Paclitaxel in Lung Cancer

Case Study

A 66-year-old female with newly diagnosed non-small cell lung cancer (NSCLC) presents to clinic. She is diagnosed with a stage IV adenocarcinoma. She was previously treated at an outside institution with pemetrexed in a clinical trial. She is epidermal growth factor receptor (EGFR) mutant and anaplastic lymphoma kinase (ALK) fusion oncogene negative. With an Eastern Cooperative Oncology Group (ECOG) performance status of 2, we decided against the use of cisplatin. We know standard of care is a platinum doublet and decide on a carboplatin and paclitaxel combination. She receives her first dose without incident, but develops a hypersensitivity reaction (HSR) with the second dose, as evidenced by some hives and back pain during the infusion. She also starts developing some arthralgias and myalgias for about 4 to 5 days after each dose. She finds these painful and lies in bed for most of this time period. What measures can be taken to get her safely and comfortably through chemotherapy?

Paclitaxel

Paclitaxel was discovered as part of the National Cancer Institute program in which thousands of plants were screened for anticancer activity. In 1963, preclinical studies found that taxol, a crude extract from the bark of the Pacific yew, Taxus brevifolia, a scarce and slow-growing evergreen found in the old-growth forests of the Pacific Northwest, has cytotoxic activity against many tumors.1 Paclitaxel was identified as the active constituent of this extract in 1971. Paclitaxel promotes the polymerization of tubulin, disrupting normal microtubule dynamics essential to cell division and vital interphase processes, thereby causing cell death.2 Paclitaxel has demonstrated cytotoxicity in a broad range of tumor types, including breast, ovarian, lung, and head and neck cancers, as well as malignancies refractory to conventional chemotherapy, such as previously treated lymphoma, small cell lung cancer, and esophageal, gastric, endometrial, bladder, and germ cell tumors. Paclitaxel is also active against AIDS-associated Kaposi sarcoma. Toxicities associated with pac-litaxel include HSRs, neurotoxicity, and hematologic toxicities.

Paclitaxel in NSCLC

In 2002, the ECOG 1594 was published, looking at a comparison of platinum doublets in the treatment of patients with advanced NSCLC.3 The 4 doublets in the trial included cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, and carboplatin/paclitaxel. There was no difference in overall survival (OS) between the 4 doublets. The overall similarity of these results suggests that treatment decisions should be made based on other parameters, such as cost, adverse events, and scheduling.

In 2004, several studies looked at the efficacy of platinum doublets in the setting of adjuvant use. The International Adjuvant Lung Cancer Trial compared platinum doublets (cisplatin plus either etoposide, vinorelbine, vinblastine, or vindesine) versus observation in postoperative stage I-IIIA patients.4 The result was a 5% improvement in both disease-free survival and 5-year OS. That same year, the JBR.10 study compared cisplatin/vinorelbine to observation in patients with stage I-II NSCLC and confirmed the benefit of receiving adjuvant cisplatin-based chemotherapy.5 The results were grossly positive, with a difference of 15% in 5-year survival between the 2 arms (69% cisplatin/vinorelbine vs 54% observation). Based on the results of previous trials, carboplatin is used frequently in patients who may not be able to tolerate cisplatin.

Toxicities
Hypersensitivity reactions

In addition to a limited supply of drug from Pacific yew tree bark, paclitaxel’s aqueous insolubility requires the use of a pharmaceutical vehicle consisting of 50% Cremophor EL (polyoxyethylated castor oil) and 50% ethanol.6 Although it was initially unclear whether paclitaxel or Cremophor EL was responsible for the relatively high incidence of major HSRs observed during preclinical and early phase 1 studies, Cremophor EL, by inducing the direct release of histamines from circulating cells, has generally been felt to be the causative agent.7
The incidence of major HSRs in early phase 1 trials approached 25% to 30%.8,9 Most affected patients had type I HSRs, including dyspnea, bronchospasm, urticaria, and hypotension. HSRs usually occurred within 2 to 3 minutes after treatment and are almost always noticed within the first 10 minutes; most occur with the first or second dose, indicating that prior sensitization is not necessary. For this reason these reactions are thought to be non-IgE mediated.10-14 Most major HSRs resolve completely after stopping the paclitaxel infusion and administering histamine receptor (H1) antagonists, fluids, and occasionally vasopressors. Minor HSRs, such as flushing and rashes, have also been reported in as many as 40% of patients. Minor HSRs do not predict the development of major reactions. Patients with major HSRs have been successfully rechallenged with paclitaxel, using substantially lower infusion rates along with treatment with dexamethasone 20 mg IV every 6 hours for 4 doses, although this approach is not always successful.14

