Evolution of Combined Modality Therapy for Stage III Non–Small-Cell Lung Cancer

ABSTRACT: A number of randomized clinical trials and meta-analyses now support the conclusion that combined modality regimens that include cisplatin (Platinol)-based chemotherapy improve survival in stage III non–small-cell lung cancer (NSCLC) more effectively than radiotherapy or surgery alone. Depending on the therapy, chemotherapy may play a cytoreductive role by eradicating distant micrometastases, a radiosensitizing role by improving local control, or do both. In general, sequential therapies in which platinum-based chemotherapy precedes thoracic radiation or surgery have improved outcome by affecting distant metastases. In contrast, concurrent chemoradiotherapy utilizing low-dose cisplatin improves survival by reducing local recurrence without an effect on distant failure rates. In view of these observations, chemoradiotherapy strategies that integrate both radiosensitizing agents and dose levels of chemotherapy that are effective against micrometastases may prove to be most efficacious. Since distant metastases remain the major site of failure, it is also likely that more effective chemotherapy or other systemic antitumor agents are necessary to increase the current level of response and survival. Fortunately, several new chemotherapeutic agents are highly effective against NSCLC as well as potent radiosensitizers. [ONCOLOGY 14(Suppl 5):35-41, 2000]

Introduction

Non–small-cell lung cancer (NSCLC) is the most common cause of cancer-related death in both men and women in the United States each year. As the recently revised international staging system indicates,[1] patient survival is directly related to stage. Survival rates with surgical resection of early stage disease (stage I and II) have improved. However, this subgroup accounts for only a small fraction of the 140,000 new cases of NSCLC each year. Even in this favorable category, 20% to 40% of patients develop recurrence, which typically manifests as distant metastases.

Locally advanced (stage III) disease, which represents approximately 50,000 cases annually, is more common. This category of tumors is heterogeneous and, for treatment planning purposes, can be divided into several patient subgroups (Table 1): stage IIIA without mediastinal node involvement (T3 N1), IIIA N2 (minimal bulk), IIIA N2 (bulky)/IIIB (T4 or N3 without malignant pleural effusion), and stage IIIB (malignant pleural effusion). All of these subgroups are now candidates for combined modality therapy with curative intent—except in those patients with malignant pleural effusion (whose natural history and treatment options mimic those of stage IV [metastatic] disease).

A multidisciplinary clinical research effort that integrates combinations of chemotherapy, radiotherapy, and/or surgery into the therapeutic approach against advanced NSCLC has evolved within the past 10 years.[2] In a number of phase III clinical trials, cisplatin (Platinol)-based chemotherapy—either in combination with thoracic radiation or administered before surgery—has improved survival more effectively than radiotherapy or surgery alone.[3-9] In addition, a number of new chemotherapeutic agents are now incorporated into combined modality regimens. These recent advances, including the rationale and design of ongoing clinical research studies investigating new treatment regimens, are reviewed on the following pages.

Combined Modality Approaches

A variety of approaches that integrate chemotherapy, radiation, and/or surgery into combined modality treatment of NSCLC are illustrated in Table 2. Each has potential advantages and disadvantages. Both bimodality (chemotherapy plus radiotherapy, or chemotherapy plus surgery) and trimodality (chemotherapy plus radiotherapy plus surgery) options are under investigation.

In both options, NSCLC is considered to be a two-compartment model consisting of a combination of local-regional disease and distant micrometastases in which thoracic irradiation or surgical resection addresses the issue of local control, while the use of chemotherapy (or other systemic antineoplastic agents) addresses occult distant spread.[2] Additionally, chemotherapy may play a cytoreductive role locally or a radiosensitizing role, as described above.

For the purpose of this discussion, these approaches to combined modality therapy can be divided into two avenues: (1) definitive chemoradiotherapy (nonsurgical combined modality therapy), and (2) preoperative (neoadjuvant or induction) chemotherapy with or without radiotherapy followed by surgical resection. A third avenue, postoperative adjuvant therapy, is not detailed in this review.

