43 Complications of Medical Therapy

Elizabeth J. Hovey and Susan M. Chang

The treatment of patients with brain tumors remains a significant challenge. New treatment approaches have already demonstrated that combined modalities of surgery, radiotherapy, and systemic drug therapy can prolong survival without significantly adversely affecting the patients’ quality of life.^1,2 However, the prognosis remains poor, and efforts to further improve patient outcome are ongoing. To optimally care for these patients, neuro-oncologists must be knowledgeable about the potential complications associated with such therapeutic modalities. Specifically, neuro-oncologists should be intimately familiar with the side effects of anti-tumor therapy and those associated with supportive medical treatments commonly used in this patient population. They should also appreciate the potential morbidity of the brain tumor itself on the function of the central nervous system (CNS), which can be difficult to differentiate from the neurotoxic side effects of medical intervention.

Due to the limited benefit of standard therapy on overall survival in patients with primary brain tumors, various experimental approaches are under investigation. Advances in the understanding of cell biology and cellular genetics have been translated into many complex and novel treatment strategies.² Some of these experimental approaches involve the direct interstitial delivery of drugs or agents into the brain parenchyma. Examples include gene therapy, immunologic therapy using monoclonal antibodies conjugated to either toxins or radiopharmaceutical analogues, and drug-impregnated biodegradable polymers. The potential side effects of these therapies include not only the operative risks and complications of interstitial delivery but also the effects of the actual agent. These are very complex approaches to therapy, and many are undergoing phase 1 evaluation of their respective toxicities. Alternative methods of improving drug intensity and drug delivery (e.g., intra-arterial administration or highdose systemic chemotherapy with stem cell or bone marrow support) are also associated with unique risks.^3,4 It is clear that neuro-oncologists will have to remain vigilant to the potential harmful effects of a multimodality therapeutic approach to the patient.

Other unique aspects in the management of patients with brain tumors involve the use of concomitant supportive medical treatments that themselves may have direct effects on the patient. Examples include the use of anticonvulsants, corticosteroids, and anticoagulant therapies. The potential for adverse drug interactions from such supportive agents warrants special attention. The sequelae of therapy may often require drug intervention (e.g., postoperative cerebral edema requiring corticosteroid use). Similarly, some of the side effects of radiotherapy may also require medical treatment (e.g., hypothalamic and pituitary dysfunction requiring neuroendocrine replacement therapy). Patients with a malignant tumor, particularly a glioma, also have an inherently increased risk of thromboembolic disease and hence may suffer the medical complications of anticoagulant therapy.

This chapter discusses the complications of agents used in the setting of primary brain tumors rather than secondary brain tumors (metastases), emphasizing the toxicities related to the management of gliomas in adults. Some of the toxicities related to the management of other CNS tumors are briefly discussed.

Chemotherapy

The use of cytotoxic drugs has been shown to be beneficial for treating various histological subtypes of primary brain tumors.⁵ These include anaplastic gliomas, such as grade III oligodendroglioma, grade III anaplastic astrocytoma, grade III mixed oligoastrocytoma, and grade IV glioblastoma multiforme (GBM); primitive neuroectodermal tumors (PNETs); primary germ cell tumors; and primary CNS lymphomas. Based on the international multicenter cooperative trial group data in 2005, standard treatment of newly diagnosed GBM, which accounts for 45% of primary adult brain tumors, usually consists of cytoreductive surgery followed by chemoradiation (standard radiation is 60 Gy in 30 fractions) in combination with the oral alkylating agent temozolomide, followed by adjuvant temozolomide.^6,7

Although these results have led to general agreement on the initial treatment of GBM, in the setting of recurrent/progressive disease there is no consensus regarding the most appropriate salvage agent.⁸ Regardless of this lack of accord, some patients likely benefit from additional chemotherapeutic regimens, and many patients receive agents such as temozolomide given in alternate schedules (often referred to as metronomic temozolomide), lomustine (chloroethylcyclohexylnitrosourea [CCNU]), carboplatin, or irinotecan in the recurrent setting.⁸ Another agent now approved by the Food and Drug Administration (FDA) in the recurrent GBM setting is the targeted agent bevacizumab,^9,10 a monoclonal antibody against vascular endothelial growth factor (VEGF), which, strictly speaking, is not considered to be a cytotoxic agent.

Some neurosurgeons also use chemotherapy wafers (small biodegradable polymer wafers infused with carmustine) at the time of surgery, placed in the neurosurgical cavity bed, due to evidence of improved survival in both the initial and recurrent setting.11,12 In the initial setting of GBM, the uptake of this local chemotherapy agent is not as widespread as that of the use of systemic temozolomide. There is currently no high-level evidence to combine the use of intraoperative carmustine wafers with sequential concurrent chemoradiation with temozolomide and then adjuvant temozolomide.

