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The prognosis of patients with advanced non–small-cell lung cancer(NSCLC) remains poor. Systemic chemotherapy prolongs survivalin this group of patients and palliates symptoms compared to bestsupportive care alone but more effective therapeutic strategies areneeded. Novel agents that selectively target biological pathways oftumor growth offer hope of improving response and survival ratesbeyond what has been achieved with standard cytotoxic chemotherapy.Part 2 of this two-part article addresses the role of chemotherapy inlocally advanced and advanced NSCLC, including the use of novelagents, considerations in elderly patients, and studies of second-linetreatment.
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.
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.
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.
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.
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%).
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.
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).
Although chemotherapy can improve survival rates for patients with advanced NSCLC, the median survival is still less than 1 year. Nevertheless, novel agents that selectively target biological pathways of tumor growth offer hope beyond what has been achieved so far with standard cytotoxic chemotherapy.
Pemetrexed (Alimta) is a novel, multitargeted antifolate that inhibits several enzymes of the folate pathways and has demonstrated a broad spectrum of clinical activity in multiple tumor types, including NSCLC in both the front-line and refractorydisease settings. Two phase II studies of pemetrexed monotherapy as first-line treatment were conducted in patients with NSCLC-one by a Canadian investigator and the other by Australian and South African investigators. Response rates were 23% and 17%, and the median survival was 9.6 and 9.8 months, respectively.[ 52,53] Two other phase II studies demonstrated that the combination of pemetrexed and cisplatin as first-line therapy is active and tolerable in patients with advanced NSCLC.[54,55]
The combination of pemetrexed and gemcitabine was evaluated in a phase I study in which gemcitabine was administered on days 1 and 8 and pemetrexed on day 8 every 3 weeks. The recommended phase II dose of gemcitabine was 1,250 mg/m2 and of pemetrexed, 500 mg/m2. A two-stage phase II trial of gemcitabine and pemetrexed in chemonaive patients with locally advanced or metastatic NSCLC was conducted in the United States and France, and the results will be presented soon.
Pemetrexed has also shown activity in the second-line setting as a single agent. Its impact seems to be more significant in patients who have failed non-platinum-containing regimens.
Tirapazamine is a hypoxic cytotoxin with selective toxicity to hypoxic cells. It has proven to enhance survival (34.6 vs 27.7 weeks) in patients with advanced NSCLC when combined with standard chemotherapy vs chemotherapy alone. In two phase II trials in unresectable NSCLC patients, tirapazamine (260-390 mg/m2) administered as a 1-to 3-hour infusion followed 1 to 3 hours later by cisplatin (75 mg/m2) produced response rates of 23% and 29%.[58,59]
In the Cisplatin and Tirapazamine Against Previously Untreated Lung Tumors (CATAPULT) II study, 550 patients with advanced NSCLC were randomized to receive cisplatin/etoposide or cisplatin/tirapazamine. An overall response rate of 25% was reported for both arms, with the median survival (31.4 vs 26.7 weeks) and 1-year survival (28.8% vs 21%) higher for the cisplatin/etoposide combination. Recently, a French trial evaluated the combination of vinorelbine, tirapazamine, and cisplatin in inoperable NSCLC patients. Results showed promising activity and were the basis of a large phase III study.
There is considerable evidence that the epidermal growth factor receptor (EGFR) is overexpressed in a broad range of human cancers including NSCLC. The oral agent ZD1839 (Iressa) is a specific and potent inhibitor of EGFR-associated tyrosine kinase. Several randomized trials of ZD1839 alone or in combination with gemcitabine/cisplatin or paclitaxel/ carboplatin have been conducted in Europe and the United States.[63,64] Although these trials were robust (with more than 1,000 patients enrolled in each trial) and well designed, ZD1839 produced no additional benefit in survival or in any of the other end points when combined with cisplatin/ gemcitabine or carboplatin/ paclitaxel.
