Concurrent Chemoradiation Strategies in the Management of Unresectable Stage III non—small-Cell Lung Cancer

Concurrent Chemoradiation Strategies in the Management of Unresectable Stage III non—small-Cell Lung Cancer

Concurrent Chemoradiation Strategies in the Management of Unresectable Stage III Non–SmallCell Lung Cancer Primo N. Lara, Jr.,1 Zelanna Goldberg,2 Ang...

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Concurrent Chemoradiation Strategies in the Management of Unresectable Stage III Non–SmallCell Lung Cancer Primo N. Lara, Jr.,1 Zelanna Goldberg,2 Angela Davies,1 Derick H.M. Lau,1 David R. Gandara1 Abstract Locally advanced or unresectable stage III non–small-cell lung cancer (NSCLC) patients treated with combined-modality therapy with chemotherapy plus thoracic radiation have improved survival compared to those treated with radiotherapy alone. Furthermore, recent studies in good performance status, stage III patients have shown that concurrent chemoradiotherapy improves survival compared to sequential chemoradiotherapy. However, the optimal chemoradiation approach continues to evolve and is the subject of this review. Since the majority of patients completing chemoradiotherapy will succumb to distant metastatic disease, active systemic agents targeting this tumor compartment are required. Recent data suggest that full-dose chemotherapy designed to eradicate distant micrometastases given either as induction or consolidation has the potential to yield improved patient outcomes. Many of these chemotherapeutic agents are also potent radiosensitizers, hence providing enhanced local control. The integration of these chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC is the focus of current trials. Ongoing research with novel therapeutic agents with activity against distant micrometastases, refined radiation techniques, and enhanced imaging methodologies to aid in accurate staging are being pursued and should lead to improved survival and toxicity outcomes in this disease. Clinical Lung Cancer, Vol. 3, Suppl. 2, S42-S48, 2002

Key words: Concurrent and sequential chemoradiation, Radiation therapy, Docetaxel, Gemcitabine, Irinotecan, Tirapazamine

Introduction

III NSCLC and will evaluate emerging treatment strategies incorporating newer chemotherapeutic and biologic agents.

The optimal treatment for patients with locally advanced, unresectable stage III non–small-cell lung cancer (NSCLC), many with bulky mediastinal lymphadenopathy (N2 or N3) or primary tumors invading vital structures (T4), has continued to evolve in the past decade. In the past, < 5% of stage III patients 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 combinedmodality therapy (chemoradiation) in this patient population.1 Specifically, recent phase III trials have yielded enhanced survival in good performance status patients treated with concurrent platinum-based chemoradiation versus sequential chemotherapy followed by radiation therapy. This review will summarize the current status of concurrent chemoradiation therapy in stage 1 Department 2 Department

of Medicine of Radiation Oncology University of California, Davis Cancer Center, Sacramento, CA Submitted: Jan. 30, 2002; Revised: Feb. 25, 2002; Accepted: March 5, 2002 Address for correspondence: Primo N. Lara, Jr., MD, UC Davis Cancer Center, 4501 X Street, Sacramento CA 95817 Fax: 916-734-7946; e-mail: [email protected]

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Rationale for Chemoradiation Therapy Theoretically, chemoradiation has several advantages over single-modality therapy. 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 it provides cytoreduction of bulky locoregional disease. This paradigm of chemoradiation has been established not only for locally advanced NSCLC but also for tumor types such as cervical and head and neck cancers.2,3 A variety of approaches to combining chemotherapy and radiation therapy have been utilized in unresectable stage III disease, including induction chemotherapy followed by radiation, concurrent chemoradiotherapy, induction chemotherapy followed by concurrent chemoradiotherapy, and concurrent chemoradiotherapy followed by consolidation chemotherapy.4 There are theoretical advantages and disadvantages to each approach, as outlined in Table 1. Recent data suggest that full-dose chemotherapy designed to eradicate distant micrometastases

Table 1

Approaches to Combining Chemotherapy and Thoracic Radiation Sequence

Chemotherapy → Radiation Therapy

Chemotherapy + Radiation Therapy

Theoretical Advantages

Theoretical Disadvantages

Full doses of each modality can be delivered without combined toxicity.

No benefit from potential radiosensitizing action of the chemotherapy.

Cytoreduction from the chemotherapy may allow smaller Chemoinsensitive disease continues to grow and potentially radiation portals, decreasing radiation toxicity. It may also metastasize before radiation therapy begins. decrease regions of hypoxia that are relatively radioresistant.

Exploits potential synergy between the modalities.

Enhanced toxicity leading to inability to deliver full dose of both modalities. No preradiation therapy cytoreduction.

