26.

Treatment Strategies for Advanced NonSmall Cell Lung Cancer

Authors: David R. Gandara, MD; Mark R. Green, MD; Primo N. Lara, Jr, MD; Mario L. Meyer, MD Published: 09/22/2003; Updated: 09/29/2003

Management of Unresectable Stage III NSCLC Introduction

The optimal treatment of patients with locally advanced, unresectable (or stage III) non-small cell lung cancer (NSCLC), many of whom have bulky mediastinal lymphadenopathy (N2 of N3) or primary tumors invading vital structures (T4), has continued to evolve in the last decade. In the past, only a small fraction (< 5%) with stage III disease achieved long-term survival when treated with surgery or radiation therapy alone. Data from recent clinical trials have demonstrated therapeutic advances in the application of combined modality therapy (ie, chemoradiation) in this patient population.[1] Specifically, recent phase 3 trials have yielded enhanced survival in patients with good performance status scores when treated with concurrent platinum-based chemoradiation vs sequential administration of chemotherapy followed by radiation therapy. Rationale for Chemoradiation Therapy Theoretically, chemoradiation combinations have several advantages. Local therapy with radiation or surgery aims to control and sterilize the intrathoracic tumor compartment while chemotherapy works to eradicate systemic micrometastases. Chemotherapy is also active within the thorax, working as a radiosensitizer, and provides cytoreduction of bulky locoregional disease. This paradigm of chemoradiation has been established not only for locally advanced NSCLC but also for such tumor types as cervical[2] and head and neck cancer.[3] Various approaches to combined chemotherapy and radiation therapy have been used in unresectable stage III NSCLC, including sequential chemotherapy followed by radiation, concurrent chemoradiotherapy, induction chemotherapy followed by concurrent chemoradiotherapy, and concurrent chemoradiotherapy followed by consolidation chemotherapy.[4] Each approach has theoretical advantages and disadvantages, as outlined in Table 1. In general, sequential approaches to chemoradiotherapy, in which full-dose platinum-based chemotherapy precedes thoracic radiation, improve survival outcomes by reducing distant failure rates, while administration of low doses of chemotherapy concurrent with radiation does so by reducing local failure rates. More recently, randomized trials conducted by the West Japan Lung Cancer Group and the Radiation Therapy Oncology Group (RTOG) have directly compared sequential and

concurrent chemoradiotherapy regimens. Each demonstrated superior survival with the concurrent approach, as discussed below. Emerging data also suggest that full-dose chemotherapy designed to eradicate distant micrometastases given either as induction or consolidation therapy may further improve patient outcomes. Since distant metastases remain the major site of failure, more effective systemic treatments will be required to improve the current level of response and survival.

Table 1. Approaches to Combining Chemotherapy and Thoracic Radiation: Theoretical Advantages and Disadvantages
Sequence Chemo --> RT Theoretical Advantages Full doses of each therapy can be delivered without combined toxicity. Cytoreduction from chemotherapy may allow smaller radiation portals, decreasing radiation toxicity. Also may decrease relatively radioresistant regions of hypoxia. Chemo + RT Exploits potential synergy between the modalities. Enhanced toxicity leads to inability to deliver full dose of both modalities. No pre-RT cytoreduction. Chemo --> Chemo+RT Cytoreduction from induction Chemotherapy-insensitive chemotherapy may allow smaller radiation disease continues to grow and portals, decreasing radiation toxicity. potentially metastasize before CMT begins. Full-dose chemotherapy may sterilize micrometastatic disease while clonogen Enhanced toxicity; completing number is minimal. CMT after induction chemotherapy may be too difficult for all but the best performance status patients. Delivers maximal antitumor efficacy up front. Exploits potential synergy between modalities. Most intense treatment is given early Long treatment schedule. Enhanced toxicity; completing CMT after induction chemotherapy may be too difficult for all but the best performance status patients. Theoretical Disadvantages No benefit from potential radiosensitizing action of the chemotherapy. Chemotherapy-insensitive disease continues to grow and may metastasize before RT begins.

Chemo + RT --> Chemo

when the patient is most physically and psychologically stable. CMT = combined modality therapy; RT = radiation therapy.

Concurrent Chemoradiation
The first trial to establish the superiority of concurrent chemoradiation over radiation alone was a study by the European Organization for Research and Treatment of Cancer (EORTC). This study, published a decade ago, compared radiation therapy alone with the same dose of radiation plus either weekly cisplatin (30 mg/m2) or daily cisplatin (6 mg/m2).[5] The survival advantage seen in patients receiving low-dose daily cisplatin with radiation was due to an improvement in local control with no change in distant metastatic rates. The results of this trial are particularly instructive, indicating that frequent administration of lowdose chemotherapy can improve outcomes solely through radiosensitization. However, this study incorporated split-course radiation therapy, a suboptimal strategy because of potential tumor cell repopulation during the "off" period. In addition, the total radiation dose of 55 Gy (30 + 25 Gy split) is no longer considered sufficient for curative treatment. Daily cisplatin also results in cumulative nausea and is logistically difficult to deliver. As a result, this regimen has limited clinical applicability. Two consecutive trials by Jeremic and colleagues[6,7] investigating hyperfractionated radiation therapy provide additional evidence for the superiority of concurrent chemoradiation over radiation alone. In the first trial, 169 patients were randomly assigned to either hyperfractionated radiotherapy alone (arm 1: 1.2 Gy twice daily to 64.8 Gy) or the same radiation concurrent with carboplatin and etoposide delivered at 2 different dose schedules (arm 2: carboplatin 100 mg on days 1 and 2 plus etoposide 100 mg days 1 to 3 given weekly; arm 3: carboplatin 200 mg on days 1 and 2 plus etoposide 100 mg days 1 to 5 on weeks 1, 3, and 5).[6] The 3-year survival rates for the treatment groups were 6.6%, 23%, and 16%, respectively. The survival rates for arms 1 and 2 were statistically different (P = .0027), but arms 1 and 3 were not. Although toxicity was higher in both chemoradiation arms, there were no treatment-related deaths. The second trial randomized 131 patients to either hyperfractionated radiotherapy alone (1.2 Gy twice daily to 69.6 Gy) or the same radiation therapy concurrent with carboplatin and etoposide delivered with each day of radiation.[7] Patients receiving concurrent chemoradiation had a 4year survival rate of 23% vs 9% in the radiation alone arm (P = .02). This survival advantage was solely due to enhanced local control, as the distant metastasis-free survival rate showed no difference between the groups. These findings mimic those observed in the earlier EORTC trial. More recently, the West Japan Lung Cancer Study Group performed a phase 3 study comparing sequential vs concurrent chemoradiotherapy (Table 2).[8] The trial involved over 300 patients and compared full-dose induction chemotherapy consisting of mitomycin, vindesine, and cisplatin followed by once-daily radiation of 56 Gy/28 fractions/5.5 weeks vs concurrent chemoradiation using the same chemotherapy regimen but with split-course radiation to a total dose of 56 Gy.

Despite using split-course radiation in the concurrent treatment arm, there was a significant survival benefit for concurrent chemoradiation.

Table 2. West Japan Lung Cancer Group Study of Concurrent vs Sequential Chemoradiation
Chemoradiation Regimen Concurrent Sequential *P = .04 The Japanese experience was affirmed in the United States following the completion of RTOG 9410, a 3-arm phase 3 trial comparing sequential vs concurrent chemoradiotherapy that also examined altered radiation fractionation as part of combined modality therapy (Table 3).[9,10] Arm 1 (standard) was identical to that of CALGB 8433, consisting of sequential administration of cisplatin and vinblastine followed by once-daily radiation of 2 Gy to a total of 60 Gy. Arm 2 (concurrent chemoradiation) used the same chemotherapy and radiation protocol as arm 1, but the thoracic radiation started concurrently with the chemotherapy on day 1. Arm 3 (concurrent hyperfractionated radiochemotherapy) used a different chemotherapy regimen (cisplatin and oral etoposide) with twice-daily radiation of 1.2 Gy/fraction to 69.2 Gy total dose over 6 weeks beginning day 1. The recently updated results of this trial demonstrate that concurrent chemotherapy with oncedaily radiation was superior to sequential treatment (median survival, 17 vs 14.6 months; P = .038), but hyperfractionated chemoradiation did not improve outcome (median survival, 15.6 months). However, hyperfractionated radiation did improve local control, decreasing in-field failure from the 38% seen with sequential therapy to 25% but also caused substantially more nonhematologic toxicity that cannot be justified in light of the failure to improve survival. These recent trials established concurrent platinum-based chemoradiation using once-daily radiation schedules as the standard of care in appropriately selected NSCLC patients with unresectable stage III disease. Response Rate 84% 66% Median Survival (months) 16.5* 13.3 3-Year Survival 22% 15% 5-Year Survival 16% 9%

Table 3. RTOG 9410: Sequential vs Concurrent Chemoradiotherapy in Unresectable Locally Advanced NSCLC
Chemotherapy Regimen Median Survival 4-Year Survival Nonhematologic Toxicity (months) (Grade 3-4) Sequential Concurrent Concurrent/HFRT 14.6 17.0* 15.2 12% 21% 17% 30% 48% 62%