Another inhibitor of EGFR, erlotinib (OSI-774, Tarceva), has been used as second-line therapy in patients with NSCLC who previously received cisplatin-based chemotherapy and had tumors composed of more than 10% EGFR-positive cells. Patients given 150 mg of erlotinib daily achieved a response rate of 12.3%, a median survival of 8.5 months, and a 1-year survival of 48%.
The results of a phase I/II study of ISIS 3521, an antisense oligonucleotide inhibitor of protein kinase C-alpha, were also recently reported. Patients with chemonaive advanced NSCLC received escalating doses of ISIS 3521 via 14-day continuous infusion, along with carboplatin (AUC of 6) and paclitaxel (175 mg/m2) on day 4. The overall response rate was 46%, with a median survival of 15.9 months. The most common grade 3/4 adverse events were neutropenia (26%/43%) and thrombocytopenia (21%/11%).
Elderly patients with lung cancer constitute a critical group that has been underrepresented in previous lung cancer studies. In the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS), single-agent vinorelbine produced a significant improvement in survival compared with best supportive care.
The same Italian group recently reported the first analysis of the phase III Multicenter Italian Lung Cancer in the Elderly Study (MILES), in which patients older than age 70 years with stage IIIB/IV NSCLC were randomized to receive vinorelbine vs gemcitabine vs gemcitabine/vinorelbine (Table 6). There was no difference in response or survival between the combination and singleagent groups. However, the combination produced significantly more myelosuppression.
Data from the ELVIS and MILES trials support the use of single-agent chemotherapy in patients over 70. In addition, two recently reported analyses of the ECOG and European vinorelbine studies suggested that performance status, not age, should be the key criterion in selecting patients for treatment.[69,70]
With current chemotherapy regimens producing 1-year survival rates of approximately 40%, second-line treatment has become an important issue for patients whose disease progresses after first-line treatment with platinum-based combinations. Failure of first-line chemotherapy is predictive of the development of resistant clones, and the question of non-cross-resistance between novel agents and cisplatin has not been fully answered. Also in NSCLC, the delay between the completion of firstline cisplatin-based chemotherapy and relapse is not clearly predictive of response to second-line therapy.
In previously treated patients, response rates to single-agent vindesine, etoposide, epirubicin (Ellence), and cisplatin have not exceeded 10%. With the advent of novel agents, the use of second-line therapy must be reconsidered. Studies of paclitaxel,[ 72-75] vinorelbine, irinotecan,[ 77,78] and gemcitabine,[79,80] have produced response rates ranging from 0% to 23% (Table 7).
Of the second-generation agents with activity against previously treated NSCLC, docetaxel has appeared promising, with response rates of approximately 20% in the initial phase II studies and with some activity against platinum-resistant or refractory NSCLC.[81,82] These data led to two large phase III randomized trials (Table 8) that compared (1) docetaxel at 100 mg/m2 or 75 mg/m2 to best supportive care, and (2) docetaxel at 100 mg/m2 or 75 mg/m2 to vinorelbine or ifosfamide (Ifex) in patients previously treated with platinumbased therapy.[83,84]
In the trial of docetaxel vs best supportive care, the docetaxel group (at the 75-mg/m2 dose) had a longer median survival and statistically better quality-of-life assessments (pain, fatigue, and use of cancer-related medications) compared to best supportive care. The second trial confirmed the statistical advantage of docetaxel in the second-line setting and showed that the lower dose (75 mg/m2) was associated with a notably superior survival compared to the higher dose (100 mg/m2). This probably stems from the higher rates of toxicity, mainly neutropenia, in patients receiving the 100-mg/m2 dose. Docetaxel is the only drug specifically registered for second-line treatment of NSCLC in the United States.
