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Nothing Good for Older Lung Cancer Patients From Add-On Cisplatin

— Two trials show no survival benefit and more toxicity

MedpageToday

The addition of cisplatin to either gemcitabine (Gemzar) or pemetrexed (Alimta) did not improve overall survival in elderly patients with advanced non-small cell lung cancer (NSCLC) and the doublet was associated with a significantly greater toxicity than single-agent chemotherapy, a joint analysis of two randomized phase III trials has shown.

At a median follow-up of 2 years, overall survival was not significantly extended with the addition of cisplatin to either gemcitabine or pemetrexed at a hazard ratio (HR) of 0.86 (95% CI 0.70-1.05; P=0.14) in patients with NSCLC at a mean age of 75 years, reported Cesare Gridelli, MD, Azienda Ospedaliera San Guiseppe Moscati, Avelino, Italy and colleagues in the Journal of Clinical Oncology.

Action Points

  • Adding cisplatin to single-agent chemotherapy does not significantly prolong overall survival nor does it improve global health status of elderly patients with advanced non-small cell lung cancer (NSCLC), according to a joint analysis of two phase III trials.
  • Note that these results support European oncology guidelines that say standard treatment for elderly patients should remain single-agent chemotherapy, whereas carboplatin-based combinations might be considered as an alternative in selected cases, with caution regarding potential toxicity.

Patients receiving additional cisplatin also experienced more severe hematologic toxicity, fatigue, and anorexia than patients in either of the single-agent arms.

"This result fully supports the treatment algorithm proposed for elderly patients in the European Society of Medical Oncology guidelines," Gridelli and colleagues observed.

"Standard treatment should remain single-agent chemotherapy whereas carboplatin-based combinations might be considered as an alternative in selected cases, with caution regarding potential toxicity," they concluded.

The MILES-3 (Cisplatin in Combination with Gemcitabine for Elderly Patients with Lung Cancer) and MILES-4 (A Factorial Study of Cisplatin Added to Pemetrexed or Gemcitabine in Elderly Patients with Nonsquamous Lung Cancer) involved a total of 268 patients who received either gemcitabine or pemetrexed alone and another 263 patients who received the combination of gemcitabine or pemetrexed plus cisplatin.

In MILES-3, patients received gemcitabine at a dose of 1,200 mg/m2 on days 1 and 8 every 3 weeks for six cycles or cisplatin, 60 mg/m2 on day 1 plus gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks for six cycles. In MILES-4, there were 4 treatment arms: gemcitabine again at a dose of 1,200 mg/m2 on days 1 and 8 every 3 weeks for six cycles; gemcitabine 1,000 mg/m2 on days 1 and 8 plus cisplatin, 60 mg/m2 on day 1 every 3 weeks for six cycles; pemetrexed, 500 mg/m2 on day 1 once every 3 weeks for six cycles or pemetrexed, 500 mg/m2 plus cisplatin, 60 mg/m2 on day 1 every 3 weeks for six cycles.

"The median number of treatment cycles was three ... without cisplatin and four ... with cisplatin," investigators observed. Relatively equal percentage of patients completed treatment as planned with and without cisplatin at 40.6% and 34%, respectively. "Both trials were closed prematurely because of slow accrual," researchers observed.

However, data from both trials was combined and a joint analysis of the combined data permitted the team to evaluate whether adding cisplatin to either single-agent regimen prolonged survival. At study endpoint, median overall survival was 7.5 months (95% CI 6.2-9.5 months) in the single agent arms, versus 9.6 months (95% CI 8.1-11.7 months) in the additional cisplatin arms. Median progression-free survival (PFS) was slightly longer with additional cisplatin at 3.0 months (95% CI 2.5-3.8 months) in the single agent arms versus 4.6 months (95% CI 4.1-5.3 months) in the combination arms.

However, "patients receiving the cisplatin combination experienced significantly more hematologic and neurologic toxicity, mucositis, nausea, and vomiting and significantly more severe thrombocytopenia, leukopenia, neutropenia, febrile neutropenia, fatigue and anorexia,"the study authors reported. Global health status scores reflecting quality of life were also not improved after cycle 1 or 2 in patients receiving cisplatin, they added. "In conclusion, the addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival nor does it improve global health status core of QOL of elderly patients with advanced NSCLC," Gridelli and colleagues concluded.

"It should no longer be among the preferred options for first-line treatment in clinical practice," they advised. Commenting on the findings, editorialists Paul Bunn Jr, MD, University of Colorado Denver and Anastasios Dimou, MD, University of Colorado Cancer Center, Aurora, cautioned that the authors' conclusion that cisplatin-based doublets should not be standard first-line therapy for elderly patients with NSCLC should not be applied for all doublet chemotherapies, "especially those using carboplatin and/or pemetrexed," as they underscored.

"[F]itness for chemotherapy varies considerably among elderly patients with PS (performance status) 0 to 1 because of factors such as multiple chronic conditions, polypharmacy, geriatric syndromes, and frailty," they observed. They go on to detail trials in which it was shown that platinum-based combinations led to superior overall survival and PFS compared with non-platinum regimens. "In patients with nonsquamous NSCLC, pemetrexed combinations have a more favorable toxicity profile and the benefit of pemetrexed is similar in elderly and younger patients," Bunn and Dimou observed.

The editorialists also reviewed the role of the newer antiangiogenic monoclonal antibody agents, which have also been evaluated in elderly patients both as first and second-line therapy. Based on their assessment of these studies, Bunn and Dimou concluded that angiogenic agents, whether added to a platinum doublet or to a single agent, should not be used in the elderly except if they are extremely fit. They also reviewed the evidence evaluating first, second, and even third generation epidermal growth factor tyrosine kinase inhibitors in younger and older patients with NSCLC.

Results to date suggest that elderly patients likely benefit from these agents as much as younger patients do. Lastly, they evaluated the track record of the immune checkpoint inhibitors in NSCLC. Although there are concerns about their toxicity profile in the elderly, there is evidence to suggest that age alone should not rule out treating older patients with these agents. "[T]he question of when to offer new treatments to older and younger patients, including platinum doublets with or without antiangiogenics and immune checkpoint inhibitors, and when to offer molecularly targeted TKIs, is an important one because many new treatments and drug combinations receive approval by regulatory agencies," Bunn and Dimou pointed out.

"[R]esults indicate that most fit elderly patients with PS of 0 to 1 may be offered carboplatin-based doublets with or without checkpoint inhibitor antibodies, checkpoint inhibitor antibodies alone, or molecularly targeted tyrosine kinase inhibitors," they added. "Ultimately, physicians need to use their judgment and include patient informed preference and quality of life in addition to survival end points in decision making," the editorialists concluded.

Disclosures

The study was funded by the Italian Drug agency and by Eli Lilly.

Gridelli disclosed relevant relationships with Bristol-Myers Squibb, MSD Oncology, Genentech, and Eli Lilly.

Bunn Jr. disclosed relevant relationships with AstraZeneca/MedImmune, Merck, Genentech, Merck Serono, Eli Lilly, AbbVie, Novartis, and Bristol-Myers Squibb.

Dimou declared no financial ties to industry.

Primary Source

Journal of Clinical Oncology.

Gridelli C, et al "Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: Joint analysis of MILES-3 and MILES-4 phase III trials" J Clin Oncol 2018; DOI:10.1200/JCO.2017.76.8390.

Secondary Source

Journal of Clinical Oncology

Bunn P, Dimou A "Systemic therapy for elderly patients with advanced non-small-cell lung cancers" J Clin Oncol 2018; DOI: 10.1200/JCO.2018.79.2457.