The Triple Helix @ UChicago

Spring 2014

"Complexities of Cancer Treatments" by Austen Smith

 

Thanks to improvements in clinical treatments and chemotherapy drugs, the worldwide population of cancer survivors has grown to an estimated 28 million.[1] Concurrent with this uplifting positive trend, however, is the leaden reality that these new and improved treatments often cause additional suffering. Increasingly, those who survive cancer are subjected to pain caused by both their disease and their medical treatments. Indeed, even if the cancerous cells are eliminated, survivors are often left to cope with treatment-related maladies. In light of these truths, researchers are continuing to seek modified chemotherapy drugs whose side effects are attenuated. 

Among the existing set of preferred medications is paclitaxel, a first-line chemotherapy drug for the treatment of various cancers, including metastatic breast cancer, advanced ovarian cancer, non-small-cell lung cancer, and Kaposi’s sarcoma.[2] As with other taxane-class drugs, paclitaxel’s mechanism of action involves stabilizing microtubules to prevent depolymerization of the tubulin monomeric units. The breakdown of microtubules is necessary to allow cell division to proceed from the metaphase stage into the anaphase and telophase stages. Thus, microtubule stabilization halts cell division in metaphase, causing cell death in cancer cells.[6] Paclitaxel and other related taxane-class drugs do not come without unwanted effects, however. One of its most prevalent adverse effects is chemotherapy-induced peripheral neuropathy (CIPN). Among cancer patients treated specifically with paclitaxel, more than 80% experience concurrent, dose-dependent neuropathic pain and sensory disturbances associated with CIPN.[3] 

While the adverse effects of paclitaxel chemotherapy may seem secondary in comparison with the immediate destructive effects of cancer—such as tumor growth, metastasis, and widespread cell death—neuropathic pain can actually impair a patient’s regular chemotherapy regimen. Chemotherapy treatment may even be terminated early if the patient and doctor agree that the adverse neuropathic side effects outweigh potential benefits. The National Cancer Institute (NCI) has reported that CIPN is one of the most common reasons that cancer patients stop their treatment early, and in turn experience decreased quality of life and survival rates.[4] 

Researchers have yet to obtain a complete mechanistic understanding of taxane-induced peripheral neuropathy. However, the adverse effects of taxane drugs seem to be localized within a relatively small region in the roots of the spinal cord—namely, the sensory cell bodies in the dorsal root ganglion (DRG).[5] This fairly specific localization has allowed a multitude of research groups to examine the putative mechanisms by which paclitaxel, the most commonly used taxane drug, causes neuronal damage. For example, recent research suggests that the peripheral changes caused by taxane chemotherapy treatments tend to disrupt homeostasis within sensory neurons by altering extracellular ion concentrations, such as that of Ca2+, within the DRG.[5] Clinical manifestations of disrupted homeostasis are variable and may include persistent paresthesia of the hands and feet, loss of reflexes, numbness, and mild fatigue.[6] While certain treatments (e.g. lithium, as will be discussed) may help to maintain appropriate physiological calcium levels, such treatments do not constitute a reliable protective treatment strategy against CIPN. 

Due to the complexity and relative obscurity of the mechanisms underlying CIPN, there is currently no standard treatment for it.[7] Moreover, cancer patients’ chemotherapy regimens frequently involve a combination of drugs, which adds complexity and variability to the severity of taxane-induced toxicity. For example, paclitaxel is often administered in conjunction with platinum-based chemotherapy agents, such as cisplatin or oxaliplatin, which prevent cell division by tightly binding DNA. Platinum-based agents may produce additional neurotoxicity, however, especially in patients with BRCA gene-related breast cancer, triple negative cancer, or ovarian cancer.[8] 

At present, one of the more promising lines of CIPN research examines the use of lithium as a preventative measure against CIPN.[9] Preliminary studies suggest that lithium pretreatment may prove to be sufficient for the prevention of paclitaxel-induced peripheral neuropathy (PIPN). In addition, several clinical trials are collecting data on lithium pretreatment in human patients. One study at the Washington University School of Medicine, titled “Neuroprotective Effects of Lithium in Patients With Small Cell Lung Cancer Undergoing Radiation Therapy in the Brain,” promises to reveal the safety and efficacy of lithium treatments in humans. Started in March 2012, the study is due to be completed in April 2017.[10] 

