Combination treatment including chemotherapy and radiation therapy has only recently been introduced in clinical trials of lung cancer and some other malignancies. An extensive series of clinical trials[1-4] was conducted to evaluate the significance of in vitro synergy between chemotherapy, particularly cisplatin (Platinol), and radiation therapy in the treatment of lung cancer. Numerous preclinical studies[5-10] have suggested that the taxanes as a group may be more effective potentiators of radiation than are the platinum compounds, but their interactions appear to be complex, and additional preclinical studies are ongoing in hopes of increasing our understanding of the radiation-enhancing mechanisms of these agents. In this presentation we discuss clinical trials[11,12] incorporating paclitaxel (Taxol) and radiation that have been conducted to evaluate the effectiveness and the role for this combination in the treatment of lung cancer.
Various agents have been used either sequentially or concurrently in clinical trials of combination chemo-radiotherapy for advanced non-small-cell lung cancer (NSCLC).
Cancer and Leukemia Group B (CALGB) 8433 was the first major randomized clinical trial to demonstrate a significant survival advantage for the combination of sequential chemotherapy and radiation for patients with inoperable stage III non-small-cell lung cancer. The treatment used in that study consisted of radiation (60 Gy in 2-Gy fractions) with or without two cycles of prior cisplatin and weekly vinblastine (Velban) for 5 weeks. Response rates were 56% for patients receiving the combination therapy vs 43% for patients receiving radiation alone, with median survivals of 13.7 and 9.6 months, respectively (P = .0066).
Reanalysis of this trial at 7 years showed that the initial findings persisted, with 5-year survivals of 17% and 6%, respectively. The trial results also have been confirmed independently in an Intergroup study by the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group, with similar findings of improved 1-year and median survivals of 60% and 13.8 months for patients given the combined therapy vs a 1-year survival rate of 46% and a median survival of 11.4 months for those treated with radiation alone.
In another randomized study demonstrating an improvement in 3-year survival for sequential chemoradiotherapy vs radiation alone, a decreased frequency of distant relapses also was noted.
Concomitant chemoradiotherapy offers an alternative strategy for combined treatment. Its potential advantages over sequential therapy are the immediate and simultaneous treatment of both local and distant sites of disease and the opportunity for synergy between the modalities that may enhance local control. These advantages, however, must be balanced against the potential for enhancement of toxicity to normal tissues. The principle of synergy between concomitant radiation and chemotherapy has been well described in vitro,[10,18] but it is more difficult to prove in clinical practice.
In a three-arm, randomized study of patients with stage III inoperable non-small-cell lung cancer conducted by the European Organization for Research and Treatment of Cancer, patients were treated with radiation alone (split course: 55 Gy in 20 fractions, with a 3- to 4-week midcourse break), the identical radiation schedule plus cisplatin 30 mg/m²/week during radiation, or the same radiation plus cisplatin 6 mg/m²/day. In both combination arms, the total dose of cisplatin given was identical. Although overall response rates were similar for all three arms, an improvement in overall survival was noted for patients given radiation plus cisplatin vs radiation alone (P = .04); the difference was most apparent when radiation plus daily cisplatin was compared with radiation only (P < .009). Analyses of patterns of failure showed improvement was confined to regional control.
Combined Modalities vs Radiation Alone
A recent meta-analysis evaluating multiple clinical trials from the pretaxane era confirms an overall beneficial effect for combined therapy over radiation alone. However, local and distant failures still occurred in the majority of patients. Combined-modality therapy resulted in a mean gain in life expectancy of approximately 2 months by the end of 3 years, and a median survival improvement from 10.3 to 12 months. Clearly, incorporation of newer, more active chemotherapeutic agents and regimens is needed to improve local and distant control of disease.