Drugs such as pemetrexed and other targeted agents, have already shown promising activity in secondline therapy. Although the survival benefit concerns a small proportion of the population, better definition of candidates might allow more appropriate selection, avoiding useless toxicity and expenses among those who would gain no benefit from secondline treatment.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Johnson DH: Locally advanced, unresectablenon-small cell lung cancer: New treatmentstrategies. Chest 117:123S-126S, 2000.
Perez CA, Stanley K, Grundy G, et al:Impact of irradiation technique and tumor extentin tumor control and survival of patientswith unresectable non-small-cell lung carcinoma:Report by the Radiation Therapy OncologyGroup. Cancer 50:1091-1099, 1982.
Cox JD, Azarnia N, Byhardt RW, et al: Arandomized phase I/II trial of hyperfractionatedradiation therapy with total doses of 60.0 Gyto 79.2 Gy: Possible survival benefit with 69.6Gy in favorable patients with Radiation TherapyOncology Group stage III non-small-celllung carcinoma: Report of Radiation TherapyOncology Group 83-11. J Clin Oncol 8:1543-1555, 1990.
Saunders M, Dische S, Barrett A, et al:Continuous hyperfractionated accelerated radiotherapy(CHART) versus conventional radiotherapyin non-small cell lung cancer: Arandomized multicentre trial. CHART SteeringCommittee. Lancet 350:161-165, 1997.
Saunders MI, Rojas A, Lyn BE, et al:Experience with dose escalation usingCHARTWEL (continuous hyperfractionatedaccelerated radiotherapy weekend less) in nonsmall-cell lung cancer. Br J Cancer 78:1323-1328, 1998.
Dillman RO, Herndon J, Seagren SL, etal: Improved survival in stage III non-smallcelllung cancer: Seven-year follow-up of cancerand leukemia group B (CALGB) 8433 trial.J Natl Cancer Inst 88:1210-1215, 1996.
Le Chevalier T, Arriagada R, Quoix E, etal: Radiotherapy alone vs combined chemotherapyand radiotherapy in nonresectable nonsmall-cell lung cancer: First analysis of arandomized trial in 353 patients. J Natl CancerInst 83:417-423, 1991.
Mattson K, Holsti LR, Holsti P, et al:Inoperable non-small cell lung cancer: Radiationwith or without chemotherapy. Eur J CancerClin Oncol 24:477-482, 1988.
Dillman RO, Seagren SL, Propert KJ, etal: A randomized trial of induction chemotherapyplus high-dose radiation versus radiationalone in stage III non-small-cell lung cancer. NEngl J Med 323:940-945, 1990.
Sause WT, Scott C, Taylor S, et al: RadiationTherapy Oncology Group (RTOG) 88-08and Eastern Cooperative Oncology Group(ECOG) 4588: Preliminary results of a phaseIII trial in regionally advanced unresectablenon-small-cell lung cancer. J Natl Cancer Inst87:198-205, 1995.
Arriagada R, Le Chevalier T, Quoix E, etal: ASTRO (American Society for TherapeuticRadiology and Oncology) plenary: Effect ofchemotherapy on locally advanced non-smallcell lung carcinoma: A randomized study of353 patients. GETCB (Groupe d’Etude et Traitementde Cancers Bronchiques), FNCLCC(Federation Nationale des Centres de Lutte contrele Cancer), and the CEBI trialists. Int JRadiat Oncol Biol Phys 20:1183-1190, 1991.
Le Chevalier T, Arriagada R, Tarayre M,et al: Significant effect of adjuvant chemotherapyon survival in locally advanced non-smallcellcarcinoma. J Natl Cancer Inst 84:58, 1992.
Furuse K, Fukuoka M, Kawahara M, etal: Phase III study of concurrent versus sequentialthoracic radiotherapy in combinationwith mitomycin, vindesine, and cisplatin in unresectablestage III non-small cell lung cancer.J Clin Oncol 17:2692-2699, 1999.