Definitive Chemoradiotherapy Studies

Sequential therapy, in which chemotherapy is completed prior to the administration of radiotherapy, is the most widely recognized approach to chemoradiotherapy for locally advanced NSCLC. Because sequential chemoradiation avoids overlapping toxicities, full doses and optimal schedules of both modalities may be used, but the duration of therapy is prolonged. In addition, the potential for chemotherapeutic radiosensitization is lost. By comparison, concurrent chemoradiation optimizes both the radiosensitizing and local cytoreductive potential of chemotherapy. There is no delay in use of either modality, but concurrent therapy entails the risk of overlapping toxicity. Conceptually, enhanced toxicity with concurrent therapy may preclude delivery of full doses of either modality, depending on the chemotherapeutic regimen and radiation dose schedule.

A number of phase III trials have compared sequential chemoradiation to radiotherapy alone in stage III NSCLC and their overall results have been subjected to meta-analysis.[3-7,10] In a landmark Cancer and Leukemia Group B (CALGB) study, a limited 5-week course of chemotherapy (100 mg/m² cisplatin during weeks 1 and 5 plus vinblastine (Velban), 5 mg/m²/week during weeks 1–5) followed by radiotherapy (60 Gy/30 fractions) was delivered in clinical stage III patients who had good performance status (0–1) and minimal weight loss (< 5%). Results were compared to patients who received the same radiotherapy alone. Despite the brief duration of exposure to this platinum-based chemotherapy, survival was significantly greater in the combined modality treatment arm (P = .006). Although median survival was modestly improved (13.8 vs 9.7 mo), survival at 2 years (26% vs 13%) doubled.[3] These results were confirmed in a subsequent Intergroup trial (Radiation Therapy and Oncology Group [RTOG] 88-08),[4] comparing identical radiotherapy and sequential chemoradiotherapy arms with those of the previous CALGB study.

A third treatment arm evaluated the role of hyperfractionated radiotherapy. Median and 2-year survival in the chemoradiotherapy arm (13.8 mo/31%) were significantly superior to both standard radiotherapy (11.4 mo/20%) and hyperfractionated radiation (12.3 mo/24%) (log rank, P = .03). However, at 5-year follow-up, survival was less than 10% in all three arms, which substantiates the need for better chemoradiotherapy strategies.[11]

A French study in stage III disease by Le Chevalier compared a control arm of radiotherapy alone (65 Gy) to three monthly cycles of PCVC (cisplatin, lomustine [CeeNU], vindesine [Eldesine], and cyclophosphamide [Cytoxan, Neosar]) followed by the same radiotherapy.[5] At 3 years, 12% of patients treated with sequential chemoradiotherapy were alive vs 4% of those treated with radiotherapy alone (P = .02).[5,6] In this study, the rate of distant metastasis was significantly lower in the combined modality group (P < .001). With rigorous restaging that included bronchoscopy, local control was less than 20% on either treatment arm, which demonstrates one of the limitations of sequential chemoradiotherapy.

Several phase III trials have compared concurrent cisplatin-based chemoradiotherapy to radiotherapy alone.[12-15] The hypothesis that improved local control from chemoradiosensitization could improve survival is supported by a study from the European Organization for Research and Treatment of Cancer (EORTC), reported by Schaake-Koning et al.[12]

Three treatment arms were evaluated: split-course radiotherapy alone, split-course radiotherapy administered concurrently with either weekly cisplatin (30 mg/m²/week), or daily cisplatin (6 mg/m²) on the days of radiotherapy. Both cisplatin-containing arms showed superior results to radiation alone, with a statistically significant survival advantage using daily cisplatin over radiotherapy alone (P = .009).

