Chemotherapy for Tumors of the Spine

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Chapter 13 Chemotherapy for Tumors of the Spine

INTRODUCTION

The goal of this chapter is to discuss the general principles of chemotherapeutic management for metastatic spinal disease. The vast majority of spinal metastases are extradural, originating in the marrow of spinal vertebral bodies.1 These bone lesions can significantly diminish the quality of life of cancer patients, creating pain, medical problems such as hypercalcemia, fractures that may be unstable, and the potential for spinal cord compromise. The most common primary tumors that disseminate to bone in adults are multiple myeloma and common solid tumors such as breast, prostate, lung, and kidney. In children, bony metastases are rare and are caused by Ewing’s sarcoma, neuroblastoma, and sarcomas.2 Spinal metastatic tumors that present in non-acute fashion are treated with systemic chemotherapy. Successful treatment of spinal metastases, especially when they present with acute symptoms, requires the combined efforts of multiple disciplines, including radiation oncology, neurosurgery, orthopedics, anesthesia, and medical oncology.

Only a minority of metastatic lesions to the spine lie within the central nervous system (CNS). Most CNS metastatic tumors are intradural and extramedullary, and they originate from intracranial lesions that disseminate to the spine via cerebrospinal fluid (CSF) pathways. Unfortunately, the prognosis for patients with leptomeningeal disease is poor, and chemotherapy directed into the CSF cisterns is palliative. Intramedullary metastases originate from hematogenous seeding of the spinal cord and comprise only 0.5% of spinal axis metastases.1,3 They are so rare that treatment options are not well-studied.

We begin this chapter by reviewing the imaging, physical examination, and laboratory components of the diagnostic evaluation because the determination of a diagnosis is critical in guiding the chemotherapeutic treatment of patients with metastatic spinal disease. The initial interventions preceding chemotherapy treatment will be discussed briefly. Options for systemic chemotherapeutic treatment will be presented for the most common metastatic spinal tumor diagnoses. Principles relevant to the treatment of all metastatic spinal tumor diseases, including CSF-delivered chemotherapeutics and intramedullary metastases treatment, will then be reviewed. We will end by discussing follow-up care for patients with spinal metastases after the diagnosis of their disease and the institution of systemic chemotherapy.

DIAGNOSIS

More than 90% of patients with metastatic spinal disease present with pain. If the pain is more severe with movement, spinal stability must be evaluated, and consultation by a spine surgeon is necessary if instability is uncovered.4 A general physical examination with a detailed musculoskeletal exam is warranted for all patients with possible metastatic spinal disease. As lesions progress in size, they eventually impinge on neurological structures, resulting in neurological deficits that can progress to paraplegia without appropriate intervention. Symptomatic lesions occur most often in the thoracic rather than the lumbar spine because of the smaller dimension of the thoracic spinal canal relative to the spinal cord.5 Patients presenting with neurological deficit require urgent evaluation, and if deficits are rapidly progressive, urgent local therapy with radiation or surgical intervention may be indicated. Rapid progression and severe deficits indicate a poor prognosis.

Full diagnostic neuroimaging should be performed during the initial work-up of the patient with spinal metastases. Initially, plain radiographs should be obtained to evaluate spinal stability in terms of alignment and to rule out the presence of large, destabilizing bony lesions. They also serve as a baseline for future follow-up evaluation. Bone scans are more sensitive than plain radiographs. They are part of the initial staging work-up to quickly evaluate the entire body for metastases and similarly serve as a baseline for future bone scans for the evaluation of therapeutic efficacy. Magnetic resonance imaging (MRI) with gadolinium administration is required for definitive detection and evaluation of spinal metastatic lesions. If MRI is not possible, myelography is necessary. If there is a question about stability from initial plain radiographs, or if biopsy or surgery is required, then a computed tomography (CT) scan of the spine is indicated to evaluate bone integrity and architecture for preprocedural planning. If spinal compression is evidenced by diagnostic imaging, local treatment with radiation or surgical decompression may be necessary. Routine imaging studies for either an initial metastatic work-up or for restaging of known metastatic disease consists of a CT scan of the chest, abdomen, and pelvis, and either a bone or a positron emission tomography (PET) scan of the body.

Plain radiography is not sensitive for metastatic disease, but it is invaluable for evaluation of spinal stability. Upright and flexion-extension views are used to evaluate spinal alignment. Instability with anterolisthesis, vertebral collapse, kyphosis, or scoliosis requires immobilization, CT for better imaging resolution, and the attention of a surgeon. On plain film, osteolytic tumors create lucencies, osteoblastic lesions have sclerotic margins, and large masses invading paraspinal structures produce soft tissue shadows. Technetium-99 bone scan has good sensitivity but poor specificity for metastatic disease. Radionuclide build-up from osteoid formation6 is a reactive process to insults, including trauma, infection, and degenerative disease, and results in falsely positive studies.7 However, this same reactive process is difficult to generate with aggressive, fast-growing lytic lesions, such as multiple myeloma, renal and lung tumors, and certain sarcomas, resulting in false negatives.8 MRI, the gold standard in neoplasm imaging, allows evaluation of the entire spine in multiple orthogonal views, resulting in sensitivity and specificity in excess of 90%. However, long acquisition time can lead to patient claustrophobia and thoracic motion artifact.8 CT myelography, performed when MRI is not possible, can reveal the location and level of metastases and their anatomical relationship to the dura, spinal cord, and spinal roots. As an invasive procedure, risks of myelography include spinal cord herniation or “coning” in the presence of a complete spinal block from a large tumor mass. In the absence of a previously biopsied primary lesion, or if a diagnosis requires confirmation, a biopsy should be performed before the initiation of treatment.