*vs sequential, P = .046. vs sequential, P = .296 P < .05. HFRT = hyperfractionated radiation therapy Despite these advances, more than 75% of patients completing chemoradiation in these trials died of recurrent disease. The most common reason for failure was systemic recurrence. Therefore, identification of new systemic therapies that eradicate micrometastases is essential to improving outcome. Several new anticancer agents have become available in the past decade that demonstrate single-agent activity against NSCLC, including the taxanes (paclitaxel and docetaxel), the nucleoside analogue gemcitabine, the vinca alkaloid vinorelbine, and the topoisomerase inhibitor irinotecan.[11] Early-phase trials have evaluated the tolerability and efficacy of docetaxel with concurrent radiation in NSCLC. In a trial by Mauer and colleagues,[12] patients with thoracic malignancies (including 20 with locally advanced NSCLC) were treated with docetaxel using 1 of 3 regimens (every 3 weeks, 2 of every 3 weeks, or weekly) in escalating doses. The chemotherapy was given concurrently with daily radiation (1.8-2.0 Gy to a total dose of 60 Gy). The weekly schedule at a dose of 20 mg/m2 per week was recommended for further study based on tolerability.[13] In a second phase 2 study, docetaxel and cisplatin were given on days 1, 8, 29, and 36, with concomitant thoracic radiation (60 Gy) to 33 patients with stage III NSCLC.[14] The recommended doses for phase 2 trials were docetaxel at 40 mg/m2 and cisplatin at 40 mg/m2. Similarly, Mudad and colleagues[15] evaluated weekly docetaxel and cisplatin with concurrent thoracic radiation (64 Gy) in locally advanced NSCLC. Recommended phase 2 doses were 25 mg/m2 per week for both agents. Ongoing investigations are determining the optimal dose and schedule for concurrent administration of gemcitabine, an exquisite radiosensitizer, with thoracic radiotherapy. For example, Fossella and colleagues[16] conducted a 7-week phase 1 trial of weekly gemcitabine with concurrent chest radiation (63 Gy/35 fractions) followed by consolidation cisplatin/gemcitabine in patients with locally advanced NSCLC. The maximum tolerated dose (MTD) of gemcitabine concurrent with conventional 2-dimensional radiation was 125 mg/m2/wk. However, with 3-dimensional conformal radiation, the MTD increased to 190 mg/m2/wk. The investigators noted a strong relationship between the volume of esophagus in the radiation port and subsequent esophagitis severity. With a median follow-up of 40 weeks, estimated median survival was 14 months and estimated 1-year survival was 53%. The authors concluded that gemcitabine was better tolerated in a combined modality regimen when 3dimensional conformal radiation therapy was used, likely due to decreased exposure of the esophagus. Future studies defining the radiosensitizing role of gemcitabine in clinical practice are eagerly anticipated. Novel molecularly targeted agents with activity in advanced NSCLC, including epidermal growth factor-receptor inhibitors, the hypoxic cytotoxin tirapazamine, and an antibody directed against the vascular endothelial growth factor, are now commercially available or in late-phase clinical trials testing. How to best integrate these newer chemotherapeutic and biologic agents

into chemoradiation strategies for stage III NSCLC will require carefully designed and conducted clinical trial strategies.

Induction Chemotherapy Followed by Concurrent Chemoradiation

On the basis of 2 large randomized studies that demonstrated the superiority of induction chemotherapy followed by thoracic radiation over radiotherapy alone,[17,18] the Cancer and Leukemia Group B (CALGB) performed a phase 3 trial randomizing patients with inoperable stage III NSCLC to induction chemotherapy (vinblastine/cisplatin) followed by radiotherapy (60 Gy) vs the same induction chemotherapy followed by concurrent radiation plus weekly singleagent carboplatin (100 mg/m2/week).[19] This CALGB trial found no difference in failure-free and overall survival between the 2 arms. Specifically, 4-year survival was 13% with concurrent chemoradiation vs 10% with radiation alone (P = .7). Although there was an almost 20% decrease in local failure rate in the carboplatin-radiation arm, it was not enough to influence overall survival. Thus, the use of radiosensitizing doses of carboplatin may be analogous to the EORTC trial[5]; however, it did not yield a clinically relevant improvement in outcome. The authors noted that patients with "less favorable characteristics," specifically, those who had more advanced disease or were too ill to be considered for a competing preoperative chemotherapy trial, contributed to the disappointing overall results. The CALGB continued to explore the strategy of induction chemotherapy prior to definitive chemoradiotherapy in subsequent trials. Vokes and colleagues[20] conducted a randomized phase 2 trial of 3 cisplatin-based regimens incorporating 1 of 2 newer chemotherapeutic agents (vinorelbine, paclitaxel, and gemcitabine) given at full doses in the induction phase and at attenuated doses in the concurrent chemoradiation phase. One hundred eighty patients were entered. Although the trial was not designed to provide definitive comparisons, efficacy was relatively equivalent between the 3 regimens: Median survival was 17 months across all 3 arms. However, toxicity patterns varied considerably. Grade 3/4 neutropenia was greatest in the paclitaxel-containing arm, while neuropathy was most common with vinorelbine. In patients receiving gemcitabine, thrombocytopenia was common, and grade 3/4 esophagitis was observed in 50% of cases. This trial also established the feasibility of incorporating newer agents in chemoradiation strategies for stage III disease. Socinski and colleagues[21] incorporated 3-dimensional conformal radiation therapy in a phase 1/2 trial of induction chemotherapy and concurrent chemoradiation. In this study, 62 patients with unresectable stage III NSCLC were treated initially with 2 cycles of paclitaxel (225 mg/m2 over 3 hours) and carboplatin (AUC 6), followed by weekly paclitaxel (45 mg/m2/week) and carboplatin (AUC 2) over 6 weeks concurrent with escalating doses of 3-dimensional conformal radiation. Grade 3/4 esophagitis developed in less than 10% of patients. The survival rates were encouraging: 3-year progression-free survival was 29%, 3-year survival was 40%, and the median survival time was 26 months. In 58 patients with available progression data, 35 developed progressive disease, predominantly systemic in nature (54%). Ten of 19 patients with distant metastasis alone experienced treatment failure in the brain only.

Irinotecan was evaluated in combination with cisplatin by Japanese investigators for induction treatment followed by concurrent full-dose standard thoracic radiation in patients with stage III NSCLC.[22] During the concurrent phase of treatment, irinotecan was given at 60 mg/m2 weekly combined with once-daily thoracic radiation to a total dose of 60 Gy in 6 weeks. The reported 1year survival was 71.7%. These impressive early results await further confirmation. Other Japanese investigators had reported a phase 1 study of irinotecan (on days 1, 8, and 15) plus cisplatin (day 1) with concurrent radiation.[23] Twenty-four patients with locally advanced NSCLC were enrolled. Split-course thoracic radiation was started on day 2 of each chemotherapy cycle, and a total 24 Gy and 26 to 36 Gy were given at first and second cycle, respectively. An overall response rate of 65% was observed, and the recommended phase 2 doses were irinotecan 60 mg/m2 and cisplatin 80 mg/m2 concurrent with radiation. Ongoing studies are exploring alternative dosing schedules of irinotecan with or without cisplatin concurrent with radiation.[24,25] The RTOG is continuing to study ways to treat patients with induction chemotherapy followed by concurrent chemoradiotherapy using hyperfractionated radiation. The goal is to increase the tolerability of this regimen, which blends the survival advantage of induction chemotherapy with the increased local control seen with hyperfractionated radiation therapy. One approach added amifostine, a purported radioprotective agent, during concurrent chemoradiotherapy in an attempt to decrease the acute mucosal toxicity expected with this aggressive approach. Komaki and colleagues[26] reported a small phase 3 study (N = 60) demonstrating that amifostine reduced the rate of acute pneumonitis and esophagitis in NSCLC patients receiving concurrent chemoradiation for inoperable disease. However, the RTOG recently reported the results of a randomized trial (RTOG 9801) of amifostine vs no amifostine in patients with locally advanced NSCLC receiving concurrent carboplatin/paclitaxel-based chemoradiation.[27] The principal objective of the trial was to assess the rate of chemoradiation-induced esophagitis. Two hundred forty-three patients with stage II to IIIA/B NSCLC received induction paclitaxel 225mg/m2 on days 1 and 22 plus carboplatin (AUC 6) on days 1 and 22 followed by concurrent weekly paclitaxel (50 mg/m2) plus carboplatin (AUC 2) and hyperfractionated RT (69.6Gy/1.2Gy twice daily) starting on day 43. Patients were randomized to amifostine 500 mg four times a week (120 patients) vs no amifostine (123 patients). Results showed that the grade 3 or 4 esophagitis rate was 36% with amifostine vs 40% without, a difference that was not statistically different, and thus failed to demonstrate the ability of amifostine to substantially reduce the rate of severe chemoradiation-induced esophagitis.

