Introduction

Two late-breaking abstracts presented at the 2004 annual meeting of the American Society of Clinical Oncology (ASCO 2004) have further validated the efficacy of adjuvant chemotherapy for non-small cell lung cancer (NSCLC). The magnitude of benefit noted with adjuvant chemotherapy in these 2 trials (one by the National Cancer Institute of Canada [NCIC]^[1] and the other by the Cancer and Lymphoma Group B [CALGB]^[2]) is a remarkable progression in the history of lung cancer treatment and compares favorably with the benefit from post-operative chemotherapy for breast and colon cancers. Another possible factor in the success of both NCIC and CALGB trials may be attributed to use of third generation chemotherapeutic agents, which appear to be better tolerated. These recent studies prove that adjuvant chemotherapy should now be considered the unequivocal ‘standard of care’ for the treatment of patients with completely resected early stage NSCLC.

Background

For the majority of patients, NSCLC remains a lethal disease even when it is detected early. The 5-year survival rate for patients with stage IB NSCLC is 57% and less than 50% for patients with stage II disease following surgical resection.^[3] Although there have been major improvements in surgical techniques and post-operative care, the long-term outlook for patients has not changed significantly over the past few decades.

While local disease recurs in approximately one-third of patients following surgical resection, distant disease is the primary cause of death for patients with early stage NSCLC. Several pilot studies have established both the presence of micro-metastasis at systemic sites in patients with early stage NSCLC^[4],[5] and a concomitant trend towards inferior survival for those patients.

Historically, attempts to improve post-surgical outcomes have focused on a variety of chemotherapy regimens aimed at eliminating disease recurrence and/or distant disease development.  Initial attempts did not yield much success, as evidenced by lack of survival benefit with chemotherapy alone or chemoradiotherapy following surgical resection in randomized clinical trials.^[6],[7] Results of early trials were often confounded by the concurrent use of post-operative radiation and chemotherapy. However, a meta-analysis of randomized trials demonstrated a modest 5% survival benefit for patients who received cisplatin-based chemotherapy following surgical resection.^[8]

ASCO 2003: The International Adjuvant Lung Trial

The first results to show a benefit from adjuvant chemotherapy in NSCLC were presented at the 2003 ASCO meeting.^[9] The IALT was the first large clinical trial (N=1867 patients) that demonstrated survival benefit from 3-4 cycles of cisplatin (Platinol®)-based chemotherapy following surgery for patients with stages I, II, and IIIA NSCLC.^[10] There was an absolute survival benefit of 4.1% at 5-years with chemotherapy (p= 0.03) and an improvement in disease-free survival by 5% at 5-years (p=0.003).

Patients were treated with the doublet combination of Platinol® with etoposide, vinorelbine (Navelbine®), vinblastine (Velban®) or vindesine. Approximately 75% of patients received a cumulative dose of Platinol® >240 mg/m2. Improvements in outcome with chemotherapy were modest, but the differences were statistically significant, leading to a paradigm shift for resected NSCLC patients.

National Cancer Institute of Canada (NCIC): JBR 10 Trial

Presented at an oral session of the 2004 ASCO meeting were the results of an NCIC study that demonstrated major improvement in survival with Platinol®-Navelbine® chemotherapy following surgical resection for patients with stages IB and II NSCLC.^[11]

Between July 1994 and April 2001, 482 patients with stages IB and II NSCLC were recruited to a randomized clinical trial. Within 40 days following complete surgical resection, patients received either 4 cycles of Platinol® and Navelbine® or observation. (Patients with stage T3N0 were not included, as they were classified as stage III according to guidelines current at study inception). Patients were stratified based on nodal involvement (N0 vs. N1) and presence of k-ras mutations (present vs absent). The primary endpoint of the study was overall survival and the secondary endpoints were relapse-free survival, toxicity, quality of life, and prognostic significance of k-ras mutations. The study was designed to detect an absolute improvement in survival of 10% at 3-years with chemotherapy, compared to observation. Patients who underwent sub-lobar resections and bronchioloalveolar histology, mixed SCLC-NSCLC pattern, significant co-morbid illnesses, and presence of mediastinal nodal involvement (N2) were excluded from the trial.

Patient baseline characteristics were evenly distributed between study and control.  Approximately 45% of the patients had stage IB disease and 23% had k-ras mutations. Toxicities included febrile neutropenia which occurred in 7% of patients.

