In the JournalsPerspective

Zoledronic acid offered no significant survival benefit for patients with stage III NSCLC

Zoledronic acid did not significantly improve PFS or OS in patients with controlled stage IIIA/IIIB non–small cell lung cancer, according to study results.

In fact, longer-term follow-up showed patients assigned to the treatment showed signs of worsening PFS.

Previous studies have demonstrated that zoledronic acid offers clinical benefit for maintaining skeletal health and reducing the risk of skeletal-related events in patients with malignant bone disease, and could have anticancer benefits in patients with advanced NSCLC.

The current study was designed to determine whether the addition of zoledronic acid could improve PFS, delay time to bone metastases and disease progression, and/or reduce the rate of bone metastases and mortality in patients with stage IIIA/IIIB NSCLC.

Researchers enrolled 437 patients and randomly assigned them to receive either 4 mg intravenous zoledronic acid every 3 to 4 weeks, or no treatment.

At development of bone metastases, patients in the control group received zoledronic acid and continued the treatment until 24 months from study entry. Throughout the study, all patients also received oral supplementation with calcium 500 mg and vitamin D 400–500 IU daily.

Researchers observed no significant differences in PFS or OS between the two study groups. Of them, 154 patients completed the study, 68 of whom were assigned to zoledronic acid treatment and 86 were assigned to the control group.

The estimated 1-year OS was 81.8% for each group.

The median PFS was 9 months for patients in the treatment group vs. 11.3 months for patients in the control group. Median PFS at 24 months was 25.7 months among patients in the treatment group (95% CI, 19.8-32.0) vs. 36 months for patients in the control group (95% CI, 29.2-42.8).

Fifteen patients in the treatment group and 19 patients in the control group developed bone metastases.

“Patients treated with [zoledronic acid] had a numerically lower incidence and slight delay in the onset of bone metastases,” the researchers wrote. “However, the data were not statistically significant, nor did this translate into an observable benefit in the overall disease outcome. In both PFS and OS analyses, the later time points showed a trend toward a worsening outcome in the [zoledronic acid] group compared with the control group.”

Nearly 65% of patients initially enrolled in the study discontinued treatment. Of them, 158 were in the zoledronic acid arm and 125 were in the control arm.

The most frequent reasons for discontinuation were death (18.6% in the zoledronic acid group vs. 19.9% in the control groups), consent withdrawal (16.4% in the zoledronic acid group vs. 11.8% in the control group), and adverse events (11.9% in the zoledronic acid group vs. 6.2% in the control groups).

“In this study, disease predominantly progressed in sites other than bone, limiting potential anticancer benefits of [zoledronic acid],” the researchers wrote. “Thus, the clinical efficacy of [zoledronic acid] in the NSCLC setting may be more pronounced in patients with skeletal involvement. Indeed, it should be noted that, with the baseline screening for bone metastases, it is likely that many patients with early and asymptomatic bone lesions who would not have been diagnosed using standard screening practices (which recommend bone scans only in the event of symptoms of bone metastases) were excluded from this study. In patients with early bone disease, [zoledronic acid] could still have the potential to deter progression to overt bone metastases.”

Disclosure: The researchers report receiving employment/consulting fees and honoraria from Eli Lilly and AstraZeneca, Roche, Pfizer and Novartis.

Zoledronic acid did not significantly improve PFS or OS in patients with controlled stage IIIA/IIIB non–small cell lung cancer, according to study results.

In fact, longer-term follow-up showed patients assigned to the treatment showed signs of worsening PFS.

Previous studies have demonstrated that zoledronic acid offers clinical benefit for maintaining skeletal health and reducing the risk of skeletal-related events in patients with malignant bone disease, and could have anticancer benefits in patients with advanced NSCLC.

The current study was designed to determine whether the addition of zoledronic acid could improve PFS, delay time to bone metastases and disease progression, and/or reduce the rate of bone metastases and mortality in patients with stage IIIA/IIIB NSCLC.

Researchers enrolled 437 patients and randomly assigned them to receive either 4 mg intravenous zoledronic acid every 3 to 4 weeks, or no treatment.

At development of bone metastases, patients in the control group received zoledronic acid and continued the treatment until 24 months from study entry. Throughout the study, all patients also received oral supplementation with calcium 500 mg and vitamin D 400–500 IU daily.

Researchers observed no significant differences in PFS or OS between the two study groups. Of them, 154 patients completed the study, 68 of whom were assigned to zoledronic acid treatment and 86 were assigned to the control group.

The estimated 1-year OS was 81.8% for each group.

The median PFS was 9 months for patients in the treatment group vs. 11.3 months for patients in the control group. Median PFS at 24 months was 25.7 months among patients in the treatment group (95% CI, 19.8-32.0) vs. 36 months for patients in the control group (95% CI, 29.2-42.8).

Fifteen patients in the treatment group and 19 patients in the control group developed bone metastases.

“Patients treated with [zoledronic acid] had a numerically lower incidence and slight delay in the onset of bone metastases,” the researchers wrote. “However, the data were not statistically significant, nor did this translate into an observable benefit in the overall disease outcome. In both PFS and OS analyses, the later time points showed a trend toward a worsening outcome in the [zoledronic acid] group compared with the control group.”

Nearly 65% of patients initially enrolled in the study discontinued treatment. Of them, 158 were in the zoledronic acid arm and 125 were in the control arm.

The most frequent reasons for discontinuation were death (18.6% in the zoledronic acid group vs. 19.9% in the control groups), consent withdrawal (16.4% in the zoledronic acid group vs. 11.8% in the control group), and adverse events (11.9% in the zoledronic acid group vs. 6.2% in the control groups).

“In this study, disease predominantly progressed in sites other than bone, limiting potential anticancer benefits of [zoledronic acid],” the researchers wrote. “Thus, the clinical efficacy of [zoledronic acid] in the NSCLC setting may be more pronounced in patients with skeletal involvement. Indeed, it should be noted that, with the baseline screening for bone metastases, it is likely that many patients with early and asymptomatic bone lesions who would not have been diagnosed using standard screening practices (which recommend bone scans only in the event of symptoms of bone metastases) were excluded from this study. In patients with early bone disease, [zoledronic acid] could still have the potential to deter progression to overt bone metastases.”

Disclosure: The researchers report receiving employment/consulting fees and honoraria from Eli Lilly and AstraZeneca, Roche, Pfizer and Novartis.

    Perspective
    Barbara G. Campling

    Barbara G. Campling

    The osteoclast inhibitor zoledronic acid can delay progression of bony metastases in variety of solid tumors. Intriguing preclinical studies have suggested that it may also have a direct antitumor effect. Scagliotti et al studied 437 patients who had completed therapy for stage IIIA/B NSCLC.  Subjects were randomly assigned to receive zoledronic acid or no further therapy. It is disappointing that they found no reduction in frequency of bone metastases or improvement in disease-free or overall survival.

    • Barbara G. Campling, MD
    • Professor, department of medical oncology, Thomas Jefferson University’s Kimmel Cancer Center