Other chemosensitive CNS tumors include PNET, medulloblastoma, CNS lymphoma, and germ cell tumors. Drugs often used to treat both PNET and medulloblastoma include cisplatin, carboplatin, cyclophosphamide, vincristine, etoposide, ifosfamide, thiotepa, and methotrexate. Methotrexate and highdose cytarabine are commonly used first-line treatments, in association with high-dose steroids, for CNS lymphoma; other drugs used in this setting are vindesine and thiotepa. Drugs commonly used in the setting of CNS germ cell tumors are ifosfamide, etoposide, carboplatin, and cisplatin.¹³

The limitations of cytotoxic drugs include the inherent and acquired resistance to these agents, the inability to deliver adequate concentrations of the drug to the tumor, and the potential complications of the agents. Most currently used anticancer drugs are selected for their ability to kill rapidly dividing tumor cells. These drugs can affect almost every organ system, but especially those with rapidly dividing cells such as bone marrow, the gastrointestinal tract, germinal epithelium, lymphoid tissue, and hair follicles.

These side effects tend to be reversible because of the capacity for stem cell renewal. Other side effects can be delayed, dose dependent, or cumulative, and may be partially reversible when therapy is stopped. It is therefore crucial to evaluate how much drug toxicity can adversely affect a patient’s quality of life and to try to balance this against the therapeutic benefit to the disease process. Many of the potential side effects of anticancer therapy have been abrogated by supportive measures such as the use of antiemetic agents to control chemotherapy-related nausea and the use of colony-stimulating growth factors for cell lines of the hematopoietic system to counteract the myelosuppressive effects of anticancer agents. Another supportive measure is the use of prophylactic antibiotics to prevent infections associated with prolonged lymphopenia such as combined sulfamethoxazole and trimethoprim in the setting of newly diagnosed GBM to prevent Pneumocystis jirovecii.⁷ As more effective supportive measures are introduced, the side-effect profile of agents can shift, and irreversible toxicities may become more apparent. Some of the drugs introduced as supportive measures can have specific side effects associated with them, such as constipation associated with antiemetic agents and rash associated with antibiotics.

There are several important principles to be learned from the clinical toxicities of anticancer drugs. For instance, the toxicities can be schedule dependent, and patients may have variable toxic responses. Factors to consider before the administration of anticancer drugs include the age of the patient, the severity of the disease, concomitant renal and hepatic function, previous exposure to chemotherapy or radiotherapy, and concomitant medications that may affect the metabolism of other drugs.

The common side effects of chemotherapy can be conveniently divided into the categories immediate, early, delayed, and late. Immediate side effects are those that occur within the first 24 hours, such as nausea and vomiting, local tissue necrosis, phlebitis, anaphylaxis, skin rash, and renal failure. Early side effects have their onset within days to weeks and include myelosuppression, alopecia, stomatitis, and diarrhea. Delayed side effects occur within weeks to months after administration and include anemia, azoospermia (absence of sperm in the ejaculate) or teratospermia (abnormal sperm morphology), hepatocellular damage, hyperpigmentation, and pulmonary fibrosis. Late effects are less well known and are those that become evident months to years later. They include sterility, hypogonadism, premature menopause, and secondary malignancies. The chemotherapeutic agents commonly used for the treatment of malignant brain tumors and their potential risks are listed in Table 43.1.

In an attempt to better improve the outcome of patients with brain tumors, several phase 1 and 2 studies and a few phase 3 studies of new molecular agents are ongoing. These studies involve differentiating agents, antiangiogenic agents, antiinvasive agents, modulators of cell growth, and immunesystem modulators used either alone or in combination with standard cytotoxic agents. More detailed information regarding these novel agents and how they may affect cell signaling pathways may be found elsewhere.^2,14–18 Many of their toxicity profiles are yet to be fully defined. To date, of these new molecular agents, only bevacizumab is approved for use against recurrent GBM. Nonetheless, there are some commercially available agents such as isotretinoin, tamoxifen, and erlotinib that are used in patients with brain tumors on a largely anecdotal basis. Phase 2 studies of these agents have not demonstrated significant improvement in clinical outcomes, but the agents tend to be used in refractory disease because of their ease of administration and relatively low side-effect profile. The mechanisms and main side effects of these agents are also listed in Table 43.1. Note that these molecular or target-based agents can have a variety of side effects that, due to their novel mechanism of action, may be very different from traditional cytotoxic agents. Also, one should be aware that when traditional and novel agents are combined, the side-effect profile of each agent may change in an unexpected manner.

Table 43.1 Chemotherapeutic Agents Commonly Used for the Treatment of Malignant Brain Tumors and Their Potential Risks

An enormous range of neurologic symptoms and complications can occur in this patient population. Some may clearly be disease related, but some can also be treatment related. The nervous system is relatively protected against potentially neurotoxic effects of antitumor therapy. Most of the dose-limiting toxicities of anticancer agents are due to the effects on normally dividing cells and occur at doses that do not affect the CNS, a relatively quiescent organ in terms of dividing cells. The blood–brain barrier also protects the brain from exposure to toxic agents. However, several factors have changed the side-effect profile of these agents, resulting in an increase in clinically important neurotoxicity. These include the multimodality approach involving radiotherapy and chemotherapy, novel methods of administration such as intra-arterial or interstitial delivery, and the development of agents that are specifically targeted to the brain.

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