Concurrent Chemoradiation Followed by Consolidation Chemotherapy

Several ongoing or recently completed phase 2 studies have evaluated platinum-based chemotherapy given concurrently with thoracic radiation, followed by additional cycles of the same platinum-based chemotherapy. A recently reported phase 2 trial of the California Cancer Consortium by Lau and colleagues[28] delivered twice-weekly paclitaxel (30mg/m2), weekly carboplatin (AUC 1.5), and concurrent radiotherapy (61 Gy) to 34 eligible patients. This regimen was followed by two 21-day cycles of paclitaxel (200 mg/m2) and carboplatin (AUC 6). Grade 3/4 esophagitis was noted in 38% of patients. The overall response rate was 71%, the median survival time 17 months, and actuarial 2-year survival rate was 40%.

The Southwest Oncology Group (SWOG) evaluated a similar strategy in the past decade. SWOG 9019 was a phase 2 trial in patients with pathologically demonstrated stage IIIB disease. This study evaluated concurrent cisplatin, etoposide, and thoracic radiation of 61 Gy/33 fractions/6.5 weeks followed by consolidative cisplatin and etoposide for 2 more cycles.[29] Median survival was 15 months; 2-year and 3-year survival rates were 34% and 17%, respectively. The follow-up study was SWOG 9504, a phase 2 study of the same concurrent therapy, followed by consolidation chemotherapy with 3 doses of docetaxel instead of continued cisplatin and etoposide.[30] Docetaxel was chosen for consolidation therapy because of its activity as a secondline therapy as well as its p53-independent effects on apoptosis.[31] The study included 83 patients with pathologically proven stage IIIB disease (N3 or T4 disease, excluding pleural effusion). Median survival was 26 months, with 2-year and 3-year survival rates of 53% and 37%, respectively.[30] Therapy was reasonably well tolerated. During the concurrent chemoradiation phase, grade 3/4 esophagitis occurred in only 11% of patients. Neutropenia was the most common toxicity in the consolidation docetaxel phase, with over half the patients developing grade 4 neutropenia. There were also 2 treatment-related deaths attributed to radiation pneumonitis. In a similar vein, the Hoosier Oncology Group is currently randomizing patients with unresectable stage III NSCLC who are completing concurrent cisplatin/etoposide-based chemoradiation to consolidation docetaxel (as in SWOG 9504) or to no further therapy. This study will ultimately answer the question of whether taxane consolidation results in superior survival in this patient cohort. Of note, an ongoing Intergroup phase 3 trial (SWOG 0023) is evaluating the role of the epidermal growth factor-receptor inhibitor gefitinib as long-term maintenance therapy. The study involves delivering concurrent chemoradiotherapy followed by consolidation docetaxel (identical to the treatment in SWOG 9504) followed by randomization to maintenance therapy with either gefitinib or placebo. Participants include the SWOG, NCI Canada, and the North Central Cancer Treatment Group. Tirapazamine, a novel hypoxic cytotoxin that is bioactivated under hypoxic conditions, has synergistic or additive antitumor activity when given with cisplatin or radiation.[32] Under aerobic conditions, such as in normal tissue, tirapazamine undergoes futile cycling back to the inactive parent compound. Tirapazamine has already been shown to improve survival in stage IV NSCLC when combined with cisplatin vs treatment with cisplatin alone.[33] While combination trials for advanced-stage disease are ongoing, several phase 1/2 trials have begun using tirapazamine with platinum-based chemotherapy and concurrent thoracic radiation, followed by consolidation chemotherapy. For example, the California Cancer Consortium is currently conducting a phase 1/2 trial of tirapazamine plus carboplatin/paclitaxel concurrent with radiation in patients with stage III NSCLC followed by 2 additional cycles of carboplatin/paclitaxel to nonprogressing patients.

Induction vs Consolidation
Although induction and consolidation approaches have not been directly compared in the phase 3 setting, a randomized phase 2 trial by Choy and colleagues[34] compared 3 treatment arms. The first arm consisted of sequential therapy with paclitaxel/carboplatin followed by thoracic

radiation; the second consisted of the same chemotherapy given as induction-first followed by concurrent therapy; and the third arm consisted of the same agents given as concurrent-first followed by consolidation with paclitaxel/carboplatin. In this multi-institutional study, 276 patients with stage IIIA or stage IIIB NSCLC were recruited. All arms were prospectively planned to be compared with the RTOG reference survival data for sequential chemoradiation (median survival time of 14.5 months). The preliminary results showed that the induction-first strategy resulted in reduced delivery of concurrent chemoradiation and numerically lower survival. With a median follow-up time of 26 months, patients in the first, second, and third arms had median survival times of 12.5 months, 11 months, and 16.1 months, respectively. Although a recently completed Cancer and Leukemia Group B phase 3 trial directly compared concurrent chemoradiation alone with induction first, the results are not yet available.

Chemoradiation in Patients With Poor Performance Status

While there is strong evidence supporting the value of sequential and concurrent chemoradiation in patients with good performance status, how this applies to patients with underlying comorbid conditions and functional impairment is less well defined; in these patients, it is unclear whether treatment toxicity outweighs the expected survival benefits. Few trials have evaluated patients with "poor risk" features regardless of age. Lau and colleagues[35] studied concurrent carboplatin, etoposide, and thoracic radiation in a group of patients that had 1 or more "poor risk factors" (Table 4). The regimen was well tolerated, and patients had a median survival of 12 months, comparing favorably with historical data demonstrating a median survival of less than 6 months in this patient population.[36] The chemoradiation approach using carboplatin/etoposide was further studied in SWOG 9429, a phase 2 study of "poor risk" patients that yielded a median survival time of 13 months and a 2year survival rate of 21%.[37] Fifty-two of 60 patients were able to complete chemoradiotherapy without toxicity-induced interruption, and there were no treatment related deaths.

Table 4. "Poor Risk" Criteria

FEV1 < 2.0 and 1.0 L SWOG performance status of 2 and either albumin level < 85% of lower institutional normal value or weight loss > 10% Creatinine clearance < 50 and > 20 mL/min History of congestive heart failure Peripheral neuropathy Adapted from Lau DH, et al. J Clin Oncol. 1998;16:3078-3081. SWOG = Southwest Oncology Group. Finally, the RTOG reported a randomized phase 3 trial of standard thoracic radiation with or without recombinant beta-interferon in patients with poor performance status.[38] Overall survival at 1 and 2 years was 50% and 21%, respectively. The RTOG is in the process of designing a

phase 2 study for poor-prognosis patients combining a cyclooxygenase-2 inhibitor and standard thoracic radiation. The difficulties in conducting clinical trials with this group of patients are significant and create opportunities for testing additional nonchemotherapeutic antitumor agents. While sequential or concurrent chemoradiation is typically not a standard approach for poor performance status patients, a regimen such as that tested in SWOG 9428 may be offered to such patients. This regimen appears to be both reasonably well tolerated and active. Alternative treatment options for these challenging patients need to be identified and the risk-benefit ratio more clearly defined for existing treatment options.

Conclusions
The optimal treatment of locally advanced, unresectable NSCLC continues to evolve. For patients with acceptable performance status and no significant comorbid conditions, the best results have been obtained from concurrent chemoradiation approaches. Continued clinical research is required to identify the most appropriate therapy for patients with compromised functional status. Nevertheless, stage III disease remains highly lethal despite recent advances in treatment. Ongoing research with novel therapeutic agents, refined radiation techniques, and enhanced imaging methods to aid in accurate staging are being pursued and should lead to improved survival and toxicity outcomes in this disease.

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9. Curran WJ, Scott C, Langer R, et al. Phase III comparison of sequential vs. concurrent chemoradiation for PTS with unresected stage III non-small cell lung cancer (NSCLC): Initial report of radiation therapy oncology group (RTOG) 9410. Proc Am Soc Clin Oncol. 2000;19:Abstract 1891. 10. Curran WJ, Scott C, Langer R, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol. 2003;22:Abstract 2499. 11. Gandara DR, Lara PN, Goldberg Z, Lau D. Integration of new chemotherapeutic agents into chemoradiotherapy for stage III non-small cell lung cancer: focus on docetaxel. Semin Oncol. 2001;28(suppl G):26-32. 12. Mauer AM, Masters GA, Haraf DJ, et al. Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol. 1998;16:159-164. Abstract 13. Vokes EE, Masters GA, Mauer AM, Haraf DJ, Hoffman PC, Golomb HM. Clinical studies of docetaxel (Taxotere) and concomitant chest therapy. Semin Oncol. 1997;24 (suppl 14):26-29. 14. Segawa Y, Ueoka H, Kira K, et al. A phase I/II study of docetaxel (TXT) and cisplatin (CDDP) with concurrent thoracic radiotherapy (TRT) for locally advanced non-small-cell lung cancer (LA-NSCLC). Proc Am Soc Clin Oncol. 2000;19:508a. Abstract 1988. 15. Mudad R, Ramsey M, Kovitz K, et al. Concomitant weekly docetaxel, cisplatin and radiation therapy in locally advanced non-small cell lung cancer: a dose finding study. Lung Cancer. 2003;39:173-177. 16. Fossella FV, Zinner RG, Komaki R, et al. Gemcitabine (G) with concurrent chest radiation (XRT) followed by consolidation chemotherapy with gemcitabine plus cisplatin (CDDP): a phase I trial for patients with stage III non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2001;20:312a. Abstract 1243. 17. Dillman RO, Herndon J, Seagren SL, et al. Improved survival in stage III non-small cell lung cancer: seven year follow-up of Cancer and Leukemia Group B 8433 trial. J Natl Cancer Inst. 1996;88:1210-1215. Abstract 18. Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced unresectable non small cell lung cancer. J Natl Cancer Inst. 1995;87:198-205. Abstract 19. Clamon G, Herndon J, Cooper R, et al. Radiosensitization with carboplatin for patients with unresectable stage III non-small cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol. 1999;17:4-11. Abstract 20. Vokes EE, Herndon JE, Crawford J, et al. Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: Cancer and Leukemia Group B Study 9431. J Clin Oncol. 2002;20:4191-4198. Abstract 21. Socinski MA, Rosenman JG, Halle J, et al. Dose escalating conformal thoracic radiation therapy with induction and concurrent carboplatin/paclitaxel in unresectable stage IIIA/B non small cell lung carcinoma. Cancer. 2001;92:1213-1223. Abstract 22. Yamamoto N, et al. A phase II study of induction chemotherapy (IND CT) with CPT-11 and cisplatin followed by thoracic radiation (TRT) combined with weekly CPT-11 in