Of particular interest, improved survival with cisplatin was entirely due to increased control, with a significant difference in 2-year freedom from local recurrence in those treated in the radiotherapy-alone arm (19%) vs the chemotherapy treatment arm (30%). There was no difference in time to development of distant metastasis. These results suggest that low-dose cisplatin functioned primarily as a radiosensitizer—leading to improved local control but proving ineffective against occult systemic disease. Conversely, fully cytotoxic doses of cisplatin-based chemotherapy, sequenced prior to radiation in the Le Chevalier study, were effective in eradicating distant micrometastases without an impact on local control.[5,6]

Concurrent vs Sequential Chemoradiotherapy

Most recently, the results of a Japanese study by Furuse et al directly compared concurrent vs sequential chemoradiotherapy in stage III NSCLC.[16] In this randomized study, median and long-term survival were clearly superior in the concurrent arm (Table 3). Patients on the sequential arm received two cycles of mitomycin (Mutamycin)/vindesine/cisplatin (MVP) chemotherapy (56 Gy/2 Gy daily) prior to thoracic radiotherapy; patients on the second arm received split-course thoracic radiotherapy (56 Gy) concurrent with MVP. Median survival for the concurrent chemoradiotherapy arm was 16.5 months, significantly better than the 13.3 months observed in the sequential arm (P = .05). At 3 years, survival was 27% with concurrent therapy compared to 12.5% with sequential therapy. Furthermore, toxicity profiles were acceptable in both of these combined modality approaches, although esophagitis and myelosuppression were more frequent in the concurrent arm. If these data are confirmed by a recently completed RTOG trial, concurrent chemoradiotherapy will become the standard of care for nonsurgical therapy of stage III disease. Most ongoing clinical trials have already incorporated concurrent chemoradiotherapy into the study design.

Preoperative Chemotherapy (± Radiotherapy) Followed by Surgical Resection

The concept of preoperative or neoadjuvant therapy was initially explored in pilot studies that demonstrated feasibility, high response rates, high resectability rates, and acceptable perioperative morbidity and mortality.[17-23] All studies used a cisplatin-based chemotherapeutic regimen. In most studies, concurrent radiation therapy was delivered preoperatively, to a total dose of 30 to 45 Gy.

Long-term outcome was recently reported for the largest of these phase II studies (Southwest Oncology Group [SWOG] 8805) and is particularly instructive.[23,24] In this study, Albain et al treated 126 patients with pathologically confirmed stage IIIA N2 and IIIB NSCLC with cisplatin (Platinol)/etoposide (VePesid, VP-16) (PE) and concurrent radiotherapy (45 Gy) before attempting surgical resection.[24] In addition to a requirement for pathologic demonstration of N2 status in stage IIIA patients, over one-third of the patients had pathologically documented stage IIIB disease (T4 or N3), which makes this study unique. Complete resection following induction chemoradiotherapy was accomplished in 73% of patients. In 57% of surgical specimens, pathologic complete or near-complete response (only a few remaining microscopic tumor foci) was achieved, including 46% of patients whose response by CT scan was judged to be “stable disease.”

The status of N2 disease at the time of surgical resection was the most significant predictor of subsequent survival. If residual N2 disease was present, median survival was markedly shorter (10 months) compared with patients in whom N2 disease had been eradicated by neoadjuvant chemoradiation (30 months). This finding implies that, in this setting, surgical resection may have been more prognostic than therapeutic, by identifying patients destined for long-term survival based on response to preoperative therapy. There was no difference in long-term survival between stage IIIA (20%) and IIIB (22%) at a 6-year follow-up. Perioperative morbidity and mortality were acceptable. However, late pulmonary death occurred in approximately 10% of patients following surgery or boost radiotherapy. This trial provides the basis for the surgical arm of the current Intergroup study that randomizes patients with stage IIIA N2 disease to either preoperative chemoradiotherapy (45 Gy) or definitive chemoradiotherapy (61 Gy).

