Optimal Duration of Chemotherapy in Advanced Non-Small Cell Lung Cancer

Abstract

NSCLC is the leading cause of cancer mortality in the United States. Approximately 30-40% of patients present with advanced stage disease (Stage IIIb with malignant effusion and Stage IV) and the majority of those who present with "earlier" disease will ultimately develop and succumb to metastatic lung cancer. Although platinum-based combination chemotherapy has been shown to impact overall survival and quality of life, it is not curative and less than 25% of patients survive 2 years. Therefore, the benefits of chemotherapy must be weighed against toxicity, inconvenience, and cost. Several randomized trials have shown that there is no added benefit of extending first line, platinum-based chemotherapy beyond four cycles. There was no additional survival benefit and patients experienced increased toxicity with longer durations of therapy. Attempts to improve outcome by planned sequential therapy, i.e. shifting from one cytotoxic regimen to another after a fixed number of cycles have also not been successful. Several new so-called "targeted" therapeutic agents have recently been evaluated in clinical trials to assess whether the efficacy of first line chemotherapy with platinum doublets can be improved with the addition of these agents. These include bevacizumab, epidermal growth factor receptor inhibitors (erlotinib and gefitinib), bexarotene, matrix metalloproteinase inhibitors, and others. Other than bevacizumab, none have demonstrated benefit in this scenario. The design of most of these trials employed the concurrent use of the new agent with six cycles of platinum-based chemotherapy (usually either carboplatin/paclitaxel or cisplatin/gemcitabine) and then continued the new agent until relapse. Three agents have demonstrated benefit in randomized studies in the second line setting, docetaxel, pemetrexed, and erlotinib. No study has evaluated the optimal duration of therapy for these agents, though for erlotinib, it appears that use until progression is optimal. Future studies of novel agents will need to explore not only the potential use of these agents in combination or in comparison with standard therapy, but also the duration of therapy and consider issues of survival, quality of life, and cost.

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

“…Since the homogeneous JMDB patient population received a median of six cycles of pemetrexed/cisplatin and the PARAMOUNT placebo patients received four cycles, the approximately two additional treatment cycles did not significantly impact survival in this patient population. This result is consistent with other studies demonstrating that four cycles of first-line NSCLC treatment is sufficient to elicit an efficacy response [15], [16], [17] and [18].…”

The characterization and evaluation of cisplatin-loaded magnetite–hydroxyapatite nanoparticles (mHAp/CDDP) as dual treatment of hyperthermia and chemotherapy for lung cancer therapy

“…Chemotherapy is one of the major treatments for NSCLC after surgery. The platinum derivative, cisplatin, is one of the chemotherapeutic agents commonly used in NSCLC as the first-line of treatment [1]. Cisplatin can bound to the purine base of DNA to form DNA-adduct that would cause various cellular responses to result in cell apoptosis [2].…”

Changes in intracellular redox status influence multidrug resistance in gastric adenocarcinoma cells

“…As the predominant cellular thiol, intracellular GSH concentrations may exceed 10 mM (23). Levels of GSH are reported to be elevated in various tumor cells, for example in bone marrow, breast, ovary, colon, larynx and lung cancer cells (24)(25)(26)(27)(28)(29). Elevated levels of GSH are often associated with an increased resistance to cancer chemotherapeutic agents due to the protective conjugation and detoxification effects of GSH (30).…”