ABSTRACT: The prognosis of patients with advanced non–small-cell lung cancer (NSCLC) remains poor. Systemic chemotherapy prolongs survival in this group of patients and palliates symptoms compared to best supportive care alone but more effective therapeutic strategies are needed. Novel agents that selectively target biological pathways of tumor growth offer hope of improving response and survival rates beyond what has been achieved with standard cytotoxic chemotherapy. Part 2 of this two-part article addresses the role of chemotherapy in locally advanced and advanced NSCLC, including the use of novel agents, considerations in elderly patients, and studies of second-line treatment.
As we noted in part 1 of this article, which appeared in the March 2003 issue of ONCOLOGY, the prognosis of patients with clinical stage IIIA or IIIB non-small-cell lung cancer (NSCLC) continues to be poor, with 5-year-survival rates ranging from 5% to 10% and median survivals from 12 to 15 months. Furthermore, untreated patients with advanced NSCLC have a median survival of 4 months, and a 10% to 15% 1-year survival rate. Although chemotherapy has traditionally had a small role in this disease, new drugs and combined strategies have shown some promise in improving survival rates.
Part 1 of this article explored the use of chemotherapy in early-stage NSCLC. In part 2, we review studies of chemotherapy in locally advanced and advanced NSCLC.
Locally Advanced NSCLC
At diagnosis, approximately 25% of patients present with locally advanced disease and are thus considered unresectable (stage IIIB). Historically, thoracic irradiation was the main treatment for these patients; however, its curative potential is poor. Several phase II and III studies have suggested a benefit with the addition of chemotherapy to radiotherapy.
Up to the late 1980s, standard management of most patients with locally advanced NSCLC comprised conventional external-beam thoracic radiotherapy alone to a total dose of 60 Gy over 6 weeks, with a standard fractionation of 1.8 to 2 Gy per day. The median survival was less than 1 year, and 2-and 5-year survival rates averaged 15% and 5%, respectively.[ 2] A large Radiation Therapy Oncology Group (RTOG) phase II study aimed to optimize the total radiation dose with the use of a hyperfractionated schedule, and a doseresponse relationship was observed. The greatest benefit was seen with a dose of 69.6 Gy delivered over 5.5 weeks, which resulted in 1-and 3-year survival rates of 58% and 20%, respectively.
In the continuous hyperfractionated accelerated radiotherapy (CHART) model, all treatment is compressed into 12 consecutive days by giving three fractions of 1.5 Gy/d at 6-hour intervals to a total dose of 54 Gy and continuing treatment over the weekend. A randomized clinical trial comparing CHART with conventional radiotherapy in 563 patients with locally advanced NSCLC showed a 24% reduction in the risk of death in the CHART group.
A modification of this schema has been developed, in which patients are given the weekend off (CHART-WEL, ie, CHART weekend-less). Modern techniques such as three-dimensional (3D) conformal radiotherapy might also significantly improve the efficacy of thoracic radiotherapy.
Sequential Chemotherapy and Radiotherapy
Many studies have explored the impact of the sequential addition of chemotherapy to radiotherapy.[6-8] The Medical Research Council–Institut Gustave-Roussy (MRC-IGR) overview included 3,033 patients with locally advanced NSCLC from 22 randomized trials comparing radiotherapy alone to radiotherapy combined with chemotherapy. The analysis showed a significant benefit for cisplatin-based chemotherapy combined with sequential radiotherapy, with a 10% reduction in the risk of death corresponding to an absolute survival benefit of 3% at 2 years and 2% at 5 years. However, identifying patients who might benefit from combined therapy is difficult because of the heterogeneity of the populations included in each study.
In the Cancer and Leukemia Group B (CALGB) 8433 trial, patients were randomized to either standard 60-Gy radiotherapy administered over 6 weeks, or two cycles of chemotherapy (vinblastine/cisplatin) followed by the same radiotherapy. The authors reported a significant improvement in survival favoring the chemoradiotherapy arm: Median survival was 13.7 vs 9.6 months, 5-year survival was 17% vs 7%, and 7-year survival was 13% vs 6%.[6,9]
In a confirmatory study led by the RTOG, patients were randomized to radiotherapy alone (60 Gy) vs two cycles of cisplatin/vinblastine followed by standard radiotherapy at the same dose or hyperfractionated radiotherapy (69.6 Gy). This trial confirmed the improvement in median survival for the combined-therapy arm (13.7 vs 11.6 months), but hyperfractionated radiotherapy produced no significant benefit over standard radiotherapy.
