IALT

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Arriagada R, et al. "Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer". The New England Journal of Medicine. 2004. 350(4):351-360.
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Clinical Question

Do patients with completely resected non-small cell lung cancer have improved survival with cisplatin-based adjuvant chemotherapy compared to observation alone?

Bottom Line

Adjuvant cisplatin-based chemotherapy improves overall survival at five years in patients with complete surgical resection of Stage I-III non-small cell lung cancer.

Major Points

Surgery, chemotherapy, and radiation therapy all play a role in the treatment of non-small cell lung cancer (NSCLC). Particularly for patients with Stage I and II disease, surgical resection offers the best chance at a cure. The International Adjuvant Lung Cancer Trial (IALT)[1] was the first large randomized clinical trial to demonstrate that adjuvant chemotherapy, after complete surgical resection, had a clear mortality benefit at 5 years. However, after reassessment at 7.5 years, this mortality benefit waned and became nonsignificant. This trial was done with cisplatin-containing adjuvant chemotherapy in patients with Stage I-III disease.

The JBR.10 trial[2] replicated the effectiveness of cisplatin and vinorelbine in patients with complete resection of Stage II disease at 9 years, 6.8 years versus 3.6 years median survival, however it failed to detect a mortality benefit in patients with Stage IB disease. The ANITA trial[3] similarly identified mortality benefit with adjuvant cisplatin and vinorelbine in Stage II and IIIA disease NSCLC, but not Stage IB. The CALGB 9633 trial[4], which was limited to patients with Stage IB disease, found significant mortality benefit at 3 years but not at 6 years. Current guidelines limit the use of adjuvant chemotherapy in this population.

Beginning chemotherapy before or after surgery (neoadjuvant vs. adjuvant) appears to make confer similar mortality benefits; the NATCH trial demonstrated greater completion rates for neoadjuvant vs. adjuvant chemotherapy for NSCLC (90% vs. 61%), but with equal overall survival at 3 years.

Guidelines

NCCN Guidelines on Non-Small Cell Lung Cancer, 2.2016[5]
Adjuvant chemotherapy ns ot recommended for patients with Stage IA NSCLC
Adjuvant chemotherapy may be considered for patients with high-risk or margin-negative Stage IB NSCLC
Adjuvant chemoradiation or chemotherapy is recommended for Stage II and IIIA NSCLC
All regimens recommended for adjuvant chemotherapy for NSCLC include cisplatin (with vinorelbin, etoposide, gemcitabine, docetaxel, or pemetrexed) with the exception of one cisplatin-sparing alternative

Design

  • Multicenter randomized trial (no blinding, no placebo-control)
  • N=1867
    • Cisplatin-based chemotherapy with adjuvant determined by individual site (n=932)
    • Observation (n=935)
  • Setting: 148 centers in 33 countries
  • Enrollment: February 1995 to December 2000
  • Mean follow-up: 56 months, 98.1% of patients
  • Analysis: Intention-to-treat
  • Primary outcome: Overall survival
  • Secondary outcomes: Disease-free survival and second primary cancers

Population

Inclusion Criteria

  • NSCLC Stage I-III, pathologically-proven
  • Complete surgical resection
  • Age 18 - 75

Exclusion Criteria

  • Prior chemotherapy or radiotherapy
  • Contraindication to chemotherapy
  • No prior cancer, aside from nonmelanoma skin cancer or cervical carcinoma in situ

Baseline Characteristics

From experimental group (similar to control)

  • Demographics: Age 59 years, 80.7% male
  • Type of cancer: Squamous (46%), Adenocarcinoma (41%), Large-cell carcinoma (6%), Mixed (4%)
  • TNM Stage: I (36%), II (25%), III (40%)
  • ECOG performance status: 0 (54%), 1 (38%), 2 (7%)
  • Type of surgery: Pneumonectomy (35%), Lobectomy (64%), Segmentectomy (1%)

Interventions

  • Randomized to experimental vs. control, stratified by center, surgery type, and pathologic stage
  • Each center individually determined their policy for dose of cisplatin and choice/dose of second agent for each stage of NSCLC
    • Experimental group received cisplatin-based adjuvant chemotherapy as pre-planned by each center within 60 days of surgery
    • Control group received observation only (no placebo given)
  • All patients were to complete a one-page follow-up form on adverse events at 6 months and annually
Drug Combined with Cisplatin:
  • Etoposide (56.5%), Vinorelbine (26.7%), Vinblastine (10.9%), Vindesine (5.8%)

Outcomes

Comparisons are adjuvant chemotherapy vs. observation.

Primary Outcomes

Overall Survival
Five-year survival: 44.5% vs. 40.4% (P<0.03)
Two-year survival: 70.3% vs. 66.7%
Death: HR 0.86; (95% CI 0.76-0.98; P<0.03)

Secondary Outcomes

Disease-free survival
Five-year: 39.4% vs. 34.3% (P<0.003)
Two-year: 61.0% vs. 55.5%
Disease-progression or death: HR 0.83; (95% CI 0.74 to 0.94; P<0.003)

Subgroup Analysis

The intervention exhibited a nonsignificant trends towards mortality benefit across a multitude of subgroup analyses including age, gender, TNM stage, histologic type, dose of cisplatin, and choice of second agent. Three subgroups with a nonsignificant trend toward harm includes worse performance status, higher dose of cisplatin (120 mg/m2), and use of vindesine as a second agent.

Mortality by TNM Stage
Stage I: 34.5% vs. 35% (nonsignificant)
Stage II: 53.4% vs. 56.7% (nonsignificant)
Stage II: 62.6% vs 70.1% (P<0.05)

Adverse Events

Lethal toxic effects
7 patients (0.8%) died due to chemotherapy-related adverse events: bone marrow aplasia (5), renal failure (1), hyponatremia (1). (2.4% of patients receiving 120mg/m2 of cisplatin vs. 0.6% for 100mg/m2 or less, P=0.15)
Grade 4 toxic effects (22.6%)
Neutropenia (17.5%), thrombocytopenia (2.6%), vomiting (3.3%)

Criticisms

  • Unclear clinical significance for patients with Stage I and II disease, as this study was underpowered to detect/reject mortality benefit in these subgroups
  • No data was collected on Grade 2-3 adverse events which would greatly inform the risk/benefit ratio
  • Choice of optimal adjuvant chemotherapy regimen remains unclear given the design of this trial alone
  • No placebo-control, concealment, or blinding were performed, introducing multiple sources of bias
  • Second primary cancers were not reported despite being a secondary outcome that was assessed

Funding

This was a large, multi-center study spanning multiple nations and institutions with a wide array of non-corporate funding sources. Conflicts of interest appear to be inevitable but minimal.

Further Reading

  1. Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non–Small-Cell Lung Cancer.
  2. Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With Observation in Completely Resected Stage IB and II Non–Small-Cell Lung Cancer: Updated Survival Analysis of JBR-10.
  3. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA): a randomised controlled trial.]
  4. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633.
  5. NCCN Guidelines on Non-Small Cell Lung Cancer, 2.2016