patients with unresectable stage III non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2000;19:Abstract 1953. 23. Fukuda M, Fukuda M, Soda H, et al. Phase I study of irinotecan (CPT-11) and cisplatin (CDDP) with concurrent thoracic radiotherapy (TRT) in locally advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 1999;18:Abstract 1796. 24. Chakravarthy A, Choy H, Devore RF, et al. Phase I trial of outpatient weekly irinotecan and concurrent radiation therapy for stage III unresectable non-small-cell lung cancer: a Vanderbilt Cancer Center Affiliate Network (VCCAN) trial. Proc Am Soc Clin Oncol. 1999;18:Abstract 1924. 25. Somer R, Langer C, Movsas B, et al. Phase I study of irinotecan (CPT-11), cisplatin (cDDP) and radical thoracic radiation (TRT) in the treatment of locally advanced nonsmall cell lung carcinoma (NSCLC). Proc Am Soc Clin Oncol. 2001;20:258b. Abstract 2783. 26. Komaki R, Lee RS, Kaplan B, et al. Randomized phase III study of chemoradiation amifostine in patients with inoperable stage II-III non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2001;20:325a. Abstract 1298. 27. Movsas B, Scott C, Langer C, et al. Phase III study of amifostine in patients with locally advanced non-small cell lung cancer (NSCLC) receiving chemotherapy and hyperfractionated radiation (chemo/HFxRT): Radiation Therapy Oncology Group (RTOG) 98-01. Proc Am Soc Clin Oncol. 2003;22:636. Abstract 2559. 28. Lau D, Leigh B, Gandara D, et al. Twice-weekly paclitaxel and weekly carboplatin with concurrent thoracic radiation followed by carboplatin/paclitaxel for stage III non-smallcell lung cancer: a California Cancer Consortium phase II trial. J Clin Oncol. 2001;19:442-447. Abstract 29. Albain KS, Crowley JJ, Turrisi AT, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol. 2002;21:3454-3460. 30. Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol. 2003;21:2004-2010. Abstract 31. Gumerlock PH, Mack PC, Manorek GH, et al. p27 induction as a potential p53independent mechanism of apoptotic response to taxanes in non-small cell lung carcinoma (NSCLC). Proc Am Soc Clin Oncol. 1999;18:730a. Abstract 4879. 32. Kovacs MS, Hocking DJ, Evans JW, et al. Cisplatin anti-tumour potentiation by tirapazamine results from a hypoxia-dependent cellular sensitization to cisplatin. Br J Cancer. 1999 ;80:1245-1251. Abstract 33. von Pawel J, von Roemeling R, Gatzemeier U, et al. Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: a report of the international CATAPULT I study group. Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors. J Clin Oncol. 2000;18:1351-1359. Abstract 34. Choy H, Curran WJ, Scott CB, et al. Preliminary report of locally advanced multimodality protocol (LAMP): ACR 427: a randomized phase II study of three chemoradiation regimens with paclitaxel, carboplatin, and thoracic radiation (TRT) for patients with locally advanced non small cell lung cancer (LA-NSCLC). Proc Am Soc Clin Oncol. 2002;21:291a. Abstract 1160.

35. Lau DHM, Ryu J, Gandara D, et al. Concurrent carboplatin, etoposide and thoracic radiation for poor-risk stage III non-small-cell lung carcinoma: a pilot study. Int J Radiat Oncol Biol Phys. 1997;38:157-161. Abstract 36. Scott C, Sause WT, Byhardt R, et al. Recursive partitioning analysis of 1592 patients on four Radiation Therapy Oncology Group studies in inoperable non-small cell lung cancer. Lung Cancer. 1997;17(suppl 1):S59-S74. Abstract 37. Lau DH, Crowley JJ, Gandara DR, et al. Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer. J Clin Oncol. 1998;16:3078-3081. Abstract 38. McDonald S, Scott C, Rubin P, et al. A phase III study evaluating the efficacy of conventional radiation therapy with or without recombinant B-interferon for patients with locally advanced non-small cell lung cancer and poor prognostic characteristics (RTOG 93-04). Int J Radiat Oncol Biol Phys. 1999;45:379. Abstract 2197. Abstract

Management of Stage IV NSCLC Introduction

Lung cancer is the leading cause of cancer-related death in the United States and throughout the world.[1,2] The American Cancer Society estimates that lung cancer will be responsible for approximately 157,000 deaths in the United States in 2003, compared with 126,000 deaths from the combined mortality of colorectal, breast, and prostate cancer.[3] Notably, non-small cell lung cancer (NSCLC) comprises more than 80% of all new lung-cancer cases. Stage IV NSCLC indicates the presence of metastatic disease. The most common sites of metastatic disease are the liver, bone, adrenal gland, brain, and contralateral lung; the revision of the international staging system in 1997 included a separate tumor nodule(s) in a different lobe from the primary tumor as metastatic disease.[4] Subsets of patients with stage IIIB disease, such as those with a malignant pleural/pericardial effusion and some patients with supraclavicular adenopathy, are often not candidates for a combined-modality approach. These patients are usually included with stage IV patients in clinical trials addressing the benefit of systemic chemotherapy. Although important therapeutic advances have been made during the past 2 decades, the prognosis of patients with advanced NSCLC remains poor. Most recent large clinical trials have shown a median survival time of 8 to 10 months and a 1-year survival rate of 30% to 35%. However, the 5-year survival rate of this group of patients is 1%, and these patients are still considered to have incurable disease. Staging of Patients With Advanced NSCLC A clinical-diagnostic stage is assigned on the basis of physical examination; radiographic studies; and invasive studies such as bronchoscopy, endoesophageal ultrasound, thoracoscopy and/or mediastinoscopy, thoracentesis, and/or other diagnostic biopsies.

Computed tomography (CT) scan of the chest, including the liver and adrenal glands, is performed routinely to define the primary tumor and assess for nodal, parenchymal, or distant metastasis while bone scans and imaging of the central nervous system are typically performed when there are symptoms or signs consistent with involvement of these areas.[5] Positron emission tomography (PET) with fluoro-2-deoxyglucose (FDG) has been shown in various studies to be able to detect unsuspected M1 disease in 6% to 17% of patients who are otherwise cleared for resection by conventional screening methods (eg, CT and bone scan). PET scanning is now routinely included as part of the staging work-up for NSCLC.[6] Of note, the integration of PET and CT scanning may provide additional information beyond that provided by visual correlation of PET and CT.[7] The demonstrated cost-effectiveness of preoperative PET scanning in NSCLC is mainly the result of avoidance of "unnecessary" surgery. This was illustrated in a prospective trial of 188 patients randomly assigned to conventional diagnostic work-up alone (CWU) or to CWU with the addition of PET scanning (CWU + PET).[8] Thoracotomy was regarded as futile if the patient had pathologic stage IIIA-N2/IIIB disease, or if the patient had postoperative relapse or died within 12 months of randomization. In the CWU group, 39 patients (41%) had a futile thoracotomy compared with 19 (21%) in the CWU + PET group (P = .003). In addition, surgery was avoided in a higher number of patients assigned to the PET scan group (32 vs 18).

