Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer

Clinical and pharmacogenomic results from SWOG S0124

Primo N Lara, Ronald Natale, John Crowley, Heinz Josef Lenz, Mary W. Redman, Jane E. Carleton, James Jett, Corey J. Langer, J. Philip Kuebler, Shaker R. Dakhil, Kari Chansky, David R Gandara

Research output: Contribution to journalArticle

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Abstract

Purpose: Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. Patients and Methods: Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m 2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. Results: Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progressionfree survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia. Conclusion: This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

Original languageEnglish (US)
Pages (from-to)2530-2535
Number of pages6
JournalJournal of Clinical Oncology
Volume27
Issue number15
DOIs
StatePublished - May 20 2009

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irinotecan
Nalpha-(2-naphthylsulfonyl)-3-amidinophenylalanine-carboxymethylpiperazide
Pharmacogenetics
Small Cell Lung Carcinoma
Etoposide
Cisplatin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer : Clinical and pharmacogenomic results from SWOG S0124. / Lara, Primo N; Natale, Ronald; Crowley, John; Lenz, Heinz Josef; Redman, Mary W.; Carleton, Jane E.; Jett, James; Langer, Corey J.; Philip Kuebler, J.; Dakhil, Shaker R.; Chansky, Kari; Gandara, David R.

In: Journal of Clinical Oncology, Vol. 27, No. 15, 20.05.2009, p. 2530-2535.

Research output: Contribution to journalArticle

Lara, Primo N ; Natale, Ronald ; Crowley, John ; Lenz, Heinz Josef ; Redman, Mary W. ; Carleton, Jane E. ; Jett, James ; Langer, Corey J. ; Philip Kuebler, J. ; Dakhil, Shaker R. ; Chansky, Kari ; Gandara, David R. / Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer : Clinical and pharmacogenomic results from SWOG S0124. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 15. pp. 2530-2535.
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abstract = "Purpose: Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. Patients and Methods: Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m 2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. Results: Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60{\%} and 57{\%}, respectively (P = .56). Median progressionfree survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19{\%} v 3{\%}); severe neutropenia and thrombocytopenia were higher with EP versus IP (68{\%} v 33{\%} and 15{\%} v 4{\%}, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia. Conclusion: This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.",
author = "Lara, {Primo N} and Ronald Natale and John Crowley and Lenz, {Heinz Josef} and Redman, {Mary W.} and Carleton, {Jane E.} and James Jett and Langer, {Corey J.} and {Philip Kuebler}, J. and Dakhil, {Shaker R.} and Kari Chansky and Gandara, {David R}",
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T1 - Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer

T2 - Clinical and pharmacogenomic results from SWOG S0124

AU - Lara, Primo N

AU - Natale, Ronald

AU - Crowley, John

AU - Lenz, Heinz Josef

AU - Redman, Mary W.

AU - Carleton, Jane E.

AU - Jett, James

AU - Langer, Corey J.

AU - Philip Kuebler, J.

AU - Dakhil, Shaker R.

AU - Chansky, Kari

AU - Gandara, David R

PY - 2009/5/20

Y1 - 2009/5/20

N2 - Purpose: Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. Patients and Methods: Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m 2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. Results: Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progressionfree survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia. Conclusion: This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

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