Curran WJ, Scott C, Langer C, et al :Phase III comparison of sequential vs concurrentchemoradiation for patients (Pts) with unresectedstage III non-small cell lung cancer(NSCLC): Initial report of Radiation TherapyOncology Group (RTOG) 94-10 (abstract1891). Proc Am Soc Clin Oncol 19:484a, 2000.
Mosvas B, Scott C, Curran W, et al: Aquality-adjusted time without symptoms of toxicity(QTWiST): Analysis of Radiation TherapyOncology (RTOG) 94-10 (abstract 1247).Proc Am Soc Clin Oncol 20:313a, 2001.
Pierre F, Maurice G, Gilles R, et al : Arandomized phase III trial of sequential chemoradiotherapyversus concurrent chemo-radiotherapyin locally advanced non-small cell lungcancer (NSCLC) (GLOT-GFPC NPC 95-01study) (abstract 1246). Proc Am Soc Clin Oncol20:312a, 2001.
. Vogt HG, Martin T, Kolotas C, et al:Simultaneous paclitaxel and radiotherapy: Initialclinical experience in lung cancer and othermalignancies. Semin Oncol 24(suppl 12):S12-101-S12-105, 1997.
Choy H, Akerley W, Safran H, et al:Concurrent weekly paclitaxel and radiation therapyfor locally advanced non-small cell lungcancer. Lung Cancer 18(suppl 1):70, 269a,1997.
Lau DHM, Ryu JK, Gandara DR, et al:Twice-weekly paclitaxel and radiation for stageIII non-small cell lung cancer. Semin Oncol24(suppl 12):106-109, 1997.
Marangolo M, Emiliani E, Rosti G, et al:Phase I/II study of paclitaxel and radiotherapyin non-small cell lung cancer. Semin Oncol23(suppl 16):124-127, 1996.
Choy H, DeVore RF III, Hande KR, etal: Preliminary analysis of a phase II study ofpaclitaxel, carboplatin, and hyperfractionatedradiation therapy for locally advanced inoperablenon-small cell lung cancer. Semin Oncol24(suppl12):S12-21-S12-26, 1997.
Lopez-Picazo JM, Azinovic I, Aristu JJ,et al: Induction platinum-based chemotherapyfollowed by radical hyperfractionated radiotherapywith concurrent chemotherapy in thetreatment of locally advanced non-small-cellcarcinoma of the lung. Am J Clin Oncol 22:203-208, 1999.
Langer CJ, Movsas B, Hudes R, et al:Induction paclitaxel and carboplatin followedby concurrent chemoradiotherapy in patientswith unresectable, locally advanced non-smallcell lung carcinoma: Report of Fox Chase CancerCenter Study 94-001. Semin Oncol 24(suppl12):89-95, 1997.
Curran WJ, Scott C, Bonomi P, et al:Initial report of locally advanced multimodalityprotocol (LAMP): ACR 427: A randomized3-arm phase II study of paclitaxel (T), carboplatin(C), and thoracic radiation (TRT) forpatients with stage III non-small cell lung cancer(NSCLC) (abstract 1244). Proc Am SocClin Oncol 20:312a, 2001.
Choy H, Nabid A, Stea B, et al: Positivephase II results of RSR13 and concurrent radiationtherapy after induction chemotherapy withpaclitaxel and carboplatin for locally advancedinoperable non-small cell lung cancer (abstract1248). Proc Am Soc Clin Oncol 20:312a, 2001.
Vokes EE, Leopold KA, Herndon JE, etal: CALGB study 9431: A randomized phase IIstudy of cisplatin with gemcitabine or paclitaxelor vinorelbine with cisplatin as inductionchemotherapy (Ind CT) and concomitantchemoradiotherapy (XRT) for unresectablestage III non-small cell lung cancer (NSCLC).Lung Cancer 29(suppl 1):A158, 2000.
Choy H, DeVore RF, Porter LL, et al :Phase I trial of outpatient weekly docetaxel(DTX) carboplatin (CBDCA) and concurrentthoracic radiation therapy (TRT) for stage IIIunresectable non-small-cell lung cancer: AVanderbilt Cancer Center affiliate network (VCCAN)trial (abstract 1833). Proc Am Soc ClinOncol 18:475a, 1999.