Phase III Studies

Two small phase III trials that reported the superiority of preoperative chemotherapy followed by surgery compared to surgery alone have been recently updated in regard to long-term survival (Table 4). [8,9,25,26] In the Roth study, 60 patients with stage III (N2 or T3) NSCLC were randomized to receive either surgery alone or induction chemotherapy with three cycles of cyclophosphamide, etoposide (VePesid, VP-16), and cisplatin followed by surgery. Selected patients in both groups received postoperative radiotherapy. Median survival was 11 months for the surgery alone group vs 64 months for the combined modality group (P = .008). Long-term follow-up demonstrates survival at 5 years is 36% in the group receiving preoperative chemotherapy compared to 15% in the group receiving surgery alone.[25]

In a similar study design, Rosell and colleagues randomized 60 patients to either surgical resection followed by chest radiotherapy (50 Gy), or three courses of induction chemotherapy with mitomycin, ifosfamide (Ifex), and cisplatin (MIC) followed by surgical resection and radiotherapy.[9] There was a highly significant improvement in disease-free survival and overall survival in the chemotherapy arm, which resulted in early closure of the trial. Median survival was 26 months with preoperative chemotherapy vs 8 months with primary surgery (P < .001). At 5-year follow-up, 17% remained alive in the preoperative chemotherapy group, while there were no long-term survivors with surgery alone.[26]

The results of these trials are provocative; however, due to the small number and select nature of the patients treated, they are not definitive.[27] In addition, these trials do not address the question of whether this patient population would fare equally well if treated with definitive chemoradiotherapy, the subject of the current Intergroup trial discussed above. Nevertheless, primary surgery results in poor survival rates in most patients documented preoperatively with N2 disease and should not be encouraged, especially in view of the disappointing results of a recent trial of adjuvant chemotherapy given postoperatively.[28]

In this Intergroup study (Eastern Cooperative Oncology Group [ECOG] 3590), patients with surgically resected stage II and III NSCLC were randomized to receive postoperative cisplatin/etoposide and radiotherapy or radiotherapy alone. There were no differences in disease-free survival or overall survival.

These data bring into question the use of any type of adjuvant therapy, chemotherapy or radiation, in a nonprotocol setting in surgically resected NSCLC. As noted below, it is possible combinations containing new agents will be more effective in this regard. Studies randomizing post-resection patients to receive such regimens compared with observation are underway.

Integration of New Chemotherapeutic Agents

Although combined modality strategies do result in a positive affect on survival, a consensus therapy for stage III NSCLC has yet to be identified. The results of recent studies define new standards of care in which 20% to 30% of patients with minimal weight loss and good performance status treated with combined modality therapy achieve long-term survival. Nevertheless, most stage III patients still die of recurrent disease, mandating continued evaluation of new therapeutic approaches.

Systemic recurrence remains the major cause of treatment failure. Therefore, new and improved systemic antineoplastic agents (or improved utilization of currently available agents) remain a high priority in clinical research studies. Fortunately, there are now several new chemotherapeutic agents that demonstrate a relatively high degree of single-agent activity in NSCLC—some with novel mechanisms of action and resistance, including the taxanes (paclitaxel [Taxol] and docetaxel [Taxotere]), the vinca-alkaloid vinorelbine (Navelbine), the topoisomerase-I inhibitor irinotecan (Camptosar, CPT-11), and the nucleoside analog gemcitabine (Gemzar).[29]

Combinations With Cisplatin

In metastatic NSCLC, combinations of these new agents with cisplatin have reportedly improved response or survival rates, or both, when compared with either cisplatin alone or older cisplatin-containing regimens.[30] Additionally, all have demonstrated some evidence of radiosensitizing properties and synergistic antitumor effects in combination with radiation in preclinical models.[31-34]

Based on these preclinical data, a series of clinical trials have been initiated to combine these new chemotherapeutic agents with radiation. Critical factors considered in the design of these studies (Table 5) include (1) dose of the new agent (low-dose radiosensitizing or full-dose cytotoxic), (2) schedule of the new agent (daily, weekly, or less frequently), and (3) sequential or concurrent administration with radiation, or a combination of both. Because these new chemotherapeutic agents have most often been combined with platinum compounds (cisplatin or carboplatin [Paraplatin]) in the treatment of stage IV disease, new agents and platinum combinations have also been employed in many chemoradiation trials in stage III disease.