Platinol®-Navelbine® adjuvant chemotherapy provided a significant overall and 5-year survival benefit over observation in this patient population. Furthermore, the median relapse-free survival has not been reached for patients treated with chemotherapy, compared to 46 months with observation (table 1).

Table 1 Outcomes with adjuvant Platinol®-Navelbine® versus observation in early NSCLC

The impact of chemotherapy on quality of life was minimal with the exception of neurotoxicity (parasthesias, numbness, and hearing problems).

Cancer and Leukemia Group (CALGB) B 9633

While all previous randomized trials of adjuvant chemotherapy for NSCLC have evaluated Platinol® as the platinum compound, the CALGB 9633 trial is the first to evaluate the role of carboplatin (Paraplatin®). This randomized clinical trial evaluated the efficacy of 4 cycles of chemotherapy with Paraplatin® and paclitaxel as adjuvant therapy for patients with stage IB NSCLC.^[12] Results demonstrated a 38% reduction in all-cause mortality and a 49% reduction in lung cancer-related deaths. 

The CALGB study began in 1996 and enrolled 344 patients over seven years. The Data and Safety Monitoring Committee recommended closure of the study at 90% because of the strong survival benefit realized with chemotherapy. Patients with stage IB (T2N0) were randomized within 4-8 weeks after surgical resection to observation or chemotherapy. Chemotherapy consisted of Paraplatin® AUC=6 mg/ml.min and paclitaxel 200 mg/m^{2< /SUP> , both administered on day 1 of four 3-week cycles.}

^{A total of 173 patients were randomized to chemotherapy and 171 to observation following surgery. Stratification factors included: histology (squamous vs, non-squamous), differentiation (poorly differentiated vs. others) and mediastinoscopy (yes vs no). All baseline characteristics were evenly matched between study and control.} 

^{Chemotherapy showed a significant benefit in 4-year survival and relapse-free survival over observation (table 2). Furthermore, deaths from lung cancer were reduced by approximately 50% with chemotherapy (hazard ratio 0.49, p=0.018). In aggregate, this study demonstrated a 38% reduction in all-cause mortality and a 49% reduction in lung cancer-related deaths.} 

^{Table 2 Outcomes with adjuvant Paraplatin®/paclitaxel vs observation in early NSCLC}

Chemotherapy was well tolerated with approximately 85% of the patients receiving the planned 4 cycles of treatment. The principal toxicity was myelosuppression. Grade 3 neuropathy occurred in 5% of the patients treated with chemotherapy.

Meta-analysis of all Randomized Clinical Trials with UFT

Japanese researchers have reported a similar survival advantage in early NSCLC with the use of a different chemotherapeutic agent, UFT (tegafur and uracil), which is an orally administered pro-drug of 5-fluorouracil. UFT was compared to observation for 2 years following surgical resection and demonstrated survival advantage for patients with stage I adenocarcinoma of the lung.^[13]

Results from a meta-analysis of all randomized clinical trials with UFT reported by Japanese researchers at ASCO 2004 strongly support systemic chemotherapy for the treatment of early stage NSCLC.^[14]

Data from 2003 patients were analyzed on an intent-to-treat basis. The study population consisted of patients enrolled in six randomized clinical trials that compared adjuvant chemotherapy with UFT to surgery alone for early stage NSCLC. The meta-analysis demonstrated significantly improved survival with UFT at 5-years with a hazard ratio of 0.77 in favor of UFT (p=0.011). The 7-year overall survival rates were 77% and 69% for the UFT and observation arms respectively. 

Conclusions

In the United States, 3-4 cycles of platinum-based chemotherapy is the recommended adjuvant therapy for patients with resected NSCLC. It is unclear based on available data if Platinol® and Paraplatin® are comparable in efficacy in the adjuvant therapy setting. It is our opinion that patients with good performance status and minimal co-morbidities should be treated with Platinol®-based chemotherapy following surgical resection.

The next step will be to compare the neoadjuvant chemotherapy strategy with the adjuvant approach for early stage NSCLC. An additional comparison of adjuvant UFT with 3-4 cycles of platinum-based chemotherapy would also be most helpful, especially in the Japanese population with resected NSCLC. The incorporation of targeted agents in the early-stage setting is also being pursued.

References