Treatment-Related Infections, Thromboses, and Neuropathy in Cancer

As every clinician who treats patients with cancer knows, it involves a whole-patient approach rather than just focusing on the malignancy. Many cancers increase the risk of other serious events and many treatments have their own risks and adverse effects that must be managed. A panel of speakers at the 15th Annual Meeting of the National Comprehensive Cancer Network (NCCN) addressed some of these concerns in a presentation on "Management of Treatment-Related Infections, Thromboses, and Neuropathy." Brahm H. Segal, MD, Roswell Park Cancer Institute, Buffalo, New York, discussed NCCN clinical guidelines for prophylaxis against bacterial and fungal infections. Michael B. Streiff, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, addressed prevention, diagnosis, and management of venous thromboembolism (VTE). Michael D. Stubblefield, MD, Memorial Sloan-Kettering Cancer Center, New York, New York, concluded the meeting with a comprehensive review of neuropathy in cancer.

Treatment-Related Infections

The rate of invasive fungal and bacterial infections continues to increase and represents a major challenge to oncology providers. Segal said Candida and Aspergillus are the most common of these, and he discussed the risks and benefits of prophylaxis in intermediate- and high-risk patients, which includes those undergoing hematopoietic stem cell transplantation (HSCT). Patients with graft-versus-host disease (GVHD) are also at high risk of invasive fungal infections.

In intermediate- and higher-risk patients with chemotherapy-induced neutropenia, Segal said levofloxacin prophylaxis reduced "clinically significant bacterial infections," including Gram-negative rod bacteremia. Using quinolone as prophylaxis is an option, Segal said, but then "What do you do if neutropenic fever occurs?" He noted that outbreaks of severe C. difficile colitis had been linked to quinolone use. He also expressed concerned that studies to date have not assessed the long-term effects of prophylaxis on antimicrobial resistance.

In patients undergoing HSCT with mucositis, Segal said fluconazole is an "effective and cost-effective approach that I think most people would recommend." In patients without mucositis, he said to consider not using prophylaxis. Segal said published studies do not evaluate the safety of mold-active azoles in allogeneic HSCT but they can be considered. For those with significant GVHD, he described the newer agent posconazole as NCCN's category 1 recommendation.

Venous Thromboembolism

"At least 900,000 patients each year in the United States suffer deep vein thrombosis [DVT] or pulmonary embolism [PE]," Streiff said, adding that cancer patients have a 4- to 7-fold greater risk. He said DVT and PE are largely preventable with effective prophylaxis but US physicians lag behind their European counterparts in using prophylaxis.

Streiff said the benefits outweigh the bleeding risks associated with prophylaxis in most patients but that each patient should be evaluated for contraindications before using pharmacologic prophylaxis. In those with contraindications in whom pharmacologic prophylaxis is not recommended, like patients with thrombocytopenia, Streiff said he would consider using mechanical prophylaxis.

In most cancer patients, heparin three times daily is appropriate, Streiff said, but he acknowledged that it increases bleeding risks. Low molecular weight heparin (LMWH), fondaparinux, and unfractionated heparin are all category 1 recommendations in the NCCN guidelines. Aspirin is recommended in low risk myeloma patients getting thalidomide and lenalidomide. For patients with heparin-induced thrombocytopenia, Streiff advised using fondaparinux.

High-risk cancer surgery patients (those with previous VTE, operating time >2 hours, bed rest greater or equal to 4 days, aged >60 years, or with an intra-abdominal malignancy) should receive prophylaxis for 4 weeks after leaving the hospital. He described computed tomography angiography as the diagnostic study of choice for evaluating patients for PE and duplex ultrasound for DVT. As soon as VTE is suspected, Streiff said, "Give a shot of lovenox." This should be followed by LMWH (preferred) or unfractionated heparin based on therapeutic aPTT range.

Streiff said warfarin is still used in oncology, but he described it as a "dangerous" drug with a narrow therapeutic window and said a loading dose should never be used and physicians should watch for drug interactions. "LMWH is preferred over warfarin for chronic therapy," he said.

Diagnosing and Treating Neuropathy

"We can talk about neuropathies being a direct effect of the cancer or it can be a paraneoplastic effect or a remote effect of an antibody or hormone secreted by the cancer," said Stubblefield. "But more commonly it's an iatrogenic effect, a result of something we did, like chemotherapy, radiation, immunosuppression, or graft versus host disease." He described mononeuropathy as the most obvious distribution of neuropathy in cancer.

Stubblefield discussed mononeuropathy multiplex, distal symmetric neuropathy, and ganglionopathy (often caused by platinum drugs). He also mentioned small fiber, which many clinicians overlook. Stubblefield said many times physicians treat the symptoms of the neuropathy rather than trying to address the underlying cause of the neuropathy. Other conditions, such as carpal tunnel, might confound a neuropathy diagnosis, but carpal tunnel is also treatable, Stubblefield noted.

Examples of neurotoxic chemotherapy agents include the vinca alkaloids, taxanes, and platinum-based compounds. Thalidomide causes neuropathy, but Stubblefield said the mechanism is unclear. This is also the case with bortezomib. Regarding capecitabine, Stubblefield said, "This is one that, interestingly, supposedly does not cause neuropathy, but you've all seen hand-foot syndrome with it." He said much of the parathesis seen with capecitabine is likely caused by dysfunction of small fibers.

Radiculopathy may mimic neuropathy or predispose patients to symptoms, as can other spinal problems. In cases where you need to clarify the neuropathy or determine why one patient developed neuropathy and others did not, electromyography (EMG) might be appropriate. It can also help in chemotherapy and radiotherapy decision making, locate a PNS lesion, and predict neurological prognosis, Stubblefield said. He does not use EMG on all patients, however. "I use EMG predominantly when I'm not exactly sure what's going on, when my history and physical exam does not tell me what's going on." He also said serologic evaluation and imaging—particularly MRI of the spine—are useful assessment tools, but biopsy is rarely helpful in evaluating neuropathy.

"Pain management," said Stubblefield, "is very straightforward, at least initially." He advised starting with a nerve-stabilizing agent, escalating upward, as high as opioids, until the patient stops complaining or it is clear the drugs are not working. Other possibilities for relief include physical or occupational therapy, orthotics, or plasmapharesis. "Effective treatment of neuropathy depends on the symptoms and deficits experienced by a given patient," concluded Stubblefield.