Paclitaxel and Radiotherapy:The European Experience in Non–Small-Cell Lung Cancer

Introduction

Globally, non–small-cell lung cancer continues to be a major oncologic problem and accounts for 75% to 80% of all new cases of lung cancer. Among the estimated 175,000 new cases of lung cancer diagnosed this year in the United States, approximately 130,000 will be non–small-cell lung cancer, including the histological subtypes of squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma.

At diagnosis, only a minority of patients are candidates for surgical resection with curative intent, the only current treatment modality that offers patients with non–small-cell lung cancer the prospect of long-term survival.[1] However, in spite of current public and clinical awareness, the majority of patients with non–small-cell lung cancer present with either locally advanced disease or metastatic disease. For these patients, the median survival is approximately 12 months with 5-year survival rates of only 5% to 10%. About one-third of all newly diagnosed patients (approximately 45,000) will have stage III disease, indicating locally extensive disease in the absence of distal metastases. Such locally extensive disease with mediastinal lymph node metastases, or invasion into local soft-tissue structures, is highly predictive of micrometastatic disease and also predictive of the high risk of local failure, even when surgical resection is technically feasible.

For many patients with either stage IIIA or B non–small-cell lung cancer, treatment failure (whether after surgical resection, radiation therapy alone, or the combination of surgery and radiation therapy) is either local, systemic (metastatic), or both. Therefore any attempts to improve both the disease-free survival and overall survival for such patients would require an approach to improve the local control rate and to reduce systemic failure. Chest radiation alone plays an important role in the treatment of these patients with the achievement of good local control, and in particular, a decrease in local symptoms without any major impact on overall survival. In addition, although local control is improved with radical radiation therapy, a significant number of local failures continue to be observed.

Combined Modality Therapy for NSCLC

Over the past decade, several randomized trials have shown that combined modality treatment with chemotherapy and radiation therapy for locally advanced non–small-cell lung cancer has a significant survival advantage compared to radiation alone.[2-5] In a recent meta-analysis of all randomized trials of radiation with and without cisplatin(Drug information on cisplatin) (Platinol)-based chemotherapy, a definite median survival advantage was found when cisplatin-based chemotherapy was added to radiation therapy.[2] This combined modality therapy approach led to a 13% reduction in the risk of death with a survival advantage at 2 years of 4%.

In the study of 353 patients reported by Le Chevalier et al, the 2-year survival was 14% in those receiving radiation alone vs 21% in the combined modality therapy arm.[3] Of note, the local failure rate was similar in both groups, whereas the distal failure rate was significantly lower in the combined modality therapy group, suggesting that the improved survival was due to the systemic effects of chemotherapy.

In the Cancer and Leukemia Group B (CALGB) study of radiation vs sequential chemotherapy and radiation, the use of combined modality therapy was associated with an improvement in median survival, with the projected 5-year survival increased by a factor of 2.8 compared with radiation therapy alone.[4]

These and other studies have confirmed that combined modality therapy should be used in the treatment of locally advanced non-metastatic non–small-cell lung cancer.[6] The best chemotherapy regimen to combine with radiation therapy needs to be defined. In addition, the optimal radiation dose, volume, and fractionation schedule for radiation therapy, and the integration of it with chemotherapy (concurrent, sequential, etc.) for potentially curative treatments, have yet to be clarified. Concurrent chemotherapy may eradicate distal micrometastases directly and acts as radiosensitization to enhance the local effect of radiation therapy and increase local control. Moreover, improving local control may decrease the risk of distal metastases developing, as has been demonstrated in the use of postoperative radiation therapy in patients with breast cancer.

In recent years, several new chemotherapy agents have demonstrated improved activity in metastatic non–small-cell lung cancer patients.[7] Among these agents, paclitaxel(Drug information on paclitaxel) (Taxol) as a single agent has confirmed response rates of approximately 24%, and in combination therapy with cisplatin or carboplatin(Drug information on carboplatin) (Paraplatin) has confirmed response rates of 40% to 50%, with the median survival of patients reaching 12 months. Based on these data in patients with advanced non–small-cell lung cancer, several trials have commenced evaluating the role of paclitaxel in combination with radiation therapy in the treatment of locally advanced non–small-cell lung cancer.

Paclitaxel and Radiation

Paclitaxel is a microtubular inhibitor that acts as a mitotic inhibitor blocking cells in the G2M phase of the cell cycle. This cell-cycle block with paclitaxel is observed in vitro with relatively low concentrations of the agent and is detectable after several hours of drug exposure.

Several studies have indicated that cells in the late G2M phase of the cell cycle are more sensitive to radiation than are cells in other phases of the cell cycle. Because of the virtually complete G2M cell-cycle block observed in cells exposed to paclitaxel, it is likely that this agent may increase the radiation therapy sensitivity of human tumors.[8-10]

Several in vitro studies of human tumor cell lines evaluating the efficacy of paclitaxel as a radiation sensitizer have indicated significant interaction between paclitaxel and ionizing radiation for some, but not all, cancer cell lines.

Combined treatment using relatively low concentrations of paclitaxel and radiation results in either an enhanced response, or at least an additive response. Further studies are still required to determine the optimum doses of paclitaxel required to enhance radiation effects, and the duration of exposure of cells to paclitaxel prior to radiation to optimize the combined effects. In vitro studies have indicated that cells incubated for 24 hours with paclitaxel have a significantly greater number of cells accumulated in the G2M phase of the cell cycle (95% +), compared to 51% for cells exposed for 8 hours, and 18.2% for cells exposed for 2 hours. Although these are in vitro data, the design of in vivo clinical trials of combined modality therapy of paclitaxel and radiation therapy should take these observations into consideration.

It should also be observed that a mutated p53 oncogene is one of the most common genetic abnormalities observed in lung cancer cells. The cell cycle control gene p53 is necessary for the efficient activation of apoptosis. The cytotoxicity of ionizing radiation and most chemotherapy agents is dependent on wild-type p53. However, paclitaxel has the unique property of killing tumor cells in the absence of wild-type p53 function in vitro.[10] These properties of paclitaxel suggest that as p53 mutations are common in non–small-cell lung cancer, its activity (both as a cytotoxic agent and as a radiation sensitizer), may improve the responses to both chemotherapy and concurrent radiation therapy observed in vivo for patients with non–small-cell lung cancer.

The European Experience

The demonstration that paclitaxel is one of the most active agents in the treatment of metastatic non–small-cell lung cancer, coupled with the in vitro observation that it can function as a potent radiosensitization agent, suggests that the combination of radiation and paclitaxel may improve the outcome of patients with locally advanced stage III non–small-cell lung cancer. This improvement may be achieved by 1) reducing local regional failure (through a direct cytotoxic effect and through enhanced radiation effect), and 2) the direct cytotoxic effect on distal nondetectable micrometastatic disease. Although there are several ongoing studies in the United States, there are several parallel ongoing European studies looking at this approach with combined modality therapy in non–small-cell lung cancer.