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

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

ABSTRACT: The development of effective and well-tolerated combinations of chemotherapy and radiotherapy is of great importance to improve disease-free survival in patients treated for non–small-cell lung cancer. Studies demonstrate that paclitaxel (Taxol) is highly active in treating metastatic lung cancer. Additionally, in vitro studies show that it is a potent radiosensitization agent. Therefore, studies have been undertaken to evaluate the combination of paclitaxel and radiotherapy in advanced non–small-cell lung cancer. Results of these studies are encouraging, demonstrating that 1-year survival rates of up to 66% and impressive disease-free intervals can be achieved with acceptable toxicities. Further studies are currently being undertaken or planned to confirm these results and to establish the optimal combination of paclitaxel and radiotherapy. [ONCOLOGY 13(4):51-53, 1999]

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 (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 (Taxol) as a single agent
has confirmed response rates of approximately 24%, and in combination
therapy with cisplatin or 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.

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