Chemotherapy: The Rationale

Platinum-Based Chemotherapy vs Best Supportive Care Numerous randomized trials[9-13] and meta-analyses[14-17] have been published examining the effect of chemotherapy vs best supportive care (BSC) in patients with advanced NSCLC. Some have evaluated single agents while others have tested combination regimens, although the majority of the combination trials have evaluated cisplatin-based protocols. In 1995, the NonSmall Cell Lung Cancer Collaborative[17] reported its worldwide meta-analysis of individual patient data from 11 randomized trials (8 of which were cisplatin-based) evaluating chemotherapy vs BSC. In the trials employing cisplatin-based regimens, there was a 27% reduction in the risk of death (P < .0001) associated with chemotherapy. It is difficult to establish the magnitude of the survival benefit conferred by chemotherapy for patients with stage IV NSCLC, although the data suggest an almost doubling of the 1-year survival rate for patients who receive treatment. As shown in Table 1, recent data from the British "Big Lung Trial" (BLT) again confirm the role of platinum-based chemotherapy in patients with advanced NSCLC.[18]

Table 1. Big Lung Trial: Cisplatin-Based Chemotherapy vs BSC

Chemotherapy N Median survival 364 7.7 months BSC 361 5.7 months*

1-year survival *P = .0015 BSC, best supportive care.

28%

19%

In this trial, the benefit of chemotherapy seemed to be independent of stage (III or IV) and performance status (0-1 vs 2). In addition, a detailed quality-of-life (QOL) analysis showed no difference between the 2 arms with regard to the predefined primary and secondary end points. Single - Agent Chemotherapy vs BSC Numerous individual agents with substantial single-agent activity in NSCLC became available during the 1990s. Results of randomized trials of several of these new agents vs BSC are listed in Table 2.[19-21]

Table 2. Single-Agent Chemotherapy vs BSC in Advanced NSCLC

N Study Ranson[19] Gridelli[21] Agent Paclitaxel CT BSC 79 137 78 70 78 Stage IV 55% 53% 73% Median Survival (mos) CT 6.8 6.0 6.5 BSC 4.8* 5.7 4.9 1-Year Survival (%) CT NR 25 32 BSC NR 16 14

Roszkowski[20] Docetaxel

Vinorelbine 76

*P = .037; P = .026; P = .03 CT, chemotherapy; BSC, best supportive care. A trial of single-agent gemcitabine compared with BSC[22] has also been reported. In that trial, the primary end point was based on changes in QOL, and a significant improvement in QOL was indeed achieved in the gemcitabine-treated patients. However, no significant survival benefit was observed. Nevertheless, the survival benefit of most of these single agents is significant, and potentially competitive with that obtained with platinum-based combination regimens. On the basis of these data, some clinicians consistently use single-agent chemotherapy for selected groups of patients with advanced NSCLC, including those classified as performance status (PS) 2 as well as "frail elderly" patients. Clearly, the aggregate data show that both selected single agents and platinum-based combination chemotherapy improve survival compared with BSC in patients with advanced NSCLC.

Selection of Patients for Chemotherapy

Because there is a consistent improvement in the survival of patients who are treated with chemotherapy over BSC, it is important to identify those patients who may not derive benefit from chemotherapy. Also, it is important to determine whether there is a subset of patients in whom an intermediate therapeutic approach (eg, single-agent rather than combination chemotherapy) would be more appropriate. To date, the single most important factor predicting benefit from therapy across all studies has been PS. The 2 most commonly used PS scales are shown in Table 3.

Table 3. Performance Status Scales

ECOG Performance Status Scale Grade 0 Description Percent Karnofsky Performance Scale Description Normal; no complaints; no evidence of disease Able to carry on normal activity; minor signs or symptoms of disease Normal activity with effort; some signs or symptoms of disease Cares for self; unable to carry on normal activity or to do active work Requires occasional assistance, but is able to care for most of his/her needs Requires considerable assistance and frequent medical care Disabled; requires special care and assistance Severely disabled; hospitalization indicated; death not imminent Very sick; hospitalization indicated; death imminent

Normal activity; fully active, able to carry on all 100 predisease performance without restriction 90

Symptoms, but ambulatory; restricted in 80 physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (eg, light housework, office work) 70

In bed < 50% of the time; ambulatory and capable of all self-care, but unable to carry out any work activities; up and about > 50% of waking hours

60

50

In bed > 50% of the time; capable of only 40 limited self-care; confined to bed or chair > 50% of waking hours 30

100% bedridden; completely disabled; cannot 20 carry on any self-care; totally confined to bed or

chair 5 Dead

10 0

Moribund, fatal processes progressing rapidly Dead

ECOG, Eastern Cooperative Oncology Group. Finkelstein and colleagues[23] evaluated nearly 900 patients with advanced NSCLC and no prior chemotherapy entered into a series of ECOG phase 3 trials. The median survival time and 1-year survival rates were 9 months and 36%, respectively, for PS 0 patients; 6 months and 16%, respectively, for PS 1 patients; and 3 months and 9%, respectively, for PS 2 patients (P < .001). Patients with PS 3 or 4 are not routinely considered for participation in advanced NSCLC trials because their poor prognosis and propensity for toxicity with treatment are presumed to outweigh the small chance for benefit of chemotherapy. The number of metastatic sites may influence the prognosis as well.[24-26] Patients with disease confined to the lungs may have superior outcomes, and nonrandomized trials have suggested that patients with a solitary site of metastasis may have a superior outcome with aggressive therapy, sometimes including resection of the single focus of demonstrated metastatic site. Patients with multiple brain, liver, and bone metastases have poorer outcomes. Other factors such as age, weight loss, and histologic subtypes are not reliable prognostic determinants. Most trials suggest an improved survival for women, although the differences are generally small.[24-26] The ECOG 5592 trial[27] demonstrated that QOL scores, as measured by the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale, are important predictors of outcome in patients with advanced NSCLC.

Single Agents vs Platinum-Based Combinations

Given the fact that platinum-based chemotherapy is superior to BSC, and that the newer active single agents such as paclitaxel, docetaxel, vinorelbine, and gemcitabine have shown significant activity, the logical next question is to determine whether platinum-based combinations improve outcomes compared with optimized single agents. In metastatic NSCLC, the goal of chemotherapy is clearly palliative -- achieving the longest duration of quality life -- and improvements in survival must be considered in the context of potential toxicity and diminished QOL. Three separate randomized trials reported at the 2002 American Society of Clinical Oncology (ASCO) meeting as well as a fourth trial reported at the 2003 ASCO meeting addressed the question of whether platinum-based combinations can improve outcomes compared with the new single agents. The findings from these trials are shown in Table 4.[28-31]

Table 4. Single Agents vs Platinum-Based Combinations

Author Lilenbaum[28] Regimen Paclitaxel 225 mg/m2 q 3 wks (n = 277) Response Rates 17% vs Median Survival 6.7 mos vs 1-Year Survival 33% vs P value Log rank .20

vs paclitaxel 225 mg/m2 and carboplatin AUC 6 q 3 wks (n = 284) Sederholm[29] Gemcitabine 1250 mg/m2 days 1,8, and 15 (n = 170) vs gemcitabine 1250 mg/m2 and cisplatin 80 mg/m2 day 1 q 3 wks (n = 164)

30%

8.8 mos

37%

Wilcoxon .012

12% vs 30%

9 mos vs 11 mos

32% vs 41%

Log rank .016

Georgoulias[30] Docetaxel 100 mg/m2 q 3 wks (n = 148) vs docetaxel 100 mg/m2 and cisplatin 80 mg/m2 q 3 wks (n = 160) Groen[31] Docetaxel 35 mg/m2 weekly x 6 q 8 wks (n = 114) vs docetaxel 75 mg/m2 and carboplatin AUC 6 q 3 wks (n = 115)

20% vs 36%

8 mos vs 10 mos

40% vs 45%

> .05

16% vs 39%

27 wks vs 40 wks

NR

.021

These 4 trials show a consistent pattern of response and survival benefit for platinum combination therapy compared with "optimized" single-agent approaches. Response rates were at least 75% higher and median survival improvement was approximately 2 months in each of the studies. There was a significant overall survival benefit seen in the Sederholm[29] and Groen[31] trials, and the Lilenbaum[28] data demonstrate a significant early survival benefit for the combination regimen (Wilcoxon P = .012). In each trial, selected toxicities are somewhat increased with the combination regimen. However, the overall therapeutic index favored the combination approach. Of note, in the Lilenbaum trial, where there was prospective stratification by age and PS, the benefits of combination therapy were also seen in patients over age 70 and in those with PS 2.