INITIAL EVALUATION AND TREATMENT

Although long-term control of metastatic spinal disease requires systemic chemotherapy, initial treatment of spinal metastases can be a multidisciplinary endeavor depending on the degree of neurological compromise, the amount of bone destruction, the patient’s prognosis, and the efficacy of radiation and chemotherapy with the patient’s tumor diagnosis. Initial local treatment may be required when a patient presents with lesions demonstrating neurological deficit, significant local mass effect, instability, or pain. Patients with rapidly progressive neurological deficit will require emergent radiation or surgical therapy if the tumor is radioresistant. Patients with radiographic evidence of spinal instability may require urgent surgical stabilization. Patients with a large tumor load may require surgical debulking to increase the efficacy of chemotherapy and to reduce the effect of tumor lysis. For cases that present in acute fashion, requiring the need for emergent or urgent intervention, a multidisciplinary team is assembled to determine a comprehensive treatment plan so that a thorough discussion with the patient and patient’s family can be undertaken before treatment.

Laboratory studies in patients with suspected metastatic spinal disease are necessary to correct derangements and serve as a baseline to follow the course of the patient’s disease. Potential metabolic derangements from chemotherapy caused by tumor lysis, metastatic organ involvement including kidney and liver, and bony invasion with osteolysis and bone resorption make important the knowledge of serum sodium, potassium, blood urea nitrogen, creatinine, calcium, phosphate, magnesium, liver enzyme, and alkaline phosphatase levels as well as coagulation times. Patients who have concomitant intracranial lesions should have CSF sent for cytopathology. A complete blood count, erythrocyte sedimentation rate or C-reactive protein, and albumin and transthyretin are important to evaluate the cancer patient’s nutritional and immunological status.

Many patients present in a dehydrated state with acute renal insufficiency related to prerenal azotemia. Hypercalcemia can be seen either as a by-product of metastatic bone lysis or as a paraneoplastic syndrome. If hypercalcemia is present, electrocardiography is indicated. After initial rehydration and normalization of kidney function, hypercalcemia is treated with courses of steroids and intravenous bisphosphonates before the onset of chemotherapy. Steroids benefit patients with cord or root impingement, and severe acute pain may require local therapy with radiation or surgical intervention.9 The presence of neoplastic cells with CSF sampling is an indication for CSF-delivered chemotherapy, and a neurosurgical consultation is necessary for placement of an Ommaya reservoir for intraventricular chemotherapy and treatment monitoring. Evaluation of serum cancer markers is obtained to follow the progression of treatment. These include serum electrophoresis and urine for Bence-Jones protein in multiple myeloma, prostate-specific antigen (PSA), and carcinoembryonic antigen for cancer of the colon, breast, lung, pancreas, and ovaries. Other commonly evaluated markers for metastatic disease and bone lesions include CA15–3 and alkaline phosphatase, respectively.

SYSTEMIC CHEMOTHERAPY

Among skeletal locations, the spinal column is the most common site of metastatic dissemination10 and also is the initial site of spread in 12–20% of patients who present with spinal symptoms.1,11 Most metastatic spinal lesions originate from arterial hematogenous spread, but other primary cancers such as prostate and renal cell cancer disseminate through the venous system in retrograde fashion via the valveless venous plexus described by Batson.1214 Lesions that disseminate via hematogenous pathways are clearly accessible for treatment by systemic chemotherapy.

In systemic chemotherapy, either single agent or combination therapy is used. The choice of the specific agent is guided by the biological behavior of the tumor type of the disease, and some therapies are based on the presence of specific receptor targets unique to the cancer type. The most common components of systemic chemotherapy are hormonal drugs for breast and prostate cancer and different cytotoxic chemotherapeutic agents for almost all cancers. If metastatic disease is confined to bone, with good management, patients can go on to have a long clinical course. Because systemic chemotherapy is guided by the biology of the disease, we will address individually the most common cancers that are metastatic to the spine.