The French Center for Experimental Bioinformatics (CEBI) 138 study included 353 patients, who were randomized to a sandwich regimen of induction and postradiotherapy chemotherapy (cisplatin/lomustine [CCNU, CeeNu]/vindesine/cyclophosphamide [Cytoxan, Neosar]) or to radiotherapy alone (65 Gy over 6 weeks). Median survival for the combined-therapy arm was 12 months, compared with 10 months for the radiotherapy-alone arm, and a survival advantage was observed in the combined-therapy arm (20% vs 12% at 2 years, P = .02). In this multicenter study, local persistence or local failure after complete response occurred in over 80% of patients in both arms, without any statistical difference between the two arms. However, the incidence of distant metastasis decreased from 65% to 45% with the addition of chemotherapy (P < .001).
Two separate major cooperative groups have demonstrated superior survival in patients with locally advanced NSCLC following treatment with concurrent chemoradiation compared with sequential therapy.[13,14] In the Japanese study, the survival advantage favored the use of concurrent split-course radiation and mitomycin (Mutamycin), vinblastine, and cisplatin chemotherapy over sequential chemoradiotherapy. The overall response rate was significantly superior in the concurrent-therapy arm (84% vs 66.4%), with a median survival of 16.5 vs 13.3 months and 3- and 5-year survival rates of 27% vs 12.5% and 15.8% vs 8.9%, respectively.
These results were confirmed by the RTOG 94-10 trial, in which 611 patients were randomized to receive induction chemotherapy (cisplatin at 100 mg/m2 and vinblastine at 5 mg/m2) followed by standard radiotherapy (60 Gy) vs the same chemotherapy and concurrent radiation beginning on day 1 vs hyperfractionated radiotherapy and concomitant cisplatin and oral etoposide. Among the 597 evaluable patients, median survival favored concurrent treatment, although the difference was not statistically significant (17 months in the concurrent-therapy arm vs 14.6 months in the sequential and 15.6 months in the hyperfractionated radiotherapy arm).
Because toxicities, especially esophagitis, were substantially worse for patients in the concurrent-therapy arm, the RTOG conducted a quality-of-life analysis called QTWiST (ie, quality-adjusted time without symptoms of relapse or toxicity from treatment), to determine if the improvement in survival outweighed the increase in toxicity. Assigning a range of intermediate weights, QTWiST confirmed the superiority of concomitant therapy over sequential therapy (P ≤ .001).
A French study compared cisplatin/ vinorelbine (Navelbine) followed by standard radiotherapy with concurrent radiotherapy and cisplatin/ etoposide followed by three adjuvant cycles of vinorelbine and dose-attenuated cisplatin (the planned cumulative cisplatin dose in both arms was identical). More than 75% of patients in this study had stage IIIB disease. A nonsignificant trend toward improved survival emerged at 2 years in the concomitant-therapy arm.
Newer Agents in Chemonaive NSCLC
Several new chemotherapeutic agents have shown activity in chemonaive NSCLC, and most of them have proven to be potent radiosensitizers in vitro. These drugs include paclitaxel, docetaxel (Taxotere), vinorelbine, gemcitabine (Gemzar), and irinotecan (CPT-11, Camptosar). Several phase II studies of these new compounds alone or in combination with cisplatin and concurrent irradiation in locally advanced NSCLC have been reported.
A series of pilot studies of paclitaxel as a radiosensitizing agent were conducted, and the recommended dose for further study was 55 mg/m2/wk in conjunction with simultaneous thoracic radiation to a total dose of 59.4 Gy. Table 1 summarizes the results of several phase I and II studies in this setting.[17-20]
The combination of paclitaxel/ platinum and radiotherapy has also been widely explored. The weekly doses delivered are paclitaxel and cisplatin at approximately 40 mg/m2, and carboplatin (Paraplatin) at an area under the concentration-time curve (AUC) of 2, with a total radiation dose ranging from 60 to 65 Gy. Esophagitis is the most frequently reported side effect and appears to be the dose-limiting toxicity of this combination.
Induction Chemotherapy Followed by Chemoradiotherapy
Another feasible approach involves the administration of two to three courses of induction chemotherapy followed by concomitant chemoradiotherapy. An induction regimen of cisplatin at 120 mg/m2 on day 1 plus a 3-hour infusion of paclitaxel at 135 mg/m2 on day 1 plus vinorelbine at 30 mg/m2 on days 1, 8, or 15 was evaluated in a Spanish phase II trial in 31 patients with inoperable stage III disease. When feasible, all patients also received concurrent chemotherapy at the beginning of the radiation course and a course of hyperfractionated radiotherapy (69.6 Gy total dose) in the last week. The response rate was 58%, with a median survival of 16 months. The most common toxicity of chemotherapy was hematologic (febrile neutropenia, 13%; grade 4 neutropenia, 42%), and of radiotherapy, grade 2/3 esophagitis and dysphagia, which occurred in 41% of patients.
Langer et al used two cycles of paclitaxel (175 to 225 mg/m2 in a 3-hour infusion) plus carboplatin (AUC of 7.5), followed by thoracic radiotherapy (60 Gy in 2-Gy fractions) starting on day 43 concurrently with paclitaxel and carboplatin on days 43 and 64. The 1-year survival rate was 62% in the first 21 patients accrued into this trial.