Scalliet P, Goor C, Galdermans D, et al:Gemzar (Gemcitabine) with thoracic radiotherapy-a phase II pilot study in chemonaive patientswith advanced non-small cell lung cancer(NSCLC) (abstract 1923). Proc Am Soc ClinOncol 17:499a, 1998.
Fossella FV, Zinner RG, Komaki R, etal: Gemcitabine (G) with concurrent chest radiation(XRT) followed by consolidation chemotherapywith gemcitabine plus cisplatin(CDDP): A phase I trial for patients with stageIII Non-Small Cell Lung Cancer (NSCLC) (abstract1996). Proc Soc Am Clin Oncol 19:510a,2000.
Gridelli C, Guida C, Barletta E, et al:Thoracic radiotherapy and daily vinorelbine asradiosensitizer in locally advanced non-smallcell lung cancer: a phase I study. Lung Cancer29:131-137, 2000.
Garst J, Shafman T, Campagna L, et al:A phase II study of concurrent multidose vinorelbinewith definitive radiation therapy forinoperable stage III non-small cell lung cancer(abstract 1368). Proc Am Soc Clin Oncol20:343a, 2001.
Zatloukal P, Petruzelka L, Zemanova M,et al: Concurrent versus sequential radiochemotherapywith vinorelbine plus cisplatin in nonsmallcell lung cancer. A randomised phase IIstudy (abstract 1976). Proc Am Soc Clin Oncol19:505a, 2000.
Fukuda M, Soda H, et al: Phase I studyof irinotecan (CPT-11) and cisplatin (CDDP)with concurrent thoracic radiotherapy (TRT)in locally advanced non-small cell lung cancer(NSCLC) (abstract 1976). Proc Am Soc ClinOncol 18:466a, 1999.
Douillard JY, Riviere A, Ducolone A, etal: Navelbine (NVB)-cisplatin (CDDP) inductionchemotherapy (ICT) followed by radiationwith or without daily carboplatin (CBDCA) inlocally advanced unresectable non-small celllung cancer: Intermediate analysis of a French,multicenter phase III randomized trial. LungCancer 29 (suppl 1):A379, 2000.
Brown JM: SR 4233 (tirapazamine): Anew anticancer drug exploiting hypoxia in solidtumors. Br J Cancer 67:1163-1170, 1993.
Von Pawel, von Roemeling R: Survivalbenefit from Tirazone (tirapazamine) and cisplatinin advanced non-small cell lung cancer(NSCLC) patients: Final results from the internationalphase III CATAPULT I trial (abstract1749). Proc Am Soc Clin Oncol 17:454a, 1998.
Non-Small Cell Lung Cancer CollaborativeGroup: Chemotherapy in non-small celllung cancer: A meta-analysis using updateddata on individual patients from 52 randomizedclinical trials. Br Med J 311:899-909, 1995.
Wozniak AJ, Crowley JJ, Balcerzak SP,et al: Randomized trial comparing cisplatin withcisplatin plus vinorelbine in the treatment ofadvanced non-small-cell lung cancer. A SouthwestOncology Group Study. J Clin Oncol16:2459-2465, 1998.
Sandler AB, Nemunaitis J, Denham C, etal: Phase III trial of gemcitabine plus cisplatinvs cisplatin alone in patients with locally advncedor metastatic non-small-cell lung cancer.J Clin Oncol 18:122-130, 2000.
Gatzemeier U, von Pawel J, Gottfried M,et al: Phase III comparative study of high-dosecisplatin versus a combination of paclitaxel andcisplatin in patients with advanced non-smallcelllung cancer. J Clin Oncol 18:3390-3399,2000.