Combined Modality Therapy

Paclitaxel is the most extensively investigated combined modality therapy. In a study by Choy et al, the maximum tolerated dose in a weekly schedule concurrent with radiotherapy (60 Gy continuous) was 60 mg/m²/week, given by 3-hour infusion.[35] As in most other studies of new agents in combination with radiation, esophagitis was dose-limiting. A number of ongoing or recently completed phase II studies have evaluated paclitaxel in combination with cisplatin or carboplatin, administered sequentially before radiation or concurrently with radiotherapy, or a combination of sequential and concurrent therapy.

Docetaxel has been evaluated in the same fashion: in low doses weekly, concurrently with thoracic radiation, and in a recently completed SWOG (S 9804) trial, as full-dose consolidation therapy following concurrent cisplatin/etoposide/radiation.[36] Toxicities observed in new agent/radiation trials emphasize the need for careful dose-escalation studies before these regimens are translated into routine patient management. For example, in Japanese studies combining irinotecan with concurrent radiotherapy, severe or fatal radiation pneumonitis has been observed in a small number of patients.[37,38] Ongoing studies are defining safe dose schedules of irinotecan given concurrently with radiotherapy.

Similar findings have been reported in some of the initial trials of gemcitabine in combination with thoracic radiation.[39] A recently completed CALGB trial used a randomized phase II design to investigate three regimens combining new agents and cisplatin (gemcitabine/cisplatin, paclitaxel/cisplatin, and vinorelbine/cisplatin) plus radiotherapy. All three regimens were initially administered as induction chemotherapy for two cycles and subsequently concurrent with radiotherapy.[40] Toxicity patterns varied among the three regimens; efficacy was relatively equivalent.

Although preliminary results are encouraging, toxicity has been substantial in some studies and, to date, there are no phase III trials that demonstrate the superiority of any new agent-based regimen in combination with radiotherapy when compared with standard cisplatin/radiotherapy regimens. (The study designs for three North American cooperative group trials in chemoradiation for stage III disease are depicted in Figure 1.) An ECOG study addresses the question of improved radiation by sequencing induction chemotherapy before either standard once per day or hyperfractionated accelerated radiotherapy (HART). CALGB is testing the concept of concurrent vs sequential plus concurrent chemoradiation, where concurrent therapy consists of radiosensitizing, low-dose chemotherapy.

Lastly, an Intergroup trial involving SWOG, North Central Cancer Treatment Group (NCCTG), and National Cancer Institute of Canada (NCI-C) will evaluate the novel therapeutic epidermal growth factor receptor (EGFR) inhibitor ZD1839 (Iressa) compared to placebo following maximal cytoreduction with chemoradiotherapy. Carefully designed and conducted clinical trials such as these are needed to define the role each of these new chemotherapeutic agents (or other novel classes of antineoplastic agents) will ultimately play in combined modality approaches to stage III NSCLC.

Conclusions

These studies clearly illustrate that multimodality therapy improves therapeutic outcomes in patients with stage III NSCLC compared with either radiotherapy or surgery alone. Moreover, platinum-based chemotherapy is the common denominator of all successful approaches to date. This remains true even though the exact role of surgery and radiotherapy in local control, the best sequence of modalities, and optimal chemotherapy and radiotherapy regimens are still not defined—and may well differ for various subsets of stage III disease.

Despite these advances, stage III NSCLC remains a lethal disease in the majority of patients. The best way to integrate new chemotherapeutic agents into combined modality therapy remains unclear. Evidence is also inconclusive as to whether new-agent combinations are superior to older cisplatin-based regimens. The studies continue.

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