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
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 nonsmall-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 nonsmall-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]
Globally, nonsmall-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 nonsmall-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 nonsmall-cell lung cancer the prospect of long-term survival. However, in spite of current public and clinical awareness, the majority of patients with nonsmall-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 nonsmall-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.
Over the past decade, several randomized trials have shown that combined modality treatment with chemotherapy and radiation therapy for locally advanced nonsmall-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. 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. 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.
These and other studies have confirmed that combined modality therapy should be used in the treatment of locally advanced non-metastatic nonsmall-cell lung cancer. 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 nonsmall-cell lung cancer patients. 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 nonsmall-cell lung cancer, several trials have commenced evaluating the role of paclitaxel in combination with radiation therapy in the treatment of locally advanced nonsmall-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. These properties of paclitaxel suggest that as p53 mutations are common in nonsmall-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 nonsmall-cell lung cancer.
The demonstration that paclitaxel is one of the most active agents in the treatment of metastatic nonsmall-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 nonsmall-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 nonsmall-cell lung cancer.
Simultaneous Paclitaxel and Radiotherapy
In the study of Vogt et al, paclitaxel levels were evaluated in conjunction with simultaneous radiation (total dose radiation 59.4 Gy). A minimum of five patients were treated at each dose level. The paclitaxel doses ranged from 45 mg/m²/wk over 3 weeks to 65 mg/m²/wk for 7 weeks. Among 25 evaluable patients, complete responses (1 patient, 4%) and partial responses (16 patients, 64%) were observed; 8 patients had a minor response. Overall, therapy was well tolerated. Based on these data, a dose of 55 mg/m²/wk of paclitaxel was recommended for further study in combined modality therapy for nonsmall-cell lung cancer patients.
Wolf et al reported on a Phase II trial of escalating doses of paclitaxel and radiation therapy in 27 patients with stage IIIA/B nonsmall-cell lung cancer. Radiation therapy was given in daily doses of 2 Gy, 5 days/wk, during weeks 1 through 3 and 6 through 8. Paclitaxel was administered on day 1 of weeks 1 through 3 and 6 through 8 at a starting dose of 50 mg/m²/wk. Subsequent dose levels were 60, 72, 86, and 103 mg/m². Three to six patients were evaluated at each dose level.
Based on toxicity (chiefly myelosuppression), the maximum tolerated dose based on this study was determined to be 86 mg/m2. Mild-to-moderate esophagitis was observed in only 5 patients. Among 24 evaluable patients, 18 demonstrated responses including: major responses (4), partial responses (11), and minor responses (3), for an overall response rate in this combination of 77%. In this study, however, the major toxic effect observed was a moderate-to-severe protracted lymphopenia in most patients. Among 15 patients evaluated in detail, seven developed moderate-to-severe interstitial pneumonia; one of these seven patients had an additional herpes zoster infection; and an eighth patient had cytomegalovirus infection. Over a follow-up period of 3 months, lymphocyte recovery was not observed. Whether this lymphopenia is an additive effect of radiation therapy and paclitaxel or is induced by weekly paclitaxel, and whether the frequent use of dexamethasone contributed to it remains to be determined. If such observations are confirmed in other studies, patients undergoing combined modality therapy as outlined will need close monitoring on lymphocyte function and should be considered for prophylactic antibiotic therapy.
The study of Marangolo et al evaluated combined modality therapy in 16 patients with nonsmall-cell lung cancer. Paclitaxel, at an initial dose of 40 mg/m²/wk, was escalated in doses of 10 mg/m² until the dose-limiting toxicity was observed. Radiation therapy (2 Gy/d x 5 days to a total dose of 50 Gy) was administered concurrently with paclitaxel. Treatment was continued for a total of 5 weeks. Among 16 evaluable patients, hematologic toxicity was mild with grade 2/3 esophagitis observed in only a small number of patients. Responses were observed at all paclitaxel doses including two complete remissions and five partial remissions. The maximum tolerated dose has not yet been reached.
In the Phase I study of Frasci et al, weekly paclitaxel and cisplatin with concurrent radiation therapy was evaluated in 25 patients. Patients received 6 weekly administrations of cisplatin and paclitaxel. The starting dose of cisplatin was 30 mg/m²/wk and of paclitaxel, 35 mg/m²/wk. Radiation therapy was initially given twice daily, however, because of severe toxicity observed in the first cohort of patients, radiation was subsequently given at a dose of 2 Gy/d for 5 days/wk for 6 weeks. Grade 4 neutropenia was observed in only 4 of the 141 courses of chemotherapy administered. Significant esophageal or pulmonary toxicity was not observed. Two complete remissions and 13 partial responses were observed for an overall response rate of 60%. The median survival time was 16 months with an impressive 66% 1-year survival.
Nonsmall-cell lung cancer continues to be a major problem on a global basis with increasing numbers of cases being diagnosed each year. This disease may be totally prevented by the banning of cigarettes. Unfortunately, many of the patients with this cancer present with locally advanced disease for which cure with surgery is not always feasible. These patients are candidates for combined modality therapy of chemotherapy and radiation.
The results to date of small numbers of trials using combined modality therapy of paclitaxel and radiation therapy are encouraging in terms of overall response rates observed, the acceptable toxicity noted, and the impressive disease-free interval observed. Continued studies, however, will be required to determine the optimum combination of chemotherapy and radiation therapy in this disease and how best to combine both of these modalities in such patients.
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