment dose schedules were equally effective.
Blitzer performed a reanalysis of the RTOG study. Using a stepwise logistic regression, he examined the effect of the number of fractions, dose per fraction, and solitary versus multiple metastases on the probability of attaining complete pain relief and the need for retreatment. This multivariate technique allowed patients with solitary and multiple metastases to be analyzed together. The number of fractions was the only variable that was significantly associated with outcome. There was no correlation of the time-dose factor (TDF) with outcome. It was concluded that the more protracted schedules resulted in improved pain relief.
The concept of TDF has long been replaced by the linear quadratic model. Using this model, and assuming an α/β of 10 for tumor, we calculated the biologically effective dose (BED) for the various schedules tested by the RTOG. Figs. 29.3 and 29.4 depict pain response and freedom from retreatment as a function of BED, respectively. The solid lines are the regression functions, and the dotted lines represent the 95% confidence intervals. The results suggest that schedules with higher BEDs resulted in better pain relief and reduced the need for retreatment.
Price et al. randomized 288 patients to receive either 8 Gy in 1 fraction or 30 Gy in 10 daily fractions. Pain was assessed using a daily questionnaire completed by the patient at home. No differences were found in the probability of attaining pain relief, speed of relief, or duration of relief between the two arms.
Hoskin et al. randomized 270 patients to receive either 4 Gy or 8 Gy in one fraction. Pain (assessed by the patient) and analgesic usage were recorded before treatment and at 2, 4, 8, and 12 weeks. At 4 weeks, the response rates were 69% for 8 Gy and 44% for 4 Gy ( p < 0.001). The duration of the effect was independent of dose.
Additional studies have evaluated single- and multiple-fraction regimens. A Danish randomized trial of 241 patients showed no significant difference with regard to pain relief or quality of life after receiving either 8 Gy in a single fraction or 20 Gy in 5 fractions. Wu et al. performed a meta-analysis of 16 trials including 5455 patients and proclaimed equivalence between single and multiple fractions. Van der Linden et al. published a reanalysis of a Dutch Bone Metastasis Study that included 1171 patients. This study randomized patients to either single 8 Gy or 24 Gy in 6 fractions. Mean time to retreatment was shorter (13 vs. 21 weeks) with a single fraction. It was also more frequent: 24% after a single fraction and 6% after 6 fractions ( p = 0.001). An initial high pain score also influenced the need for retreatment. A meta-analysis by Chow et al. of 25 randomized trials, each comparing single- versus multi-fraction palliative radiation for bone metastases, showed equivalent control rates, a trend toward lower risk of spinal cord compression with fractionated treatment, and a 2.6 times increase in need for retreatment in single-fraction patients. The updated American Society for Radiation Oncology (ASTRO) evidence-based guidelines in 2017 suggest, based on available data, that initial pain control between single-fraction and multi-fraction palliative treatment is equivalent, but patients who have longer survival have a greater need for salvage treatment.
Treatment techniques.
The target volumes for EBRT should be defined after review of all appropriate diagnostic studies. Attention should be paid to soft-tissue masses, which are often associated with bone metastases and at times are responsible for the observed symptoms. Such lesions are best assessed by CT or MRI. The target volumes are treated with appropriate margins. Depending on the treatment site and volume, suppression of the bone marrow should be anticipated. In patients for whom chemotherapy is planned, treatment volumes should be kept to a minimum to preserve marrow reserves. Because many patients have repeated courses of therapy, all previous ports and radiation records must be reviewed. To minimize late radiation damage, overlap of radiation fields should be avoided. Depending on the clinical circumstances, overlapping retreatment may be appropriate in patients with short life expectancy.
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