In a randomized phase II study, Curran et al compared (1) sequential chemoradiotherapy vs (2) induction chemotherapy followed by concurrent chemoradiotherapy vs (3) a concurrent approach using the combination of carboplatin and paclitaxel. The initial report was presented recently, and the interim survival results in arms 1 and 3 were sufficiently promising to support continued accrual.
A synthetic allosteric modifier of hemoglobin (RSR13) was tested in combination with carboplatin/paclitaxel: 52 patients with stage III NSCLC received two cycles of carboplatin at an AUC of 6 and paclitaxel at 225 mg/m2 followed by radiotherapy (64 Gy) with daily RSR13 (75 mg/kg with possible adjustments to 100 or 50 mg/kg). The overall response rate was 87%, and 29% of patients experienced one or more episodes of transient RSR13-induced hypoxemia.
Vokes et al recently reported the preliminary results of the randomized phase II CALGB 9431 study, which evaluated gemcitabine, paclitaxel, or vinorelbine with cisplatin as induction chemotherapy and concurrent chemoradiotherapy in stage III NSCLC patients. The response rate in all three arms was similar, but the gemcitabine/cisplatin arm showed the highest rate of grade 3/4 thrombocytopenia (53% vs 6% and 0% in the other arms) and esophagitis (49% vs 31% and 25%). The median survival for all patients was 18 months, with a 1-year survival rate of 66% (68%, 65%, and 63% for the gemcitabine, vinorelbine, and paclitaxel arms, respectively).[ 26]
Docetaxel is another new compound whose activity leads to stabilization of the microtubules that block mitosis in phase G2/M, thus playing a potential role in enhancing radiosensitivity to ionizing radiation. The maximum tolerated dose of docetaxel was 30 mg/m2/wk × 6 when administered alone with radiotherapy and 20 mg/m2/wk × 6 when administered in combination with carboplatin at an AUC of 2.
Gemcitabine has a great radiosensitizing potential, but produces substantial toxicity when combined with radiotherapy. In a phase I trial, six weekly doses of gemcitabine at 1,000 mg/m2 during thoracic radiation (60 Gy in 2-Gy fractions) resulted in excessive nonhematologic toxicity, with esophagitis and pneumonitis developing in another three patients. Even with the use of 3D radiotherapy, the maximum tolerated dose of gemcitabine was 190 mg/m2. Although the length of esophageal exposure was consistently reduced (from 71% for conventional twodimensional [2D] radiotherapy to 11% for the 3D approach), the doselimiting toxicity remained grade 3 esophagitis.
In CALGB 9431, gemcitabine at 600 mg/m2 was safely administered during thoracic irradiation when delivered only on days 1 and 8 of a 3-week cycle. However, more grade 3/4 toxicity occurred in the gemcitabine arm during concurrent radiotherapy than in the paclitaxel/ vinorelbine arm.
Other studies have shown that vinorelbine is a powerful radiosensitizer in vitro. In a phase I study, Gridelli et al reported the feasibility of the combination of thoracic radiotherapy and concurrent vinorelbine administered daily at a maximum tolerated dose of 4 mg/m2. Recently, Garst et al reported the results of a phase II study, in which 36 patients with stage III NSCLC received vinorelbine at 5 mg/m2 three times a week and concomitant radiotherapy (66 Gy). The overall response rate was 56%, and the median survival was 20.7 months. Grade 3 esophagitis developed in five patients (14%).
Concomitant vs Sequential Chemoradiation
In a phase II randomized study, Zatloukal et al directly compared concomitant and sequential chemoradiotherapy, administering cisplatin and vinorelbine in both arms at the same dose intensities. The concomitant approach resulted in major clinical activity, with an overall response rate of 85% and median survival of 20.7 months, compared to 45% and 14.1 months for the sequential arm.
Irinotecan has also been evaluated in this setting. Based on the results of a phase I study, the recommended dose was determined to be 60 mg/m2 on days 1, 8, and 15 plus cisplatin at 80 mg/m2 on day 1 of a 28-day cycle administered concurrently with a split course of thoracic radiation (50.6 Gy in 2-Gy fractions).[ 33]
An ongoing European study is currently randomizing patients to radiotherapy alone vs daily carboplatin (15 mg/m2) in combination with radiation (66 Gy in 33 fractions over 6 weeks and 3 days), following induction therapy with cisplatin and vinorelbine. Among the first 190 randomized patients, 141 received the full dose of radiation therapy. Overall toxicity was comparable in both arms. An evaluation performed 1 month after the end of treatment showed an objective local response rate of 72% and local stabilization in 23%.
