August 9, 2011 —Elderly patients with non–small-cell lung cancer (NSCLC) should be treated with a doublet of chemotherapy; they are currently treated with a single chemotherapy agent, if they receive any chemotherapy at all.
This conclusion comes from a European study published online August 9 in the Lancet.
The trial of 451 patients between 70 and 89 years of age with advanced NSCLC was stopped early because of the significant improvement in survival over that seen with single chemotherapy.
"We saw a survival benefit with doublet chemotherapy of such magnitude that we believe the treatment paradigm for elderly patients with advanced NSCLC should be reconsidered," write the authors, headed by Elisabeth Quoix, MD, from the Université de Strasbourg, France.
Experts in the United States agreed with this sentiment when Dr. Quoix presented these findings at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO).
"This trial should change day-to-day clinical practice," said Martin Edelman, MD, from the University of Maryland in Baltimore, who acted as discussant. He noted that ASCO guidelines leave the choice of whether to use a single or double chemotherapy up to the physician, but European guidelines specially call for the use of single-agent chemotherapy.
On the basis of the superiority shown in this trial, the more aggressive approach of doublet chemotherapy should be used in NSCLC, no matter how old the patients is, he said.
These results "will inform our decisions in clinical practice," agreed Mark Kris, MD, chief of the thoracic oncology service at Memorial Sloan–Kettering Cancer Center in New York City. He noted that the average age of a lung cancer patient is 71 years, and about half of all NSCLC patients are older than 70 years.
However, an editorial published alongside the study is more circumspect. Previous studies of this issue are conflicting, writes Karen Reckamp, MD, from the City of Hope Comprehensive Cancer Center in Duarte, California.
"Questions remain about combination chemotherapy versus single-agent treatment for older adults," Dr. Reckamp notes. Additional studies are needed, she believes, to properly assess the risk/benefit ratio in treatment decisions.
The doublet chemotherapy was more toxic, she notes, and may require aggressive supportive care. Also, the patients in this trial had to have adequate renal and hepatic function to be included, but both of these functions deteriorate with age and can affect clearance, which could affect both toxic effects and efficacy.
The researchers themselves note that the patients in the trial were fit. The average age was 77 years, and performance status scores were 0 to 2 (with 27% of patients scoring 2).
Dr. Reckamp explains that this allows the results to "be generalized to a large proportion of patients." Despite the reservations she outlines in the editorial, she says the trial results "lend support" to combination chemotherapy in elderly patients with advanced NSCLC.
Direct Comparison
The trial was a direct comparison of a single agent and a doublet.
The single agent was either vinorelbine (25 mg/m2 on days 1 and 8) or gemcitabine (1150 mg/m2 on days 1 and 8), given in a cycle of 2 weeks of treatment and 1 week without, which was repeated for a maximum of 5 cycles.
The doublet comprised once-monthly carboplatin (dosed by area under the curve, AUC 6) plus paclitaxel (90 mg/m2 on days 1, 8, and 15), given in a cycle of 3 weeks of treatment and 1 week without, which was repeated for a maximum of 4 cycles.
The study was stopped early because of "the highly positive results" seen at the second interim analysis, carried out in December 2009, more than 3 years after enrolment began. At that time, 451 patients had been enrolled.
The final follow-up was carried out in September 2010, when median follow-up was 30.3 months (range, 8.6 to 45.2).
The doublet significantly improved overall survival (10.3 vs 6.2 months; P < .0001) and progression-free survival (6 vs 2.8 months; P < .0001), compared with the single agent.
However, the doublet also increased toxicity. Grade 3/4 neutropenia, febrile neutropenia, thrombocytopenia, anemia, and sensory neuropathy were significantly more frequent than with a single agent.
The researchers note that hematologic toxic effects should be carefully monitored in elderly patients, and prophylactic use of granulocyte colony-stimulating factor should be considered.
There were also more treatment-related deaths — 10 patients (4.4%) in the doublet group and 3 (1.3%) in the single-agent group.
Full details on quality-of-life assessments will be published in the future, but the authors give a hint of the findings in their current paper. Global quality-of-life scores were similar in the 2 groups. However, at week 6, there were significantly more patients in the single-agent group with pain and dyspnea, but more with diarrhea in the doublet group. At week 18, measures of role functioning and fatigue were worse in the doublet group.
Despite the increased toxicity, the survival benefit seen with the doublet chemotherapy should lead to a reconsideration of the current treatment paradigm, which recommends that a single agent be used in elderly patients, the researchers explain. There is a "pessimism" among doctors, patients, and their relatives about the relevance of treatment or drug-related adverse effects, they note. Hence, many elderly patients with advanced NSCLC do not receive any first-line chemotherapy, and when they do, it is usually with a single agent, as is stipulated in many treatment guidelines.
"We believe that monthly carboplatin and weekly paclitaxel is a feasible option for first-line therapy of advanced NSCLC in patients older than 70 years with performance status scores of 0 to 2," Dr. Quoix and colleagues conclude.
Dr. Quoix and several coauthors report receiving consultancy fees, honoraria, and travel grants from Roche and Lilly. Dr. Reckamp reports acting as a consultant for Amgen, Genentech, and Tragara Pharmaceuticals, and as a speaker for Lilly Oncology and Genentech.
Lancet. Published online August 9, 2011. Abstract, Editorial
This conclusion comes from a European study published online August 9 in the Lancet.
The trial of 451 patients between 70 and 89 years of age with advanced NSCLC was stopped early because of the significant improvement in survival over that seen with single chemotherapy.
