Monday, December 15, 2008

CALGB 9633

Journal Club – CALGB 9633

A chemotherapy question today: what is the role of adjuvant chemotherapy in stage IB NSCLC?

Started with a case of NSCLC: 7x6cm mass in the LLL. On resection, negative margins, histopathology revealed a large cell carcinoma of neuroendocrine differentiation. All nodes were negative (hilar and mediastinum sampled).

Comment at this time about the neuroendocrine differentiation: CK states that this would be approached according to the NSCLC algorithm rather than as SCLC due to the large cell morphology.

IB survival rates on the order of 50-55%, with 30-40% long term relapse rates.

Review of prior modern adjuvant CT trials:

1. ALPI – scagliotti JNCI 2003.

n=1209 I-IIIA NSCLC randomized to MVP x 3 vs observation (majority received PORT).

OS – no difference

2. Big Lung Trial

n= 381 I-III NSCLC randomized to Cis/Vind, Mito/ifos/cis, Mito/vinb/cis, vinor/cis or observation, 14% received PORT.

OS – no difference


n=1867 I-III NSCLC randomized to cisplatin based chemotherapy vs observation, fair amount of PORT in this trial

OS 44% vs 40% at 5 years – statistically significant

update at ASCO: now negative as of ASCO 2008

4. JBR 10 (Winton NEJM 2005)

n=482 IB-II NSCLC Randomized to cis/vinor

OS HR 0.69 (0.52-0.91) SS (NS in IB subgroup analysis)

5. ANITA (Douillard, lancet oncol, 2006)

n=840 randomized to cisplatin based chemotherapy vs observations

5y OS 51% vs 43% (SS). Posthoc IB subgroup – no benefit.

6. JLCRG (Kato, NEJM, 2004)

n=999 stage I adenocarcinoma randomized to UFT vs observation.

5y OS 88% vs 85% (SS)

LACE meta-analysis (Pignon, JCO 2008)

pooled #1-5 above (~4500 pts). 5yr os benefit 5.4%

CALGB 9633

T2N0 lobe or pneumonectomy randomized to paclitaxel/carboplatin vs observation

powered for 13% OS benefit at 5 years. Accrual goal: 500pts.

80% power using a two tailed log rank (p=0.05)

well balanced amoung the arms

at the planned interim analysis(Strauss JCO 2004): 4 year OS showed a HR 0.62. stastical tests changed to a one-tailed test, and the accrual was stopped early.

At 5 yr however, the OS HR had become 0.82 and was no longer statistically significant.

In subgroup analysis tumors of >= 4cm, an OS benefit was seen.

Commentary - This is an overall negative trial with a hypothesis generating signal for a benefit in tumors >=4 cm in size. At the CALGB, statistical analysis would suggest that even if the accural went all the way to 500, the trial would still be underpowered for the observed HR. Another critique has been that carboplatin was used, which is likely slightly worse than CDDP in efficacy. Many have interpreted this data to mean that cisplatin should be used in the adjuvant setting, and that with a tumor >= 4cm, chemotherapy may be more strongly considered. This is the current practice at Duke.

Ongoing investigations

Intergroup trial: Investigating Chemo +/- Bev, including IB >=4cm though IIIA

The Muligene Model from Duke (Potti, NEJM) associated a gene expression signature with a high risk of recurrence in stage I NSCLC. A CALGB Study was to go forward with randomizing IB (2-4cm) in the high risk cohort to chemotherapy or not, though now revised so that everyone is getting randomized (low or high risk).

Case Resolution: Patient recived 4 cycles of cisplatin/navelbine, however has since recurred in the pleural space.

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