Hypoxic cells are more resistant to irradiation (because of the radiosensitizing effects of oxygen) and also to standard chemotherapy (because hypoxic tumors often have poor blood flow). Tirapazamine is an investigational hypoxic cytotoxin with selective toxicity to hypoxic cells; it has been shown to enhance survival in patients with advanced NSCLC when combined with standard chemotherapy compared to chemotherapy alone, and it could be an interesting drug to use as a radiosensitizer.
Systemic chemotherapy for patients with advanced NSCLC prolongs survival and palliates symptoms compared with best supportive care alone, despite a modest improvement in survival reported in the MRC-IGR meta-analysis. The low cure rate for NSCLC can be attributed to the high rate of metastasis at diagnosis and the inability to cure metastatic disease. The 5-year survival of patients with metastatic disease is less than 5%. The MRC-IGR meta-analysis included a total of 1,190 patients with advanced disease, and the results suggest that cisplatin-based chemotherapy may have a role in the treatment of such patients. This approach reduced the risk of death by 27% (P < .0001), improved median survival by 6 weeks, and improved the survival rate by 10% at 1 year.
The combinations of cisplatin/etoposide, cisplatin/vinblastine, and cisplatin/ vindesine were considered standard regimens for NSCLC in the early 1980s, with cisplatin being the cornerstone. Cisplatin is associated with a response rate of 20% when used as a single agent in this population. More recently, several new agents have become available for the treatment of NSCLC, including antimicrotubule agents (paclitaxel and docetaxel), a vinca alkaloid (vinorelbine), an antimetabolite (gemcitabine), and topoisomerase I inhibitors (topotecan [Hycamtin] and irinotecan). Randomized trials comparing new platinum-based combinations with older combinations or singleagent therapy with cisplatin underscore the greater therapeutic potential of the newer agents.
Newer Cisplatin Combinations
In four phase III trials comparing new cisplatin doublets with singleagent cisplatin, the authors reported the superiority of the combination therapies in terms of response, survival, and time to progression.[38-41] The activity of the new combinations was confirmed in at least five randomized trials, although survival times proved to be lower than those predicted by earlier phase II studies.[42-46] These trials all suggested that platinum-based chemotherapy regimens incorporating the new agents consistently offered median survivals of 9 to 10 months and 1-year survival rates near 40%.
Recent randomized studies have compared the most commonly used platinum-based doublets. The Eastern Cooperative Oncology Group (ECOG) 1594 study compared cisplatin plus 24-hour paclitaxel with cisplatin plus docetaxel, cisplatin plus gemcitabine, and carboplatin plus 3-hour paclitaxel. No differences in survival were observed between treatment arms. This trial documented a disappointingly low response rate (15.3%) for paclitaxel/carboplatin (with the highest median survival of 8.3 months) and survival rates of only 21.3% and 21% for paclitaxel/cisplatin and gemcitabine/cisplatin, respectively. The 1-year survival rate was similar in all arms, ranging from 31% for the docetaxel/cisplatin arm to 36% for the gemcitabine/cisplatin arm. All regimens proved to be nearly equal in efficacy (Table 2), and although they are associated with different toxicity profiles and rates of toxicity, these differences may not necessarily have a significant impact on the patient's quality of life.
The Southwest Oncology Group (SWOG) conducted a randomized phase III trial of paclitaxel and carboplatin vs the SWOG standard treatment of vinorelbine/cisplatin (Table 3). Both regimens produced survival outcomes comparable to those reported in ECOG 1594 despite higher response rates.
The Italian Lung Cancer Study Group compared cisplatin/gemcitabine vs paclitaxel/carboplatin vs cisplatin/ vinorelbine in untreated inoperable NSCLC. An evaluation of toxicity data showed that all three regimens were well tolerated. Nevertheless, there was more myelosuppression with the gemcitabine- and vinorelbine-containing regimens (without clinical consequence), and the extent of thrombocytopenia was lower when cisplatin/ gemcitabine was administered on a 21-day schedule rather than the traditional 28-day schedule.
That said, the Italian study failed to demonstrate a therapeutic advantage for any of the three regimens in terms of survival or response (Table 4). These results are consistent with the results of the ECOG and SWOG trials, providing further evidence that all of these regimens remain reasonable choices for patients with advanced NSCLC.
A Spanish Lung Cancer trial showed no difference in efficacy with the use of a three-drug regimen vs a two-drug regimen. The two-drug regimen had a better toxicity profile, and there was no advantage to using a sequential doublet regimen without a platinum agent (Table 5).
In addition, a trial by the European Organization for Research and Treatment of Cancer, EORTC 08975, revealed no significant differences in response between the paclitaxel/ cisplatin, gemcitabine/cisplatin, and paclitaxel/gemcitabine arms. In this trial, the nonplatinum regimen had an inferior survival rate, but this result did not reach statistical significance (P = .09).
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