Chemotherapy → Chemotherapy + Radiation Therapy

Chemoinsensitive disease continues to grow and potentially Cytoreduction from the induction chemotherapy may allow metastasize before combined-modality therapy begins. smaller radiation portals, decreasing radiation toxicity. Enhanced toxicity. Completing combined-modality therapy Full-dose chemotherapy may sterilize micrometastatic after induction chemotherapy might be too difficult for all disease, while clonogen number is minimal. but the best performance status patients. Delivering maximal antitumor efficacy up front.

Chemotherapy + Radiation Therapy → Chemotherapy

Exploits potential synergy between the modalities. Most intense treatment is given early when the patient is best able to handle it physically and psychologically.

given either as induction or consolidation has the potential to yield improved patient outcomes. Since distant metastases remain the major site of failure, more effective systemic treatments will be required to further improve the current level of response and survival.

Concurrent Chemoradiation: Current Status 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) comparing radiation therapy alone against the same radiation with weekly cisplatin at 30 mg/m2 or daily cisplatin at 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 and no change in distant metastatic rates. The results of this trial are particularly instructive, indicating that frequent administration of low-dose chemotherapy can improve outcomes solely by its radiosensitizing effects. Unfortunately, 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 Gy + 25 Gy split) is no longer considered sufficient when treating with curative intent. Daily cisplatin also results in cumulative nausea and is logistically difficult to deliver. These deficiencies likely resulted in limited clinical applicability of this regimen. Two consecutive trials by Jeremic and colleagues, investigating hyperfractionated radiation therapy, avoided these deficiencies and provided additional evidence for the superiority of concurrent chemoradiation over radiation alone.6,7 In the first trial, 169 patients were randomly assigned to either hyperfractionat-

Long treatment schedule. Enhanced toxicity. Completing combined-modality therapy after induction chemotherapy might be too difficult for all but the best performance status patients.

ed radiation therapy alone (Arm I: 1.2 Gy twice a day to 64.8 Gy) or the same radiation concurrent with carboplatin and etoposide delivered at 2 different dose schedules (Arm II: carboplatin 100 mg/m2 on days 1 and 2 plus etoposide 100 mg/m2 on days 1-3 given weekly; Arm III: carboplatin 200 mg/m2 on days 1 and 2 plus etoposide 100 mg/m2 on days 1-5 on weeks 1, 3, and 5). The 3-year survival rates for the treatment groups were 6.6%, 23.0%, and 16.0%, respectively. The survival rates for Arms I and II were statistically different (P = 0.003), but not so for Arms I and III. Although toxicity was higher in both chemoradiation arms, there were no treatment-related deaths. The second trial randomized 131 patients to either hyperfractionated radiation therapy alone (1.2 Gy twice a day to 69.6 Gy) or the same radiation therapy concurrent with carboplatin and etoposide delivered with each radiation day. Patients receiving concurrent chemoradiation had a 4-year survival rate of 23% versus 9% in the radiation-alone arm (P = 0.02). This survival advantage was solely due to enhanced local control, as the distant metastasis–free survival rate was no different between the two groups. These findings mimic those observed in the earlier EORTC trial. More recently, the West Japan Lung Cancer Study Group performed a phase III study comparing sequential versus concurrent chemoradiotherapy (Table 2).8 The trial involved over 300 patients and compared full-dose induction chemotherapy consisting of mitomycin/vindesine/cisplatin followed by oncedaily radiation of 56 Gy/28 fractions/5.5 weeks to concurrent chemoradiation, using the same chemotherapy, but with splitcourse radiation to a total dose of 56 Gy. Despite using splitcourse radiation in the concurrent treatment arm, there was a significant survival benefit for concurrent chemoradiation.

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Concurrent Chemoradiation in Stage III NSCLC Table 2

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West Japan Lung Cancer Group Study of Concurrent Versus Sequential Chemoradiation

Therapy

Response Rate

Median Survival

3-Year Survival

5-Year Survival

Concurrent

84%

16.5 months*

22%

16%

Sequential

66%

13.3 months

15%

9%

Table 3

RTOG 9410: Sequential Versus Concurrent Chemoradiotherapy in Unresectable, Locally Advanced NSCLC