Hematologic toxicity

Neutropenia is the most common toxicity of paclitaxel.15 Onset is usually 8 to 10 days after treatment, and recovery is usually complete by days 15 to 21. In most patients, particularly in those who have received prior chemotherapy, the maximum tolerated dose of paclitaxel without granulocyte colony-stimulating factor is 175 to 200 mg/m2. The most critical pharmacologic determinant of the severity of neutropenia seems to be the length of time that paclitaxel plasma concentrations are higher than biologically active concentrations, a fact that may explain the increased incidence of neutropenia with longer infusions.16,17 Paclitaxel alone rarely causes thrombocytopenia and anemia.

Neurotoxicity
A peripheral neuropathy characterized by sensory symptoms such as numbness and paresthesia in a glove and stocking distribution is the principal neurotoxic effect of paclitaxel.15,18-21 Symptoms may begin as soon as 24 to 72 hours after treatment with higher doses (≥250 mg/m2) but usually occur only after multiple courses at 135 to 250 mg/m2. It appears that patients treated with paclitaxel over shorter (3-hour) schedules are more prone to the neurotoxic effect of paclitaxel than those treated with longer (24 or 96 hours) schedules, which argues that peak concentrations may be a principal pharmacologic determinant of neurotoxicity. The incidence of neurotoxicity has been particularly high in patients who receive paclitaxel as a 3-hour infusion combined with cisplatin.

A number of factors influence the incidence of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving neurotoxic chemotherapy, including patient age, dose intensity, cumulative dose, therapy duration, coadministration of other neurotoxic chemotherapy agents, and preexisting conditions such as diabetes and alcohol abuse. While symptoms may resolve completely, in some instances CIPN is only partly reversible, and in other cases it does not appear to be reversible at all.21,22

There is a separate paclitaxel-induced toxicity that is a bothersome syndrome of subacute aches and pains—commonly referred to as arthralgias and myalgias—described in up to 58% of patients receiving paclitaxel.6,23,24 These symptoms generally begin 1 to 3 days after drug administration and are usually self-limited, often resolving within 7 days. Symptoms have been described in large axial muscular and joint regions and generally are not accompanied by objective musculoskeletal or neurologic changes. Based on the nature and temporal occurrence of paclitaxel-induced acute pain syndrome symptoms, it is hypothesized that the acute pain syndrome occurs as a result of sensitization of nociceptors, their fibers, or the spinothalamic system, as opposed to a musculoskeletal injury.24 The paclitaxel-induced acute pain syndrome following paclitaxel infusion has commonly been treated with nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and/or opioid pain medications, among others. Few studies, mostly case series, have investigated the role of other medications in both treatment and prevention. Studies using Shakuyaku-kanzo-to (a Japanese herb),25 antihistamines,26 corticosteroids,27 opioid analgesics,28 and amifostine20 have not yielded enough evidence to establish a standard practice.

Case Study Discussion

In regard to the HSR our female patient experienced, I would recommend a rechallenge of paclitaxel. Based on the data presented above, I would decrease the infusion rate to a 24-hour rate and increase the rate as tolerated. I would also give her dexamethasone and diphenhydramine premedications in repeated doses prior to infusion. In regard to the arthralgias and myalgias she experienced, there is a lack of significant data showing how to treat these. In my personal clinical experience, I have found corticosteroids to be very effective for patients. I typically use 4 mg of oral dexamethasone with breakfast and lunch for 3 to 5 days, starting the day after chemotherapy. The IV premedication dose typically wears off about 36 hours after the administration. I always remind patients to take their oral dose of dexamethasone with food and to take it earlier in the day to help with the side effect of insomnia as well. With some adjustments to the paclitaxel administration rate, the premedication schedule, and the management of side effects, it is likely we can safely and comfortably deliver the optimal chemotherapy choice of paclitaxel and carboplatin doublet.

References
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