Von Pawel J, von Roemeling R, GatzemeierU, et al: Tirapazamine plus cisplatin versuscisplatin in advanced non-small-cell lungcancer: A report of the international CATAPULT1 study group. Cisplatin and tirapazaminein subjects with advanced previously untreatednon-small-cell lung tumors. J Clin Oncol18:1351-1359, 2000.
LeChevalier T, Brisgand D, DouillardJY, et al: Randomised study of vinorelbine andcisplatin versus vindesine and cisplatin versusvinorelbine alone in non-small-cell lung cancer.Results of an European multicenter trialincluding 612 patients. J Clin Oncol 12:360-367, 1994.
Bonomi P, Kim K, Chang A, et al: PhaseIII trial comparing etoposide/cisplatin versustaxol with cisplatin G-CSF versus Taxol/cisplatinin advanced non-small cell lung cancer(abstract). Proc Am Soc Clin Oncol 15:382a,1996.
Crino L, Scagliotti GV, Ricci S, et al:Gemcitabine and cisplatin versus mitomycin,ifosfamide, and cisplatin in advanced nonsmall-cell lung cancer: A randomized phase IIIstudy of the Italian Lung Cancer Project. J ClinOncol 17:3522-3530, 1999.
Belani CP, Natale RB, Lee JS, et al:Randomized phase III trial comparino cisplatin/etoposide versus carboplatin/paclitaxel inadvanced and metastatic non-small-cell lungcancer (NSCLC) (abstract 1751). Proc Am SocClin Oncol 17:455a, 1998.
Cardenal F, Lopez-Cabrerizo MP, AntonA, et al: Randomised phase III study ofgemcitabine-cisplatin versus etoposide-cisplatinin the treatment of locally advanced and metastaticnon-small-cell lung cancer. J Clin Oncol17:12-18, 1999.
Schiller JH, Harrington D, Sandler A, etal: Randomised phase III trial of four chemotherapyregimens in advanced non-small celllung cancer (NSCLC) (abstract 2). Proc AmSoc Clin Oncol 19:1a, 2000.
Kelly K, Crowley J, Bunn PA, et al: Arandomised phase III trial of paclitaxel pluscarboplatin (PC) versus vinorelbine plus cisplatin(VC) in untreated advanced non-small celllung cancer (NSCLC): A Southwest OncologyGroup (SWOG) trial (abstract 1777). Proc AmSoc Clin Oncol 18:461a, 1999.
Scagliotti GV, DeMarinis F, Rinaldi M,et al: Phase III randomized trial comparino threeplatinum-based doublets in advanced non-smallcell lung cancer (abstract 1227). Proc Am SocClin Oncol 20:308a, 2001.
Alberola V, Camps C, Provencia M, etal: Cisplatin/gemcitabine vs cisplatin/gemcitabine/vinorelbine vs sequential doublets ofgemcitabine/vinorelbine followed by ifosfamide/vinorelbine in advanced non-small celllung cancer: Results of a Spanish Lung CancerGroup phase III trial (GEPC/98-02) (abstract1229). Proc Am Soc Clin Oncol 20:308a, 2001.
Van Meerbeeck J, Smit F, Lianes P, et al:A EORTC randomized phase III trial of threechemotherapy regimens in advanced non-smallcell lung cancer (abstract 1228). Proc Am SocClin Oncol 20:308a, 2001.
Rusthoven J, Eisenhauer E, Butts C, etal: a phase II study of the multi-targeted antifolateLY231514 in patients with advanced nonsmallcell lung cancer (abstract 1728). Proc AmSoc Clin Oncol 16:480a, 1997.
Clarke S, Millward M, Findlay M, et al:activity of the multi-targeted antifolate MTA(LY231514) in advanced non-small-cell lungcancer (NSCLC) (abstract 416P). Ann Oncol 9(suppl 4):86, 1998.