Until early evidence favoring the use of lithium treatments is supported or refuted in clinical trials, a new form of paclitaxel bound with albumin protein-based nanoparticles, known as nab-paclitaxel, seems to exhibit clinical promise as an alternative chemotherapeutic agent to conventional paclitaxel. In September, 2013, the FDA approved nab-paclitaxel based on its improvement of overall survival in 861 patients with metastatic pancreatic cancer.[11] Initial studies suggest that nab-paclitaxel should replace paclitaxel as a first-line chemotherapeutic agent, primarily due to its improved efficacy, decreased toxicity, and more favorable tolerability.[12] A critical Phase III study showed nab-paclitaxel to be safely infused at significantly higher doses than would be possible for the standard paclitaxel drug, thereby allowing cancer patients to receive more of the paclitaxel drug in a shorter amount of time.[12] Nevertheless, since nab-paclitaxel is a drug with virtually identical pharmacological properties to paclitaxel, it comes with many of the same concerns. Clinical trials of nab-paclitaxel demonstrate a better toxicity profile than conventional paclitaxel, though the incidence of transient, lower-severity sensory neurotoxicity may be higher.[6] Even when paclitaxel is combined with stabilizing albumin, it remains essential to consider complexities of drug interactions; hypothyroidism and alcoholism, for example, are known to augment nab-paclitaxel-induced neuropathy.[6] 

Given the clinical successes of nab-paclitaxel, this new formation of paclitaxel will likely become a frontline chemotherapy drug for the various types of cancer patients already mentioned. Further experimentation is necessary to determine the efficacy and limitations of nab-paclitaxel, as well as potential differences in its physiological effects and the mechanistic reasons for those differences. Since albumin can act as a free-radical scavenger[11], it seems plausible to predict further attenuation of PIPN when nab-paclitaxel is used as the primary chemotherapy drug, leading as it should to decreased oxidative stress (i.e. to less imbalance between radicals and antioxidants). The albumin may therefore help to disarm reactive oxygen species that could otherwise lead to cell death or electrophysiological disturbances.[2] 

As paclitaxel remains, despite the success of nab-paclitaxel, a widely used and preferred chemotherapy drug, effective PIPN treatment strategies will figure centrally in increasing quality of life among cancer patients. Pending the results of current clinical trials, lithium treatments may prove to be as effective at preventing peripheral neuropathy in humans as they are in mice. Nevertheless, research to date suggests that even new technologies such as lithium and nab-paclitaxel are limited in efficacy and still result in many of the same adverse effects, even if attenuated. The near future of PIPN management will then likely see a combination of lithium and nab-paclitaxel strategies to more completely guard against the severe adverse effects of paclitaxel-induced peripheral neuropathy. In the long term, however, cancer treatments free of neuropathic side effects are unlikely to be achieved until the complex mechanisms of PIPN are more fully understood.

References

[1] Park SB et al. “Chemotherapy-Induced Peripheral Neurotoxicity: A Critical Analysis.” CA Cancer J Clin (2013) Vol. 63 No. 4: 419-37. 
[2] Areti A et al. “Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy.” Redox Biology (2014) 2: 289-95. 
[3] Winer EP et al. “Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial” J Clin Oncol (2004) Vol. 22 No. 11: 2061–8. 
[4] NCI Cancer Bulletin. “Chemotherapy-induced Peripheral Neuropathy.” National Cancer Institute. http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2010/022310/page6. Accessed 2 May 2014. 
[5] Peters et al. “An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat.” Brain Res (2007) 1168: 46-59. 
[6] Lee EQ and Wen PY. “Neurologic complications of non-platinum cancer chemotherapy.” In: UpToDate, Basow. DS (Ed). UpToDate. 2014. 
[7] Windebank AJ and Grisold W. “Chemotherapy-induced neuropathy.” Journal of the Peripheral Nervous System (2008) Vol. 13: 27-46. 
[8] Han Y and Smith MT. “Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN).” Front Parmacol (2013) Vol. 4 No. 156: 1-16. 
[9] Mo et al. “Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment.” FASEB J. (2012) 11: 4696-709. 
[10] ClinicalTrials.gov. “Neuroprotective Effects of Lithium in Patients With Small Cell Lung Cancer Undergoing Radiation Therapy to the Brain.” US NIH. http://www.clinicaltrials.gov/ct2/show/NCT01553916?term=lithium&rank=8. Accessed 9 March 2014. 
[11] Cancer Drug Information. “FDA Approval for Paclitaxel Albumin-stabilized Nanoparticle Formulation.” National Cancer Institute. http://www.cancer.gov/cancertopics/druginfo/fda-nanoparticle-paclitaxel. Accessed 2 May 2014. 
[12] Megerdichian et al. “nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer.” Cancer Treatment Reviews (2014).

 
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