Taxol and Radiation for Non-Small Cell Lung Cancer

Abstract & Commentary

Synopsis: About 40% of non-small cell lung cancers contain mutations in the p53 gene. These mutations do not predict a poor response to combined radiotherapy and paclitaxel but are associated with resistance to platinum agents.

Source: Safran H, et al. Cancer 1996;78:1203-1210.

A recent update of the calgb-8433 trial has confirmed that the median survival of patients with stage III non-small lung cancer is increased by 9.6 months when patients are treated with cisplatin plus vinblastine in combination with radiotherapy as opposed to radiotherapy alone.1 The response rate for the combined modality-treated group was 56%, whereas the response rate was 43% for the radiotherapy alone group. Although an overall prolongation of life from six to 9.6 months is a meaningful improvement for a six to seven week investment, there is ample room for improvement in lung cancer therapy.

To this end, one intriguing approach stems from research into the role of the anti-oncogene, p53, in programmed cell death (apoptosis). The p53 gene codes for a protein whose presence appears to be important in initiating the process of apoptosis. Cells that contain a mutated p53 gene are more resistant to stimuli that trigger apoptosis, such as chemotherapeutic agents.2 Previous studies have shown that non-small cell lung cancers that overexpress p53 protein (which generally indicates the presence of an underlying p53 mutation), are more resistant to platinum chemotherapy or radiation.3 In contrast, in vitro experiments suggest that paclitaxel-induced apoptosis may be independent of p53 status or may even be enhanced in the absence of p53.4 These observations are intriguing since overexpression of p53 is detected in 43-64% of non-small cell lung cancers.5

To determine whether the presence of p53 mutations influenced the probability of clinical response to paclitaxel, investigators at Brown and Vanderbilt Universities analyzed material from a subset of patients with non-small cell lung cancer that had participated in their phase I/II studies of paclitaxel and radiotherapy.6 These patients had been treated with weekly paclitaxel at doses ranging from 30 to 50 mg/m2 weekly by 1-3 hour infusions, together with chest radiotherapy (usually 60 Gy). Tumor tissue was available for analysis in 30 of 64 patients. Twelve tumors (40%) contained mutations in exons 5, 6, 7, or 8, where more than 90% of all p53 mutations reside. Mutations were detected by extracting DNA from the samples then performing PCR amplification with radiolabeled precursors to tag the amplified DNA strands. The material was then fractionated electrophoretically and visualized autoradiographically. In ten of the samples, the amplified material was also directly sequenced to identify and confirm the specific mutation (nucleotide substitution).

The response rate (complete plus partial) to paclitaxel and radiation of the patients that exhibited a mutated p53 was 75%, whereas the response rate was 83% in those with wild type p53. This difference was not significant. (In the original Brown University study, the overall response rate was 74%.)6


The prevailing paradigm holds that chemotherapy for non-small cell lung cancer should include a platinum agent in conjunction with a plant alkaloid, which until recently, meant etoposide or vinblastine. In recent years, two new drugs, paclitaxel and vinorelbine, have been approved that, when combined with cisplatin or carboplatin, have produced response rates as high as 55-60%, which is greater than that observed with previously available agents. If radiotherapy in combination with a platinum agent in combination with etoposide or vinblastine is superior to radiotherapy alone, one might expect that substituting one of the newer drugs would confer even greater efficacy; the data on paclitaxel in this setting are promising.

The improved response rates (75%) reported above are not likely attributable to paclitaxel alone. As a single agent, paclitaxel has a response rate of only about 20% and, although this was in the setting of an infusion given every three weeks rather than weekly, the observed benefits are more likely attributable to the combination of radiotherapy and paclitaxel.

Previously the presence of p53 mutations in non-small cell lung cancer has been primarily of academic interest and generally not something with which clinicians concerned themselves. Nonetheless, such mutations are present in about half of the cases of non-small cell lung cancer and may affect the efficacy of our therapies. For example, in non-small cell lung cancer, response to platinum-based chemotherapy was observed to be 65% in those without p53 mutation, as opposed to only 16% in those with p53 mutations.3 With regard to radiotherapy, presence of p53 overexpression was associated with an objective response rate of 42%, as opposed to 65% in those with normal p53 expression, and median disease-specific survival was also significantly worse in patients whose tumors expressed mutated p53 (8.4 vs 14.4 months). Thus, the present report has relevance to clinicians.

Have we finally identified an adjunct to radiation therapy superior to a platinum agent? The authors themselves downplay their data and conclude only that it "suggests a unique mechanism of action for this therapy" and "provide(s) clinical support for in vitro observations that paclitaxel can bypass mutant p53." Additional data points and longer follow-up should be forthcoming from the investigators at Brown University, and, until these data are available, we should interpret the current study with cautious optimism. However, after reviewing the CALGB data, one hopes that it will not take long to assess whether paclitaxel is a better drug than platinum to combine with radiation therapy. Independent of their mechanisms of action, the unaltered efficacy of paclitaxel in the face of p53 mutations argues for its role as the therapy of first choice.


1. Dillman RO, et al. J Natl Cancer Inst 1996;88: 1210-1215.

2. Lowe SW, et al. Science 1994;266:807-810

3. Kawasaki M, et al. Proc Annu Meet Am Soc Clin Oncol 1996;15:A40; and Langendijk JA, et al. Radiother Oncol 1995;36:218-224.

4. Fisher DE, et al. Blood 1994;84:A430; and Wahl AF, et al. Nat Med 1996;2:72-79.

5. Carbone DP, et al. Chest 1994;106(6 Suppl):377S-381S; and Mitsudomi T, et al. J Natl Cancer Inst 1993; 85: 2018-2023.

6. Choy H, et al. Semin Oncol 1995;22(6 Suppl 15):38-44.