Manegold C, Gatzemeier U, von PawelJ, et al: Front-line treatment of advanced nonsmall-cell lung cancer with MTA (LY231514,pemetrexed, ALIMTA) and cisplatin: A multicenterphase II trial. Ann Oncol 11:435-440,2000.
Shepherd F, Arnold A, Neville A, et al:Phase II study of MTA (ALIMTA) and cisplatinin patients with advanced non-small celllung cancer (NSCLC) (abstract 1984). ProcAm Soc Clin Oncol 19:507a, 2000.
Adjei AA, Erlichman C, Sloan JA, et al:A phase I and pharmacologic study of sequencesof gemcitabine and the multitargeted antifolateagent (MTA) in patients with advancedsolid tumors. J Clin Oncol 18(8):1748-1757,2000.
Postmus PE, Karen M, von Pawel C, etal: Phase II trial of MTA (LY231514) in patientswith NSCLC who relapsed after previousplatinum or non-platinum therapy. ECCO 1999.
Rodriguez GI, Valdivieso M, Von HoffDD, et al: A phase I/II trial of the combinationof tirapazamine and cisplatin in patients withnon-small cell lung cancer (abstract). Proc AmSoc Clin Oncol 15:382, 1996.
Treat J, Haynes B, Johnson E, et al:Tirapazamine with cisplatin: A phase II trial inadvanced stage non-small cell lung cancer (abstract).Proc Am Soc Clin Oncol 16:455a, 1997.
Shepherd F, Loschel E, von Pawel T, etal: Comparison of Tirazone (tirapazamine) andcisplatin vs etoposide and cisplatin in advancednon-small cell lung cancer (NSCLC):Final resultsof the international phase III CATAPULTII trial (abstract 87). Lung Cancer 29(suppl1):28, 2000.
Le Chevalier T, Gatineau M, Daniel C, etal: Phase II study of the combination of vinorelbine,cisplatin, and tirapazamine in advancednon-small cell lung cancer (NSCLC)(abstract 1894). Proc Am Soc Clin Oncol18:491a, 1999.
Salomon DS, Brandt R, Fortunato C, etal: Epidermal growth factor-related peptidesand their receptors in human malignancies. CritRev Oncol Hematol 19:183-232, 1995.
Giaccone G, Johnson DH, Manepold C,et al: A phase III clinical trial of ZD1839 (‘Iressa’)in combination with gemcitabine and cisplatinin chemotherapy-naive patients withadvanced nonâsmall-cell lung cancer (INTACT1). Ann Oncol (suppl 5):abst 4, 2002.
Johnson DH, Herbst R, Giaccone G, etal: ZD1839 (‘Iressa’) in combination with paclitaxeland carboplatin in chemotherapy-naivepatients with advanced nonâsmall-cell lung cancer(NSCLC): Results from a phase III clinicaltrial (INTACT 2). Ann Oncol (suppl 5):abst468, 2002.
Perez-Soler R, Chachoua A, HubermanM, et al: A phase II trial of the epidermal growthfactor receptor (EGFR) tyrosine kinase inhibitorOSI-774 following platinum-based chemotherapyin patients with advanced EGFRexpressing non-small cell lung cancer (abstract1235). Proc Am Soc Clin Oncol 20:310a, 2001.
Yuen A, Halsey J, Fisher G, et al: PhaseI/II trial of ISIS 3521, an antisense inhibitor ofPKC-alpha, with carboplatin and paclitaxel innon-small cell lung cancer (abstract 1234). ProcAm Soc Clin Oncol 20:309a, 2001.
Gridelli C: Effects of vinorelbine on qualityof life and survival of elderly patients withnon-small-cell lung cancer. The Elderly LungCancer Vinorelbine Italian Study Group. J NatlCancer Inst 91:66-72, 1999.
Gridelli C, Perrone F, Cigolari S, et al:The MILES (Multicenter Italian Lung cancerin the Elderly Study) phase III trial:Gemcitabine+vinorelbine vs vinorelbine vsgemcitabine in elderly advanced NSCLC patients(abstract 1230). Proc Am Soc Clin Oncol20:308a, 2001.