Platinum-Based Combination Chemotherapy

New Combinations vs Older Combinations As mentioned above, a number of chemotherapy agents (ie, paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan) were identified during the 1990s as having substantial activity in

patients with advanced NSCLC. Randomized studies demonstrate that use of platinum doublet regimens including these third-generation agents can improve survival outcomes compared with older standard therapies. A large, randomized, 3-arm trial conducted in France compared cisplatin and vindesine to vinorelbine alone or vinorelbine in combination with cisplatin.[32] This study showed a significant improvement in both median survival (40 weeks vs 32 weeks) and overall survival for the combination of cisplatin-vinorelbine compared with cisplatin-vindesine. The taxanes docetaxel and paclitaxel also fared well against the older agents. A Japanese trial comparing vindesine-cisplatin with docetaxel-cisplatin[33] found a significant survival advantage favoring the docetaxel-cisplatin regimen. ECOG investigators compared etoposide and cisplatin with 2 different combinations of cisplatin with paclitaxel given at 135 mg/m2 or 250 mg/m2 as a 24-hour infusion.[34] In this study, patients receiving the combination of cisplatin and paclitaxel showed a median survival time of 9.6 months and 10 months, respectively, for the lower and higher doses, vs 7.7 months for the cisplatin and etoposide combination. However, Belani and colleagues[35] failed to show a survival advantage for patients receiving carboplatin and paclitaxel over those receiving cisplatin and etoposide. Gemcitabine was tested against the older agents in a London Lung Group trial reported at ASCO in 2002,[36] in which carboplatin and gemcitabine was compared with a British standard regimen of mitomycin, ifosfamide, and cisplatin (MIP). In this large trial, both survival (carboplatin/gemcitabine 10.0 months, MIP 6.5 months) and QOL were improved with the newer regimen. Two trials from Japan have compared a standard regimen of cisplatin and vindesine to the new combination of cisplatin and irinotecan.[37,38] One study[37] found a median survival time of 52 weeks for patients receiving the new regimen vs 47 weeks for patients receiving the older standard, with a nonsignificant trend in the 1-year survival rate favoring the newer regimen (49% vs 40%). The other trial[38] also did not show significant differences between the 2 arms. However, a subset analysis that included only stage IV patients suggested a significant survival advantage for patients receiving cisplatin/irinotecan vs those receiving cisplatin/vindesine. Recently, Baggstrom and colleagues[39] reported a literature-based meta-analysis comparing "third-generation platinum-based regimens" to older standard platinum-based regimens. Eight trials published since 1994 were identified, and results on 3296 patients were included. A 13% absolute increase in the average objective response rates was seen with the third-generation regimens vs older platinum-based combinations (relative risk [RR], 1.80; 95% confidence interval [CI], 1.51 to 2.15). When examining the effect on 1-year survival, the third-generation regimens increased patient survival compared with the older regimens (RR, 1.14; 95% CI, 1.01 to 1.29), with an absolute increase in the 1-year survival rate of 4% (P = .04). This analysis suggests that there has been a modest but significant improvement in survival with the use of the newer third-generation regimens compared with the older standard regimens. Randomized Comparisons Among Third-Generation Platinum-Based Regimens

Several large randomized trials have compared different third-generation regimens as first-line treatment of patients with advanced NSCLC. In the Southwest Oncology Group's trial 9509, the combination of cisplatin/vinorelbine was compared with carboplatin/paclitaxel.[40] The results are shown in Table 5.

Table 5. SWOG 9509: Cisplatin/Vinorelbine vs Carboplatin/Paclitaxel

Cisplatin/Vinorelbine Carboplatin/Paclitaxel N Response rate Time to progression Median survival 1-year survival 2-year survival 202 28% 4 months 8 months 35% 16% 208 25% 4 months 8 months 36% 15%

There were no efficacy differences appreciated between the 2 arms, and no significant differences were demonstrated in a QOL analysis. The combination of cisplatin/vinorelbine produced more nausea and hematologic toxicity, but carboplatin/paclitaxel produced more alopecia and peripheral neuropathy. Despite the fact that the cisplatin/vinorelbine regimen was shown to be substantially more cost-effective, the SWOG investigators concluded that the carboplatin/paclitaxel combination demonstrated more overall tolerability and was therefore a more appropriate regimen to be used as the standard in future trials. In a much larger trial, ECOG 1594, Schiller and colleagues[41] evaluated 3 different platinum doublets: gemcitabine/cisplatin (GC), docetaxel/cisplatin (DC), and paclitaxel/carboplatin (PCb). Paclitaxel/cisplatin (PC) was used as the control arm. A total of 1155 patients were assessable, only 13% of whom had unresectable stage IIIB disease. The results are shown in Table 6.

Table 6. ECOG 1594: Randomized 4-Arm Study in Advanced NSCLC

PC N Response rate TTP 290 21% GC 280 21% DC 289 17% PCb 284 15%

3.5 mos 4.5 mos 3.3 mos 3.3 mos 8 mos 36% 16% 7 mos 31% 12% 8 mos 35% 11%

Median survival 8 mos 1-year survival 2-year survival 31% 11%

PC, paclitaxel/cisplatin; GC, gemcitabine/cisplatin; DC, docetaxel/cisplatin; PCb, paclitaxel/carboplatin; TTP, time to progression. Although no significant differences in response rate or survival were observed among the 4 arms, there were grade 3/4 toxicity differences between each comparator and the PC control. GC was associated with significantly less febrile neutropenia, but significantly more anemia and thrombocytopenia, while DC was associated with more hypersensitivity reactions. The PCb arm was associated with significantly less febrile neutropenia, nausea, and overall grade 3/4 toxicities vs PC. Following this study, ECOG investigators have routinely used carboplatin/paclitaxel as their preferred regimen for first-line treatment studies in patients with advanced NSCLC. In the largest advanced NSCLC trial reported to date, the TAX 326 Study Group[42] randomly assigned a total of 1218 patients with stage IIIB or IV NSCLC to 1 of 3 combination regimens: docetaxel/cisplatin (DC), docetaxel/carboplatin (DCb), or vinorelbine/cisplatin (VC). The study was designed to compare each of the docetaxel regimens to the vinorelbine standard; there was no plan to compare the 2 docetaxel regimens to one another, nor to collapse the 2 docetaxel regimens for comparison against the VC standard. The study findings demonstrated that the 2 comparator arms performed differently vs the standard VC arm. DC-treated patients experienced a higher overall response rate (31.6% vs 24.5%; P = .029), a longer median survival (11.3 months vs 10.1 months; P = .04), and a more favorable 2-year survival rate (21% vs 14%) when compared with VC-treated patients. Overall response and survival rates were numerically similar for patients treated with DCb and VC, but several toxicity and QOL comparisons significantly favored the docetaxel-plus-platinum regimens over the VC standard. Results of the comparison between DC and VC are shown in Table 7.

Table 7. TAX 326: Docetaxel/Cisplatin vs Vinorelbine/Cisplatin

DC N Stage IIIB Response rate 408 33% 32% VC 404 33% 25%*

Median survival 11.3 months 10.1 months 1-year survival 2-year survival 46% 21% 41% 14%

*P = .029; P = .04. DC, docetaxel/cisplatin; VC, vinorelbine/cisplatin.

Platinum-Based Combinations: Additional Considerations

Cisplatin vs Carboplatin

The introduction of cisplatin clearly improved treatment outcomes for numerous patients with a variety of solid tumors. However, cisplatin toxicities, most notably nausea and vomiting, renal dysfunction, and neurotoxicity, have been problematic. Although some of this toxicity has become much more manageable with the use of aggressive hydration and the advent of antiemetics, concerns remain regarding renal toxicity, neuropathy, ototoxicity, and generalized fatigue and asthenia. To alleviate some of these side effects, especially in the palliative therapy setting, clinicians have almost routinely turned to carboplatin. However, there are conflicting data regarding whether cisplatin and carboplatin are in fact equally effective therapies in patients with advanced NSCLC. A European Organization for Research and Treatment of Cancer (EORTC) study conducted in the late 1980s directly compared etoposide/cisplatin and etoposide/carboplatin regimens in patients with previously untreated advanced NSCLC.[43] Although there was a higher response rate among the cisplatin-treated patients, no significant difference in overall survival was noted. More recently, a relatively small study comparing carboplatin plus gemcitabine with cisplatin plus gemcitabine was reported by the Czech Lung Cancer Cooperative Group.[44] The study was powered for a QOL end point. However, a secondary survival analysis showed a similar survival rate in both treatment groups. In ECOG 1594 discussed above,[41] the comparator arm consisted of cisplatin plus paclitaxel, whereas one of the experimental arms consisted of carboplatin plus paclitaxel. Although the dose and infusion rate of the paclitaxel differed between the 2 arms (135 mg/m2 over 24 hours in the cisplatin arm vs 225 mg/m2 over 3 hours in the carboplatin arm), the overall response and median survival did not differ significantly (22% and 7.8 months, respectively, in the cisplatinplus-paclitaxel arm vs 17% and 8.1 months, respectively, in the carboplatin-plus-paclitaxel arm). The largest direct comparison of cisplatin and carboplatin in patients with advanced NSCLC was reported in late 2002 by Rosell and colleagues.[45] The doses and schedules of paclitaxel were identical between the 2 arms; the platinum doses were either cisplatin 80 mg/m2 or carboplatin AUC 6. Cycles of each regimen were repeated every 3 weeks. As shown in Table 8, among a total of 618 patients evaluated in the study, the cisplatin/paclitaxel regimen was associated with a significant improvement in median and overall survival compared with the carboplatin/paclitaxel regimen (P = .019).

Table 8. Cisplatin/Paclitaxel vs Carboplatin/Paclitaxel

Cisplatin/Paclitaxel Carboplatin/Paclitaxel N Stage III PS 0/1 Response rate Median survival 309 36% 16%/66% 26% 9.8 mos 309 29% 17%/66% 23% 8.2 mos

1-year survival PS, performance status.