BREAST CARCINOMA

Bone is the most common site of metastases for breast cancer. According to the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) database, 200,000 women develop breast cancer in the United States each year, with more than one-third of these individuals developing bone metastases, including spinal lesions.15 As with other cancer types that invade bone, control of bone disease affords several years of survival, and patients do poorly once the disease invades soft tissue organ systems, including the brain.16,17 Breast metastases are both osteolytic and osteoblastic, and patients require careful evaluation to ensure that skeletal complications are not evidenced on presentation. The use of bisphosphonates improves survival by increasing the time to skeletal complication.18,19 Receptor-positive disease is a positive predictor for a longer median survival, as is the presence of metastases solely to bone. More than 60% of breast cancers have hormonal receptors and are thus responsive to hormonal therapy.20,21

The drug most commonly used for breast cancer is tamoxifen, a selective estrogen receptor modulator with both agonist and antagonist effects. The use of hormonal systemic agents has drawbacks. Even though tamoxifen has an agonist effect that helps preserve bone density, negative side effects include hot flashes and increased incidence of venous thrombosis and endometrial cancer. Another class of hormonal agent is aromatase inhibitors, which block the peripheral conversion of androgenic precursors to estrogen. Aromatase inhibitors have been demonstrated to increase survival in postmenopausal women with metastatic disease when compared with tamoxifen, and in postmenopausal women with estrogen receptor-positive metastatic disease, they are the agents of choice after tamoxifen failure.22 Unfortunately, this hormonal agent, by decreasing systemic estrogen, leads to osteoporosis, a negative side effect. Other hormonal agents, including progestins, androgens, and estrogen, also have therapeutic effects on breast metastases. Response to therapy may take 2 to 3 months, but once it has been demonstrated, further response often can be generated by second-line agents.

When response to hormonal manipulation has run its course, breast cancer is usually responsive to treatment with chemotherapy. The most effective chemotherapeutic agents in metastatic breast disease are cytotoxic single agents, which have become the mainstays of chemotherapy after hormonal drugs. These agents include the anthracycline drugs doxorubicin and epirubicin, and the antitubulin taxanes including docetaxel and paclitaxel.23 Anthracyclines such as doxorubicin produce cell death by affecting cellular targets located within the nucleus, intercalating with DNA to create DNA topoisomerase inhibition. Taxanes are believed to exert their cytotoxic effect through stabilization of tubulin polymerization and promoting the abnormal aggregation of intracellular microtubules. Another agent with a Food and Drug Administration (FDA) indication for breast metastases is oral capecitabine, which exhibits little myelosuppression. Capecitabine has fewer side effects and is easier to administer than fluorouracil. Its decreased toxicity profile is believed to be a result of its preferential activation in malignant tissues, whereas thymidine phosphorylase, the enzyme that activates the final step in the conversion of the pro-drug capecitabine into fluorouracil, is overexpressed.

Second- and third-line therapies lacking U.S. FDA indications but used in off-label fashion in the treatment of breast cancer include vinorelbine for non-small cell lung cancer, gemcitabine for pancreatic and non-small cell lung cancer, pegylated liposomal doxorubicin for Kaposi’s sarcoma, and mitoxantrone for hormone-refractory prostate cancer and acute nonlymphocytic leukemia. In the last few years, fulvestrant and zoledronic acid also have been U.S. FDA-approved for breast cancer therapy, and there has been increased use of combination therapy for breast metastasis.23 Despite higher response rates and longer time-to-progression with the use of combination therapy, there is controversy regarding whether it improves survival over the sequential use of the same agents. Although no single trial has demonstrated a survival advantage of combination therapy over sequential administration of single agents, in all areas of oncology where cures have been produced, combination chemotherapy has been used. Combinations include capecitabine/docetaxel, gemcitabine/paclitaxel, doxorubicin/paclitaxel, and a broadly adopted class of combination chemotherapy that includes various cytotoxic agents with the drug trastuzumab, a humanized monoclonal antibody to the human epidermal growth factor receptor-2 (HER-2) protein for patients with HER-2 overexpressed metastatic disease. With trastuzumab, combination chemotherapy has been demonstrated to be clearly superior to single-agent trastuzumab therapy in multiple clinical studies.2426

PROSTATE CARCINOMA

Prostate cancer commonly metastasizes to bone. Despite widespread initiatives to screen men for the early detection of prostate cancer, rates for organ-confined disease on presentation are disappointingly low, ranging from 8–30%. Prostate cancer takes a more aggressive clinical course in African-American men because of the existence of genetic polymorphisms and CAG/GGC microsatellites of the androgen receptor gene.27,28 Organ-confined disease, associated with PSA levels of 10 ng/mL or less, can be treated with radical prostatectomy, resulting in a cure rate of more than 80%.29 Unfortunately most patients do not fall within this category, and more than 37,000 men die each year as a result, making prostate cancer the second-leading cause of cancer-related death after lung cancer in men in the United States.30

Most prostate cancers are initially responsive to hormonal therapy. Androgen deprivation, the mainstay of treatment, is provided by gonadotropin-releasing hormone (GnRH) antagonists or surgical castration. Anti-androgens such as flutamide are used to prevent an initial surge in androgen formation after the start of GnRH treatment. Secondary anti-androgens include bicalutamide31; estrogens such as diethylstilbestrol that target ER-b, an estrogen receptor expressed by prostate cancer cells;32

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