Therapy

Median Survival

Grade 3/4 Nonhematological Toxicities

Local Failure

Sequential

14.6 months

30%

38%

*P = 0.04

Concurrent

17.0 months*

48%

33%

The Japanese experience was affirmed in the United States following the completion of the Radiation Therapy Oncology Group (RTOG) study 9410, a 3-armed phase III trial comparing sequential versus concurrent chemoradiotherapy and also examining altered radiation fractionation as part of combinedmodality therapy (Table 3).9,10 Arm I (standard) was identical to that of the Cancer and Leukemia Group B (CALGB) study 8433, consisting of sequential administration of cisplatin and vinblastine followed by once-daily radiation of 2 Gy to a total dose of 60 Gy. Arm II (concurrent chemoradiation) used the same chemotherapy and radiation protocol as Arm I, but the thoracic radiation started concurrently with the chemotherapy on day 1. Arm III (concurrent hyperfractionated radiochemotherapy) used different chemotherapy (cisplatin and oral etoposide) with twice-daily radiation of 1.2 Gy/fraction to 69.6 Gy total dose over 6 weeks, beginning on day 1. The recently updated results of this trial demonstrate that concurrent chemoradiation was superior to sequential treatment (median survival 17.0 months versus 14.6 months; P = 0.038), but that hyperfractionated chemoradiation did not improve outcome (15.6 months). Hyperfractionated radiation did improve local control, decreasing in-field failure from the 38% seen in the sequential therapy to 25%, but it also caused substantially more nonhematologic toxicities that cannot be justified in light of the failure to improve survival. These recent trials established concurrent platinumbased chemoradiation using once-daily radiation schedules as a standard of care in appropriately selected NSCLC patients with unresectable stage III disease. Unfortunately, despite these advances, more than three quarters of patients completing chemoradiation in these trials succumbed to 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. Fortunately, several new anticancer agents have become available in the past decade, including the taxanes (paclitaxel and docetaxel), the nucleoside analogue gemcitabine, and the topoisomerase inhibitor irinotecan.11 In addition, novel molecularly targeted agents with activity in advanced NSCLC, including the epidermal growth factor inhibitors ZD1839 and OSI-774, the hypoxic cytotoxin tirapazamine, and the recombinant humanized vascular endothelial growth factor (VEGF) inhibitor rhuMAb-VEGF, are currently in clinical trials.12 How to best integrate these newer chemotherapeutic and biologic agents into chemoradiation strategies for stage III NSCLC requires carefully designed and conducted clinical trial strategies, as discussed below.

Concurrent/ HFRT

15.6 months

62%†

25%†

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*P = 0.038 †P < 0.05 Abbreviations: HFRT = hyperfractionated radiation therapy; NSCLC= non– small-cell lung cancer; RTOG = Radiation Therapy Oncology Group

Induction Chemotherapy Followed by Concurrent Chemoradiation On the basis of two large randomized studies that demonstrated the superiority of induction chemotherapy followed by thoracic radiation over radiation therapy alone,13,14 the CALGB performed a phase III trial randomizing inoperable stage III NSCLC patients treated with induction chemotherapy (vinblastine/cisplatin) followed by radiation therapy (60 Gy) versus the same induction chemotherapy followed by concurrent radiation plus weekly single-agent carboplatin (100 mg/m2/week).15 The use of radiosensitizing doses of carboplatin is analogous to the EORTC trial discussed above. Disappointingly, this CALGB trial found no difference in failure-free and overall survival between the two arms. Specifically, 4-year survival was 13% with concurrent chemoradiation versus 10% with radiation alone (P = 0.7). Although there was an almost 20% decrease in local failure rate in the carboplatin/radiation arm, this was not enough to influence overall survival. The authors noted that patients with less favorable characteristics (ie, more advanced disease or 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 its subsequent trials. Vokes and colleagues conducted a randomized phase II trial of 3 cisplatin-based regimens incorporating 1 of 3 newer chemotherapeutic agents (vinorelbine, paclitaxel, or gemcitabine) given at full doses in the induction phase and at attenuated doses in the concurrent chemoradiation phase.16 One hundred eighty patients were entered. Although not designed to provide definitive comparisons, efficacy was relatively equivalent between the 3 regimens, with median survival of 17 months across all 3 arms, while toxicity patterns varied considerably. Grade 3 or greater neutropenia was greatest in the paclitaxelcontaining 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 incorporated 3-D conformal radia-

Primo N. Lara, Jr. et al tion therapy in an induction chemotherapy and concurrent chemoradiation phase I/II trial.17 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 (area under the curve [AUC] = 6), followed by weekly paclitaxel (45 mg/m2/week) and carboplatin (AUC = 2) over 6 weeks concurrent with escalating doses of 3-D 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 who had distant metastasis alone failed only in the brain. The RTOG is continuing to study ways to treat patients with induction chemotherapy followed by concurrent chemoradiotherapy utilizing hyperfractionated radiation. The rationale is to try to increase the tolerability of this regimen that blends the survival advantage of induction chemotherapy with the increased local control seen with hyperfractionated radiation therapy. One current approach is to add amifostine, a radioprotective agent, during concurrent chemoradiotherapy in an attempt to decrease the acute mucosal toxicity expected with this aggressive approach. Komaki and colleagues recently reported a small phase III study (n = 60) demonstrating that amifostine reduces the acute pneumonitis and esophagitis rate in NSCLC patients receiving concurrent chemoradiation for inoperable disease.18 RTOG 9801 is also examining this question in stage II/III patients.