38%

33%

The Italian Lung Cancer Project[46] randomized approximately 200 patients to 1 of 3 chemotherapy regimens: cisplatin (75 mg/m2)/gemcitabine, carboplatin/paclitaxel, or cisplatin (100 mg/m2)/vinorelbine. No significant differences in response rate or overall survival were seen among the 3 arms. Clearly, the controversy over whether cisplatin or carboplatin doublets should be standard care for first-line therapy in NSCLC has not been put to rest. In the United States, a majority of physicians currently use carboplatin in the palliative setting of advanced NSCLC; a carboplatinbased regimen also seems more appropriate in older individuals with a decreased PS. By contrast, however, physicians are reconsidering the risk-benefit ratio of cisplatin therapy in patients with stage III disease, particularly in the adjuvant settings, where the best available data involve cisplatin-based treatment approaches. Nonplatinum-Based vs Platinum-Based Combinations One way to avoid the cisplatin vs carboplatin controversy is to not administer them at all. Within the past decade, numerous phase 3 trials comparing platinum-based vs nonplatinum-based combinations have been reported, with varying results. The Hellenic Cooperative Oncology Group[47] randomly assigned patients to receive paclitaxel with either carboplatin or gemcitabine. Median and 1-year survival rates were 10.4 months and 41.7%, respectively, for the carboplatin-plus-paclitaxel arm, and 9.8 months and 41.4%, respectively, for the gemcitabine-plus-paclitaxel arm. Both regimens were well tolerated. The Greek Oncology Cooperative Group[48] compared cisplatin/docetaxel with gemcitabine/docetaxel. Median survival was 10 months in the cisplatin/docetaxel arm and 9.5 months in the gemcitabine/docetaxel arm; 1-year survival rates were 42% and 39%, respectively. Of note, the gemcitabine/docetaxel arm had the more favorable toxicity profile. Other studies, however, have reported a trend toward inferior survival with nonplatinum-based regimens. The Greek Cooperative Group for Lung Cancer[49] compared docetaxel/gemcitabine with vinorelbine/cisplatin. Although the difference was not statistically significant, the median survival was 9 months for docetaxel/gemcitabine and 11.5 months for vinorelbine/cisplatin. In EORTC 08975, paclitaxel/gemcitabine was compared with paclitaxel/cisplatin and cisplatin/gemcitabine. Again, although the difference was not significant, there was a trend toward inferior median and 1-year survival in the paclitaxel/gemcitabine arm (P = .08).[50] More recently, Gridelly and colleagues[51] reported the results of their randomized trial comparing gemcitabine/vinorelbine with cisplatin/vinorelbine or cisplatin/gemcitabine. Patients receiving the cisplatin-based therapies had more myelosuppression, vomiting, renal toxicity, hair loss, ototoxicity, and fatigue than did patients receiving gemcitabine/vinorelbine, although global QOL was not better in the nonplatinum arm. There was no difference in response rates between

the cisplatin regimens (30%) and the gemcitabine/vinorelbine regimen ( 25%). However, the gemcitabine-plus-vinorelbine regimen had an inferior progression-free survival (32 weeks vs 38 weeks in the cisplatin-based arms, P = .004), and the survival differences, although not statistically inferior, showed a trend toward inferiority for the noncisplatin-based arm (P = .08). In summary, these trials suggest that the activity of third-generation nonplatinum doublets might be slightly inferior to cisplatin-containing doublets. However, toxicity seems to be slightly reduced as well, particularly when compared with cisplatin-based regimens. In all likelihood, there is no clinically significant difference between carboplatin-based regimens and nonplatinum-based doublets for most patients receiving first-line chemotherapy for advanced NSCLC. Adding a Third Drug Although 2-drug combinations are more active than single-agent therapy, the overall benefits of doublet therapy are still modest. More active therapy is clearly needed. As discussed earlier, there are several classes of agents with activity in NSCLC, prompting researchers to explore the possibility of adding a third active agent to the doublet regimen, either as an integrated part of a 3-drug regimen, or as a planned sequence of 2 drugs followed by a planned switch to the third agent or combination at a specified time prior to tumor progression. Some phase 2 trials of 3-drug combination therapy in NSCLC have been encouraging, but overall, this approach has failed to deliver meaningful improvements in outcomes. Comella and colleagues[52] evaluated the 3-drug combination of gemcitabine, vinorelbine, and cisplatin, with all 3 drugs given on days 1 and 8 every 3 weeks; essentially full doses of all 3 agents were used. A response rate of more than 50% and a median survival of approximately 14 months were achieved. Toxicity was tolerable. A follow-up phase 3 study of 180 patients comparing the combination with 2 cisplatin doublets was stopped early when an interim analysis was felt to show a significant survival benefit for the 3-drug combination. Subsequent work by the same investigators showed a similar benefit for the 3-drug regimen of gemcitabine, cisplatin, and paclitaxel compared with a gemcitabine/cisplatin doublet.[53] However, these reports do not discuss the use of second-line therapy, suggesting that any benefit occurring with the integrated 3-drug regimens vs the doublet might have derived in part (or in total) from the absence of additional chemotherapy at relapse or progression. Sequential 3-drug regimens have also been tested. In the SWOG 9806 trial,[54] Edelman and colleagues presented data on 2 sequential regimens: 3 cycles of carboplatin/gemcitabine followed by 3 cycles of paclitaxel; and 3 cycles of cisplatin/vinorelbine followed by 3 cycles of docetaxel. The median and 1-year survival outcomes for both regimens were similar to outcomes reported with standard doublet approaches in previous SWOG data, and significant hematologic toxicity was noted. The Spanish Lung Cancer Group[55] recently published the results of a phase 3 randomized trial where cisplatin/gemcitabine was compared with both an "integrated" cisplatin-based triplet and with nonplatinum sequential doublets. The 3-drug arm consisted of cisplatin, gemcitabine, and

vinorelbine (CGV), similar to the regimen used by Comella,[51] while the sequential arm consisted of gemcitabine/vinorelbine followed by vinorelbine/ifosfamide (GV-VI). The efficacy results as shown in Table 9 were disappointing. Neither arm even suggested superiority over the gemcitabine/cisplatin standard. In addition, toxicity was higher for the integrated triplet, with significantly more grade 3/4 neutropenia, febrile neutropenia, thrombocytopenia, nausea, and vomiting noted. These data do not support a role for either 3-drug approach as first-line therapy in patients with advanced NSCLC.

Table 9. Spanish Lung Cancer Group Trial

GC N Response rate 182 42% CGV 188 41% GV-VI 187 27%*

Median survival 9.3 months 8.2 months 8.1 months TTP 1-year survival 2-year survival 6.3 months 6.7 months 5.5 months 38% 13% 33% 16% 34% 11%

*P = .03 GC, gemcitabine/cisplatin; CGV, cisplatin/gemcitabine/vinorelbine; GV-VI, gemcitabine/vinorelbine followed by vinorelbine/ifosfamide; TTP, time to progression.

Optimal Duration of Chemotherapy

Given the palliative nature of treatment for stage IV NSCLC and the potential for cumulative toxicity even with well-tolerated therapy, determining the optimal duration of chemotherapy is of substantial clinical relevance. Two recent randomized trials have addressed this issue. In 2001, Smith and colleagues[56] reported a randomized trial of 3 cycles vs 6 cycles of mitomycin, vinblastine, and cisplatin in 308 patients with advanced NSCLC. Of the patients randomized to 3 cycles, 72% completed therapy, while only 31% of the patients randomized to 6 cycles completed therapy. The median survival times and 1-year survival rates were similar for patients in both study arms. QOL parameters were the same or were improved in patients receiving 3 cycles of therapy; lower incidences of fatigue, nausea, and vomiting (typical cumulative toxicities of cisplatin) were reported among patients receiving the shorter course of therapy. Socinski and colleagues[57] randomized 230 patients with stage IIIB/IV NSCLC to either 4 cycles of carboplatin/paclitaxel or continuous treatment until objective progression of disease. Survival and QOL were the primary end points of this trial. A median of 4 cycles of treatment was administered to each of the study groups, and no significant differences were seen in response rate, survival, or QOL between the 2 arms. However, an increasing rate of peripheral neuropathy was seen in patients receiving more than 4 cycles of therapy.

The results of these 2 randomized trials show that first-line chemotherapy need not continue until disease progression. A finite course of therapy followed by observation and additional treatment at progression can achieve maximum clinical benefit while minimizing cumulative toxicity.

