Benefit of Adjuvant Rx for Resected NSCLC Confirmed

BARCELONA, Spain—Final results of a large international phase III trial confirm the benefit of adjuvant chemotherapy after complete resection in patients with early-stage non-small-cell lung cancer (NSCLC). Rafael Rosell, MD, of Catalan Institute of Oncology, Badalona, Spain, presented the results of the trial, known as ANITA (Adjuvant Navelbine International Trialist Association), at a plenary session of the 11th World Conference on Lung Cancer. Earlier this year, Jean-Yves Douillard, MD, PhD, head, Division of Medical Oncology, Rene Gauducheau Cancer Center, Saint-Herblain, France, reported the study findings at the American Society of Clinical Oncology 41st Annual Meeting .

The survival benefit found in the ANITA study, comparing adjuvant vinorelbine (Navelbine) plus cisplatin against observation only, mirrors the results of the recently published JBR.10 study (Winton T et al: N Engl J Med 352:2589-2597, 2005). JBR.10 (initially reported at ASCO 2004) randomized 482 patients with completely resected stage Ib or II NSCLC and good performance status to receive vinorelbine/cisplatin or observation. Overall survival was significantly longer with chemotherapy (94 months vs 73 months for observation, P = .04), as was relapse-free survival (not reached vs 46.7 months for observation, P < .001). Five-year survival rates were 69% and 54%, respectively (P = .03).

Dr. Douillard pointed out in his ASCO 2005 presentation that "there is still some skepticism about the use of adjuvant chemotherapy as reflected by a controversial debate that took place at the European Society of Medical Oncology in Vienna last fall, where the audience finally was still unsure of the benefit, so we needed an additional trial to prove the benefit."

ANITA Protocol

ANITA included 840 patients with completely resected stage I (T2N0 only), stage II, or stage IIIa NSCLC, enrolled at 101 centers in 14 countries. Patients were randomized to receive four cycles of vinorelbine 30 mg/m²/wk for 16 weeks plus cisplatin 100 mg/m² on day 1 every 4 weeks or observation only. Patients could receive postoperative radiation therapy, as determined by the treating institution. Median age was 59 years; 86% were male; about 60% had squamous cell carcinoma; and 35% had stage I disease, 30% stage II, and 35% stage IIIa.

In the intent-to-treat population, with a median follow-up of more than 70 months, median relapse-free survival is 36.3 months for vinorelbine/cisplatin vs 20.7 months for observation (hazard ratio [HR] 0.76, P = .002), and median overall survival is 65.8 months vs 43.8 months (HR 0.79, P = .013).

Two-year survival was increased by 5.1% with chemotherapy (67.9% vs 62.8%, P = .013). The increase rose to 8.6% at 5 years (51.2% vs 42.6%, respectively) and remained at 8.4% at 7 years (45.2% vs 36.8%, respectively).

Analysis by stage showed no significant survival benefit for chemotherapy in patients with stage Ib NSCLC, as was also reported in JBR.10. In stage II, the difference in median survival was large: 65.8 months for chemotherapy vs 36.5 months for observation. Similar benefit was seen for stage IIIa disease (38.6 months vs 24.1 months, respectively).

Dr. Rosell reported at Barcelona that patients with N2 disease, but not those with N0 or N1 disease, may benefit from postoperative radiation therapy. Five-year survival for patients with N2 disease was 16% for surgery only, 21% for postoperative radiation therapy only, 34% for adjuvant chemotherapy only, and 47% for chemotherapy plus radiation therapy. It should be noted that patients were not randomized according to whether or not they received radiation therapy, and this was not an endpoint of the trial.

Multivariate analysis showed four major criteria that improved outcome: N0 disease (P < .001), stage Ib-II disease
(P < .001), age under 55 (P = .006), and adjuvant chemotherapy (P = .002).

There were no unexpected toxicities. Grade 3-4 neutropenia occurred in 85% of patients receiving chemotherapy, but febrile neutropenia developed in only 12.5%. Grade 3-4 nausea/vomiting, primarily related to use of cisplatin, was reported in 27.2% of patients. Five patients (1%) died of drug-related toxicity.

The researchers concluded that vinorelbine/cisplatin should be considered as a standard of care after total resection of stages IIa, IIb, and IIIa NSCLC.

Controversy Is Over

In a commentary accompanying Winton et al’s report of JBR.10, Katherine M.W. Pisters, MD, of the Department of Thoracic and Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, said that based on Winton et al and the supporting trials, including ANITA, "the controversy surrounding adjuvant chemotherapy for resectable NSCLC cancer is over. Adjuvant platinum-based chemotherapy should be recommended after complete resection of NSCLC in patients with a good performance status."

Dr. Pisters pointed out that NSCLC accounts for 80% to 85% of lung cancer cases, and that even with complete resection, the 5-year overall survival rate is only 23% to 67%, depending on the size of the primary tumor and the presence or absence of invasion and lymph-node involvement. "After surgery," she said, "relapse at distant sites occurs two to three times as frequently as local recurrence and is most often fatal." Thus, she said, the reported benefit of adjuvant chemotherapy for non-small-cell lung cancer "has tremendous implications."