Concurrent Chemoradiation Followed by Consolidation Chemotherapy A number of ongoing or recently completed phase II 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 II trial of the California Cancer Consortium by Lau and colleagues delivered twice-weekly paclitaxel at 30 mg/m2, weekly carboplatin at an AUC of 1.5, and concurrent radiation therapy (61 Gy) to 34 eligible patients, followed by two 21-day cycles of paclitaxel (200 mg/m2) and carboplatin (AUC = 6).19 Grade 3/4 esophagitis was noted in 38% of patients. The overall response rate was 71%, the median survival time was 17 months, and the actuarial 2-year survival rate was 40%. The Southwest Oncology Group (SWOG) has evaluated a similar strategy in the past decade. SWOG 9019 was a phase II trial in patients with pathological stage IIIB disease. The trial evaluated concurrent cisplatin/etoposide plus thoracic radiation of 61 Gy/33 fractions/6.5 weeks followed by consolidative cisplatin/etoposide for 2 more cycles.20 Median survival was 15 months. One- and 2-year survival rates were 58% and 34%, respectively. The follow-up study was SWOG 9504, a phase II study of the same concurrent therapy followed by consolidation chemotherapy with 3 doses of docetaxel instead of continued cisplatin/etoposide. Docetaxel was chosen for consolidation therapy due to its activity as second-line therapy as well as its p53-independent effects on apoptosis.21 The study included 83

Figure 1

Intergroup Trial (SWOG 0023) of EGFR Inhibitor ZD1839 Following Chemoradiotherapy ZD1839

Cisplatin/Etoposide/RT → Docetaxel (75 mg/m2 × 3) Placebo Chemoradiation → Consolidation → Maintainence Participants: SWOG, NCI-C, NCCTG Abbreviations: EGFR = epidermal growth factor receptor; NCCTG = North Central Cancer Treatment Group; NCI-C = National Cancer Institute of Canada; SWOG = Southwest Oncology Group

patients with pathologically proven stage IIIB disease (N3 or T4 disease, excluding pleural effusion). Patients entered on the study had a remarkable median survival of 26 months, with 2and 3-year survivals of 53% and 40%, respectively.22 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 of the patients developing grade 4 neutropenia. There were also 3 treatment-related deaths: 2 due to radiation pneumonitis and 1 due to aspiration pneumonia. The Hoosier Oncology Group has recently initiated a randomized trial comparing the SWOG 9019 and 9504 regimens in patients with unresectable stage III NSCLC. This study will ultimately answer the question of whether taxane sequencing results in superior survival outcomes in this patient cohort. An ongoing Intergroup phase III trial (SWOG 0023) is designed to evaluate the role of ZD1839 by delivering concurrent chemoradiotherapy followed by consolidation docetaxel (identical to the treatment in SWOG 9504), followed by randomization to receive maintenance therapy with either ZD1839 or placebo (Figure 1). The toxicity profile of ZD1839 suggests that it should be well tolerated for long-term maintenance therapy. Participants include the SWOG, National Cancer Institute of Canada, and the North Central Cancer Treatment Group.

Other Studies Integrating New Chemotherapeutic Agents into Concurrent Chemoradiation Strategies Docetaxel In a trial by Mauer and Vokes, patients with thoracic malignancies, including 20 patients with locally advanced NSCLC, were treated with 3 different schedules of docetaxel (every 3 weeks, 2 weekly doses repeated every 3 weeks, and weekly) given concurrently with radiation, 1.8-2.0 Gy per day to a total radiation dose of 60 Gy.23,24 Docetaxel doses were escalated in separate patient cohorts. The weekly schedule at a dose of 20 mg/m2 /week was recommended for further study based on tolerability. In a second phase I 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.25 The recommended doses for

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Concurrent Chemoradiation in Stage III NSCLC phase II trials were docetaxel 40 mg/m2 and cisplatin 40 mg/m2, respectively. Mudad and colleagues evaluated weekly docetaxel and cisplatin with concurrent thoracic radiation (64 Gy) in locally advanced NSCLC.26 Recommended phase II doses were 25 mg/m2/week for both agents. A phase II SWOG trial (S0022) of induction chemoradiotherapy with weekly docetaxel plus cisplatin followed by consolidation therapy with every-3-week docetaxel in stage IIIB NSCLC patients is underway. This trial will evaluate the efficacy of docetaxel incorporation into both concurrent and consolidation phases of treatment.