Combination Paclitaxel and Carboplatin
Paclitaxel is among the most active single agents in the treatment of non-small-cell lung cancer.[21,22] Phase II trials evaluating paclitaxel in patients with previously untreated stage IIIA, stage IIIB, or advanced stage IV non-small-cell lung cancer indicate that paclitaxel used alone was associated with a response rate of 21% to 24% and a 1-year survival rate of 42%. Carboplatin (Paraplatin) is less neurotoxic, nephrotoxic, and ototoxic than its parent drug, cisplatin.
Carboplatin is active against non-small-cell lung cancer and serves as a radiation sensitizer by potentially interfering with repair of sublethal radiation injury. In a large randomized trial conducted by the Eastern Cooperative Oncology Group, single-agent carboplatin produced the highest 1-year survival rate with the least toxicity in patients with metastatic non-small-cell lung cancer.
Our recent laboratory data also suggest a possible synergistic relationship between paclitaxel and carbo-platin. Several studies have shown that the combination of paclitaxel and carboplatin provides an impressive response rate and survival time.[25-28] The Fox Chase Cancer Center, for example, conducted a phase II study of escalating doses of paclitaxel combined with a fixed dose of carboplatin. Their response rate was 63%, with a median survival of 53 weeks, which was better than any other combination in the management of stage IV non-small-cell lung cancer.
Significant efforts have been focused on the ability of taxanes to potentiate the effects of radiation. Although support for several potential mechanisms of interaction has been demonstrated in vitro, cell synchronization appears to be the dominant factor.[5-10]
Paclitaxel, the prototype taxane, is extremely effective in arresting the activity of tumor cells in the G2/M phase of the cell cycle. After only brief and low-level exposure to paclitaxel at concentrations of 30 nmol/L for 1 hour, arrest of proliferating cells in G2/M can be noted. The effect has been observed to begin as early as 4 hours after initiation of treatment and approaches a maximum of 70% at 24 hours. These concentrations are routinely exceeded by 100-fold in the plasma and are achievable within the tumor in clinical practice. The fraction of arrested cells increases as a function of both concentration and duration of exposure.
Several groups, however, have shown that mechanisms of synergy other than the paclitaxel-induced cell-cycle perturbation must be operative, at least in the in vivo setting. Milas et al addressed the possibility that paclitaxel increases the susceptibility of tumor cells to radiation-induced apoptosis. They demonstrated that paclitaxel-induced apoptosis developed mainly from mitotically arrested cells. Consequently, the pattern of apoptosis development was similar to the kinetics of mitotic arrest but lagged several hours behind, suggesting the influence of alternative mechanisms. The apoptotic response induced by paclitaxel persists for about 2 days. In contrast, radiation-induced apoptosis in MCA-4 tumors peaks in 4 hours and then rapidly declines, approaching background levels by 12 hours after irradiation.
TimingThe efficacy of radiation-induced apoptosis in tumors treated with paclitaxel also is dependent on the timing of therapies and the phase of the cell cycle. These investigators showed that radiation delivered 1 hour after paclitaxel, when only a low percentage of cells were in mitosis, was no more effective in terms of inducing apoptosis than it was in tumors that had not been treated with paclitaxel. However, when radiation was given 9 or 24 hours after paclitaxel, when many cells were in mitosis, radiation-induced apoptosis increased significantly.
An alternative explanation for the ability of the taxanes to potentiate radiation is that treatment with paclitaxel results in reoxygenation of hypoxic tumor cells, and the reoxygenation increases with time. About one third of the total tumor-cell population is mitotically arrested within 9 hours after paclitaxel administration, and the majority of these cells die by paclitaxel-induced apoptosis or other modes of cell death. The dead cells are rapidly removed from the tumor. It is logical to anticipate that this removal of dead cells results in tumor reoxygenation, rendering them two to three times more sensitive to radiation. Since about 30% of cells in 8-mm MCA-4 tumors are hypoxic in untreated air-breathing mice, their reoxygenation would considerably increase the radioresponsiveness of the tumor.
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