Second-line Chemotherapy for NSCLC

Second-line and subsequent therapies for NSCLC are increasingly being used in the United States, and may account in part for the improved overall survival seen in patients with NSCLC over the past decade. The most significant trial in this setting is the so-called TAX 317 trial conducted by Shepherd and colleagues,[58] in which 2 doses of docetaxel (100 mg/m2 and 75 mg/m2 every 3 weeks) were compared with BSC in patients who had previously been treated with a platinum-based regimen. The original design was a 2-arm trial comparing docetaxel 100 mg/m2 to BSC, but the trial was suspended less than halfway to completion when a 6% treatment-related death rate was noted in 49 patients on the docetaxel arm. The dose of docetaxel was subsequently reduced to 75 mg/m2. At this dose, the median number of cycles delivered was 4, and no febrile neutropenic deaths occurred. The overall objective response rate with docetaxel therapy was 7.1%. Another 42.7% of patients had disease stabilization as their best response. In an analysis of all patients, both the median survival times (chemotherapy arm, 7.0 months; BSC arm, 4.6 months) and the 1-year survival rates (chemotherapy arm, 29%; BSC arm, 19%) were significantly better for patients receiving second-line docetaxel. The median survival time and the 1-year survival rate for the patients treated with docetaxel 75 mg/m2 were 7.5 months and 37%, respectively (P = .003 vs BSC). Clinical benefit was shown in a QOL study in which all QOL parameters favored the docetaxeltreated patients. In a second randomized trial,[59] second-line docetaxel at 100 mg/m2 or 75 mg/m2 every 3 weeks was compared with either vinorelbine or ifosfamide. Patients treated with docetaxel 75 mg/m2 every 3 weeks showed a significantly increased 1-year survival rate compared with those treated with either vinorelbine or ifosfamide. At ASCO 2003, Camps and colleagues[60] reported preliminary results of a randomized phase 3 trial of either weekly docetaxel or docetaxel every 21 days as second-line therapy. Nearly 19% of patients had received prior paclitaxel. Between July 2000 and October 2002, 246 patients were entered; data were available on 179. No significant differences in the response rate or median survival were noted between the 2 arms, although more hematologic toxicity was observed when docetaxel was administered every 3 weeks. This phase 3 trial established weekly docetaxel as an important option for patients with previously treated NSCLC. Also at ASCO 2003, Hanna and colleagues[61] presented the results from a randomized phase 3 study of the investigational antifolate pemetrexed given at a dose of 500 mg/m2 every 21 days (along with daily oral vitamin supplementation) vs a standard docetaxel regimen of 75 mg/m2 every 21 days. This is the largest randomized trial to date of second-line chemotherapy. The

efficacy results of this trial are shown in Table 10. Toxicity comparisons substantially favored the pemetrexed arm.

Table 10. Second-line Chemotherapy for NSCLC: Pemetrexed vs Docetaxel

Pemetrexed Docetaxel N Neutropenic fever Response rate Median survival 1-year survival 283 1.9% 9.1% 285 12.7% 8.8%

8.3 months 7.9 months 29.7% 29.7%

On the basis of these findings, pemetrexed, when available, will constitute another option for second-line treatment of NSCLC. All of the new agents, including paclitaxel, gemcitabine, irinotecan, and vinorelbine, have been studied to some extent in the second-line setting.[62,63] In general, these trials have been phase 2 studies evaluating small numbers of patients. Response rates have ranged from 0% to 20%, with median survival rates of 4 months to 8 months. With the exception of the TAX 320 evaluation of vinorelbine, none of these agents have thus far had phase 3 evaluation against either BSC or docetaxel in the salvage setting. However, a number of randomized phase 3 second-line trials comparing novel agents plus docetaxel with docetaxel alone are under way.

The Role of Molecularly Targeted Therapy

Targeted therapies with enhanced specificity against malignant cells are continuously being sought. To date, the targeted agent most extensively studied in lung-cancer patients has been gefitinib (ZD1839), an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Gefitinib was recently approved by the US Food and Drug Administration as a third-line treatment for NSCLC. The approval was based on response rate and QOL data demonstrated in 2 large randomized phase 2 trials known as IDEAL 1 and IDEAL 2.[64,65] In these studies, 2 different daily oral doses of gefitinib, either 250 mg or 500 mg, were tested in patients with NSCLC who failed 1 or 2 (IDEAL 1) or 2 or more (IDEAL 2) chemotherapy regimens. Objective responses with gefitinib were seen in 9% to 19% of patients. An additional number experienced stable disease as best response. Overall disease control rates (ie, partial response plus stable disease) ranged from 36% to 54%; symptom improvement was seen in 37% to 43% of patients, including some heavily pretreated patients. Subsequently, gefitinib was tested in 2 large phase 3 trials in combination with first-line platinum-combination regimens. INTACT-1[66] randomized 1097 inoperable stage III/IV NSCLC predominantly European patients to 1 of 3 regimens: cisplatin/gemcitabine plus placebo vs

cisplatin/gemcitabine plus 250 mg gefitinib vs cisplatin/gemcitabine plus 500 mg gefitinib. At the final analysis, there were no significant differences among the 3 treatment arms with regard to progression-free survival or overall survival. Median survival times were 11.1 vs 9.9 vs 9.9 months, respectively. The INTACT-2 trial[67] was carried out mainly in North America, and randomized 1037 patients with advanced-stage (III/IV) NSCLC to 1 of 3 regimens: carboplatin/paclitaxel plus placebo vs carboplatin/paclitaxel plus 250 mg gefitinib vs carboplatin/paclitaxel plus 500 mg gefitinib. Median survival was 9.9 vs 9.8 vs 8.7 months, respectively, with no significant difference between the gefitinib arms and the placebo arm. Another large randomized phase 3 trial of targeted therapy presented at ASCO 2003 evaluated the addition to standard chemotherapy of an antisense oligonucleotide to PKC-alpha (LY900003, ISIS 3521).[68] More than 600 patients were randomized to either carboplatin/paclitaxel or the identical chemotherapy integrated with a 14-day infusion of LY900003. No differences in response rate or survival were noted. Additional studies of targeted therapies are ongoing. The furthest along is the ECOG-led Intergroup trial of paclitaxel and the VEGF inhibitor bevacizumab as first-line therapy in advanced NSCLC. Clearly we have much to learn about how to optimally use these potentially promising agents.

Conclusions
Chemotherapy can improve survival and QOL for patients with advanced NSCLC; the benefit reaches the "fit" older patient, and probably patients with a PS of 2. Patients with good PS should be considered for a platinum-based chemotherapy regimen based on the survival advantage provided over BSC and over modern single-agent therapy. Cisplatin-based regimens might be slightly more efficacious, yet potentially more toxic, than carboplatin-based regimens or nonplatinum combinations. Reasonable alternatives for the patient with significant comorbidities or a borderline PS include carboplatin-based combination regimens, nonplatinum combinations, or even single-agent chemotherapy. The duration of first-line therapy in patients with advanced NSCLC should usually not exceed 3 to 4 cycles; first-line therapy should be discontinued as soon as there are signs of progressive disease. Patients with disease progression during or after first-line therapy should be considered for second-line chemotherapy, and third-line therapy with gefitinib should be offered to appropriate patients.

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Authors and Disclosures

Author(s)
David Gandara, MD Professor of Medicine, University of California Davis, Davis, California; Director of Clinical Research, UC Davis Medical Center, Davis, California Disclosure: Dr. Gandara has disclosed that he has received grants for clinical research and educational activities from AstraZeneca. He has reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity. Mark R. Green, MD

Gilbreth Professor of Clinical Medicine, Medical University of South Carolina, Charleston, South Carolina

Disclosure: Dr. Green has disclosed that he has acted as an advisor and consultant for Aventis, Lilly, Pharmacia-Pfizer, GlaxoSmithKline, Amgen, Genentech, and AstraZeneca. He has reported that he discusses the investigational products pemetrexed and LY900003 in this activity. Primo N. Lara, Jr, MD Associate Professor of Medicine, University of California at Davis, Sacramento, California Disclosure: Dr. Lara has disclosed that he has served as an advisor for Aventis, Lilly, BristolMyers Squibb, and AstraZeneca, and has received grants for educational activities from Lilly. He has reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity. Mario L. Meyer, MD Fellow, Medical Oncology/Hematology, Medical University of South Carolina, Charleston, South Carolina Disclosure: Dr. Meyer has disclosed that he has no significant financial relationships to disclose. He has reported that he discusses the investigational products pemetrexed and LY900003 in this activity. Contents of Treatment Strategies for Advanced Non-Small Cell Lung Cancer [http://cme.medscape.com/viewprogram/2676] 1. Treatment Strategies for Advanced Non-Small Cell Lung Cancer [http://cme.medscape.com/viewarticle/461857] [ CLOSE WINDOW ]

CME Information
CME Released: 09/29/2003; Valid for credit through 09/29/2004
This activity has expired.

The accredited provider can no longer issue certificates for this activity. Medscape cannot attest to the timeliness of expired CME activities.

Target Audience

This activity is intended for oncologists and other physicians who treat patients with non-small cell lung cancer.

Goal
The goal of this activity is to educate physicians on the treatment of unresectable stage III and stage IV non-small cell lung cancer.

Learning Objectives
Upon completion of this activity, participants will be able to: 1. Identify the rationale behind continued research on treatment modalities for patients with stage III and stage IV non-small cell lung cancer (NSCLC). 2. Review the latest data on chemoradiotherapy strategies for stage III NSCLC. 3. Detail the latest trial results on chemotherapy strategies for stage IV NSCLC.

Credits Available
Physicians - maximum of 2.0 AMA PRA Category 1 Credit(s) All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Accreditation Statements
For Physicians

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