Langer C, Manola J, Bernardo P, et al:Advanced age alone does not compromise outcomein fit non-small cell lung cancer (NSCLC)patients (pts) receiving platinum (DDP)-basedtherapy (TX): Implication of ECOG 5592 (abstract1912). Proc Am Soc Clin Oncol 18:489a,2000.
Soria JC, Brisgand D, Le Chevalier T:Do all patients with non-small-cell lung cancerbenefit from cisplatin-based combination therapy?Ann Oncol 12:1667-1670, 2001.
Belani CP: Single agents in the secondlinetreatment of non-small-cell lung cancer.Semin Oncol 25:10-14, 1998.
Murphy WK, Winn RJ, Huber M, et al:Phase II study of taxol (T) in patients (pts) withnon-small cell lung cancer (NSCLC) who havefailed platinum (P) containing chemotherapy(Ctx). Proc Am Soc Clin Oncol 13:1224, 1994.
Ruckdeschel J, Wagner H Jr, WilliamsC, et al: Second-line chemotherapy for resistantmetastatic, non-small cell lung cancer(NSCLC): The role of Taxol (TAX). Proc AmSoc Clin Oncol 13:357, 1994.
Socinski MA, Steagal A: Phase II trial of96 hour paclitaxel infusion in patients with nonsmallcell lung cancer failing previous platinumbased or short duration paclitaxel therapy.Proc Am Soc Clin Oncol 16:1735, 1997.
Hainsworth JD, Thompson DS, GrecoFA: Paclitaxel by 1-hour infusion: An activedrug in metastatic non-small cell lung cancer. JClin Oncol 13:1609-1614, 1995.
Rinaldi M, Della GM, Venturo I, et al:Vinorelbine as single agent in the treatment ofadvanced NSCLC (abstract). Proc Am Soc ClinOncol 13:360, 1994.
Nakai H, Fukuoka M, Furuse K, et al: Anearly phase II study of CPT-11 for primarylung cancer. Jpn J Cancer Chemother 18:607-612, 1991.
Negro S, Fukuoka M, Niitani H, et al: Aphase II study of CPT-11, a camptothecin derivative,in patients with primary lung cancer.CPT-11 cooperative study group (Japanese).Gan To Kagaku Ryoho 18:1013-1019, 1991.
Crino L, Mosconi AM, Scagliotti GV, etal: Salvage therapy with Gemcitabine (GEM)in pretreated, advanced non-small-cell lung cancer(NSCLC) (abstract). Proc Am Soc Clin Oncol16:446a, 1997.
Gridelli C, Perrone F, Gallo C, et al:Single-agent gemcitabine as second-line treatmentin patients with advanced non-small-celllung cancer (NSCLC): A phase II trial (In processcitation). Anticancer Res 19:4535-4538,1999.
Fossella FV, Lee JS, Shin DM, et al:Phase II study of docetaxel for advanced ormetastatic platinum refractory non-small celllung cancer. J Clin Oncol 13:645-651, 1995.
Fossella FV, Lee JS, Berille J, et al:Summary of phase II data of docetaxel (Taxotere),an active agent in the first- and secondlinetreatment of advanced non-small-cell lungcancer. Semin Oncol 22:22-29, 1995.
Fossella FV, DeVore R, Kerr Rea: PhaseIII trial of docetaxel 100 mg/m2 or 75 mg/m2versus vinorelbine/ifosfamide for NSCLC previouslytreated with platinum-based chemotherapy(abstract 1776). Proc Am Soc ClinOncol 18:460a, 1999.
Shepherd FA, Ramlau R, Mattson K, etal: Randomized study of taxotere versus bestsupportive care (BSC) in NSCLC patients previouslytreated with platinum-based chemotherapy(abstract 1784). Proc Am Soc ClinOncol 18:463a, 1999.