"We saw a survival benefit with doublet chemotherapy of such magnitude that we believe the treatment paradigm for elderly patients with advanced NSCLC should be reconsidered," write the authors, headed by Elisabeth Quoix, MD, from the Université de Strasbourg, France.
Experts in the United States agreed with this sentiment when Dr. Quoix presented these findings at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO).
"This trial should change day-to-day clinical practice," said Martin Edelman, MD, from the University of Maryland in Baltimore, who acted as discussant. He noted that ASCO guidelines leave the choice of whether to use a single or double chemotherapy up to the physician, but European guidelines specially call for the use of single-agent chemotherapy.
On the basis of the superiority shown in this trial, the more aggressive approach of doublet chemotherapy should be used in NSCLC, no matter how old the patients is, he said.
These results "will inform our decisions in clinical practice," agreed Mark Kris, MD, chief of the thoracic oncology service at Memorial Sloan–Kettering Cancer Center in New York City. He noted that the average age of a lung cancer patient is 71 years, and about half of all NSCLC patients are older than 70 years.
However, an editorial published alongside the study is more circumspect. Previous studies of this issue are conflicting, writes Karen Reckamp, MD, from the City of Hope Comprehensive Cancer Center in Duarte, California.
"Questions remain about combination chemotherapy versus single-agent treatment for older adults," Dr. Reckamp notes. Additional studies are needed, she believes, to properly assess the risk/benefit ratio in treatment decisions.
The doublet chemotherapy was more toxic, she notes, and may require aggressive supportive care. Also, the patients in this trial had to have adequate renal and hepatic function to be included, but both of these functions deteriorate with age and can affect clearance, which could affect both toxic effects and efficacy.
The researchers themselves note that the patients in the trial were fit. The average age was 77 years, and performance status scores were 0 to 2 (with 27% of patients scoring 2).
Dr. Reckamp explains that this allows the results to "be generalized to a large proportion of patients." Despite the reservations she outlines in the editorial, she says the trial results "lend support" to combination chemotherapy in elderly patients with advanced NSCLC.
Direct Comparison
The trial was a direct comparison of a single agent and a doublet.
The single agent was either vinorelbine (25 mg/m2 on days 1 and 8) or gemcitabine (1150 mg/m2 on days 1 and 8), given in a cycle of 2 weeks of treatment and 1 week without, which was repeated for a maximum of 5 cycles.
The doublet comprised once-monthly carboplatin (dosed by area under the curve, AUC 6) plus paclitaxel (90 mg/m2 on days 1, 8, and 15), given in a cycle of 3 weeks of treatment and 1 week without, which was repeated for a maximum of 4 cycles.
The study was stopped early because of "the highly positive results" seen at the second interim analysis, carried out in December 2009, more than 3 years after enrolment began. At that time, 451 patients had been enrolled.
The final follow-up was carried out in September 2010, when median follow-up was 30.3 months (range, 8.6 to 45.2).
The doublet significantly improved overall survival (10.3 vs 6.2 months; P < .0001) and progression-free survival (6 vs 2.8 months; P < .0001), compared with the single agent.
However, the doublet also increased toxicity. Grade 3/4 neutropenia, febrile neutropenia, thrombocytopenia, anemia, and sensory neuropathy were significantly more frequent than with a single agent.
| Adverse event | Single-agent total, n = 225 (%) | Single-agent grade 3 events, n = 225 (%) | Doublet total, n = 223 (%) | Doublet grade 3 events, n = 223 (%) |
| Febrile neutropenia | 6 (2.7) | 3 (1.3) | 21 (9.4) | 12 (5.4) |
| Nausea and vomiting | 2 (0.9) | 2 (0.9) | 6 (2.7) | 6 (2.7) |
| Sensory neuropathy | 1 (0.4) | 1 (0.4) | 7 (3.1) | 7 (3.1) |
The researchers note that hematologic toxic effects should be carefully monitored in elderly patients, and prophylactic use of granulocyte colony-stimulating factor should be considered.
There were also more treatment-related deaths — 10 patients (4.4%) in the doublet group and 3 (1.3%) in the single-agent group.
Full details on quality-of-life assessments will be published in the future, but the authors give a hint of the findings in their current paper. Global quality-of-life scores were similar in the 2 groups. However, at week 6, there were significantly more patients in the single-agent group with pain and dyspnea, but more with diarrhea in the doublet group. At week 18, measures of role functioning and fatigue were worse in the doublet group.
Despite the increased toxicity, the survival benefit seen with the doublet chemotherapy should lead to a reconsideration of the current treatment paradigm, which recommends that a single agent be used in elderly patients, the researchers explain. There is a "pessimism" among doctors, patients, and their relatives about the relevance of treatment or drug-related adverse effects, they note. Hence, many elderly patients with advanced NSCLC do not receive any first-line chemotherapy, and when they do, it is usually with a single agent, as is stipulated in many treatment guidelines.
"We believe that monthly carboplatin and weekly paclitaxel is a feasible option for first-line therapy of advanced NSCLC in patients older than 70 years with performance status scores of 0 to 2," Dr. Quoix and colleagues conclude.
Dr. Quoix and several coauthors report receiving consultancy fees, honoraria, and travel grants from Roche and Lilly. Dr. Reckamp reports acting as a consultant for Amgen, Genentech, and Tragara Pharmaceuticals, and as a speaker for Lilly Oncology and Genentech.
Lancet. Published online August 9, 2011. Abstract, Editorial
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