Gemcitabine Ongoing investigations are determining the optimal dose and schedule for concurrent administration of gemcitabine, an exquisite radiosensitizer, with thoracic radiation therapy. Fossella and colleagues conducted a phase I trial of weekly gemcitabine (over 7 weeks) with concurrent chest radiation (63 Gy/35 fractions) followed by consolidation cisplatin/gemcitabine in patients with locally advanced NSCLC.27 The maximum tolerated dose (MTD) of gemcitabine concurrent with conventional 2-D radiation was 125 mg/m2/week. However, with 3-D conformal radiation, the MTD increased to 190 mg/m2/week. The investigators noted that a strong relationship existed 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 3-D 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.

Irinotecan Irinotecan was evaluated in combination with cisplatin for induction treatment followed by concurrent full-dose standard thoracic radiation in stage III NSCLC patients by Japanese investigators.28 During the concurrent phase of treatment, irinotecan was given at 60 mg/m2 weekly combined with oncedaily thoracic radiation to a total dose of 60 Gy in 6 weeks. The reported 1-year survival was 71.7%. These impressive early results await further confirmation. Other Japanese investigators have reported a phase I study of irinotecan (on days 1, 8, and 15) plus cisplatin (day 1) with concurrent radiation.29 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 26-36 Gy were given at first and second cycles, respectively. An overall response rate of 65% was observed, and the recommended phase II dose was 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.30,31

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Tirapazamine Tirapazamine is a novel hypoxic cytotoxin that is bioactivated under hypoxic conditions. It 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 versus treatment with cisplatin alone.33 While combination trials for advanced-stage disease are ongoing, several phase I/II trials have begun utilizing tirapazamine with platinum-based chemotherapy and concurrent thoracic radiation. For example, the California Cancer Consortium is conducting a phase I/II trial of tirapazamine plus carboplatin/paclitaxel concurrent with radiation in stage III NSCLC followed by 2 additional cycles of the triplet to nonprogressing patients.

Chemoradiation in Patients with Poor Performance Status While there is strong evidence supporting the value of sequential and concurrent chemoradiation in good performance status patients, how this applies to patients with underlying comorbidities and functional impairment is not well defined. In this cohort of patients, it is has been unclear if the treatment toxicities outweigh the expected survival benefits. Few trials have evaluated these patients with poor-risk features, regardless of age. Lau and colleagues studied concurrent carboplatin/etoposide plus thoracic radiation in a group of patients that had 1 or more poor-risk factors (Table 4).34 The regimen was well tolerated, with a median survival of 12 months. These results compare favorably with historical data demonstrating a median survival of < 6 months in this patient population.35 This chemoradiation approach utilizing carboplatin/etoposide was then tested in SWOG 9429, a phase II study in poor-risk patients that yielded a median survival time of 13 months and a 2-year survival rate of 21%.36 Fifty-two of 60 patients were able to complete chemoradiotherapy without toxicity-induced interruption, and there were no treatment-related deaths. The RTOG launched a randomized phase III trial of standard thoracic radiation with or without recombinant β-interferon in poor performance status patients. Overall survival at 1 and 2 years in both arms of the study were 50% and 21%, respectively.37 The RTOG is in the process of designing a phase II study for poor prognosis patients combining a COX-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 typically is not a standard approach for poor performance status patients, a regimen such as that tested in SWOG 9429 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.

Primo N. Lara, Jr. et al Table 4

Poor-Risk Criteria

FEV1 < 2.0 L and ≥ 1.0 L SWOG performance status of 2 and either albumin level < 0.85 x LLN or weight loss > 10% Creatinine clearance > 20 mL/minute and < 50 mL/minute History of congestive heart failure Peripheral neuropathy Abbreviations: FEV1 = forced expiratory volume in 1 second; LLN = lower limit of normal; SWOG = Southwest Oncology Group

Conclusion The optimal treatment of locally advanced, unresectable NSCLC continues to evolve. For patients with acceptable performance status and no significant comorbidities, 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 methodologies to aid in accurate staging are being pursued and should lead to improved survival and toxicity outcomes in this disease.

Acknowledgements This work was supported in part by grants CA62505, CA46441, ACS CRTG-0019701CCE (to PNL).

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