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Prophylactic cranial radiation use in small cell lung cancer declines sharply after trial
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The use of prophylactic cranial irradiation in patients with extensive-stage small cell lung cancer has greatly decreased since the publication of a phase 3 clinical trial in 2017 that found no improvement in survival compared with MRI surveillance, according to study results scheduled for presentation at Multidisciplinary Thoracic Cancers Symposium.
“Unfortunately, despite recent advances in cancer medicine, small cell lung cancer continues to result in very poor outcomes, with overall 5-year survival ranging in the single digits,” Olsi Gjyshi, MD, PhD, radiation oncology resident at The University of Texas MD Anderson Cancer Center, said during a press cast. “One of the main reasons for this poor outcome is attributed to the fact that most of these patients will develop brain metastases at some point during their disease, especially patients with extensive-stage disease.”
Prophylactic cranial irradiation (PCI) became widely accepted as the standard of care for patients with extensive-stage small cell lung cancer after a study by Slotman and colleagues — published in 2007 in The New England Journal of Medicine — found PCI was associated with a lower rate of brain metastases and longer OS in this patient population.
However, a subsequent phase 3 trial by Toshiaki Takahashi, MD, of the division of thoracic oncology at Shizuoka Cancer Center in Shizuoka, Japan, and colleagues — published in 2017 in The Lancet Oncology — found PCI did not confer a survival benefit compared with MRI observation.
Gjyshi and colleagues studied the impact of the trial by Takahashi and colleagues on clinical practice in the United States by sending an anonymous 24-question survey on the use of PCI to 205 radiation oncologists who specialize in treatment of thoracic malignancies from 105 academic centers.
All 49 radiation oncologists who responded to the survey were aware of the trial by Takahashi and colleagues. Whereas most survey respondents (78%) routinely offered PCI to patients with extensive-stage small cell lung cancer before the trial, only 38% continued to do so after the trial results were published (P < .001). Two-thirds of the respondents (67%) reported altering their practice patterns in response to the trial.
Individual comments from the respondents indicated that close MRI surveillance is being used instead of PCI.
Researchers observed no specific trends in PCI use after the trial based on geographic location, years of practice, or volume of small cell lung cancer cases.
Gjyshi and colleagues then conducted a follow-up nationwide survey in which 431 ASTRO-registered radiation oncologists responded to similar questions.
Results showed 43% of radiation oncologists who were aware of the trial by Takahashi and colleagues reported that it had an impact on the rate of PCI use for patients with extensive-stage small cell lung cancer.
Respondents reported rates of PCI offered to patients declined from before to after publication of the trial in both academic (74% to 43%) and private/government (69% to 44%) settings.
One-quarter (25%) of ASTRO-registered radiation oncologists reported a decrease in PCI referrals for patients with extensive-stage small cell lung cancer, whereas 12% said reported a decrease for patients with limited-stage small cell lung cancer.
“The practice of PCI in patients with extensive-stage small cell lung cancer is rapidly evolving. Both MRI surveillance and PCI are acceptable options, with MRI surveillance becoming more predominant since the publication of the Takahashi et al. trial,” Gjyshi said. “However, careful consideration should be given to future studies and trials that are planning on investigating the role of PCI in this patient population. Increased awareness on the current body of literature on the topic is particularly important for physicians and patients in making an educated decision.”– by John DeRosier
References:
Gjyshi O, et al. Abstract 5. Scheduled for presentation at: Multidisciplinary Thoracic Cancers Symposium; March 14-16, 2019; San Diego.
Slotman B, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa071780.
Takahashi T, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30230-9.
Disclosures: Gjyshi reports no relevant financial disclosures. One study author reports advisory roles with AstraZeneca and research funding from Beyond Spring Pharmaceuticals, Genentech, Hitachi Chemical, New River Labs, Roche and STCube Pharmaceuticals.
Perspective
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Gregory Videtic, MD
Small cell lung cancer is classified as either limited-stage disease (LS-SCLC) or extensive-stage disease (ES-SCLC).
The standard therapy for LS-SCLC is concurrent chemoradiotherapy. PCI is considered standard of care for patients with LS-SCLC who achieve complete response or good partial response with initial therapy because it provides a survival benefit as well as reduces the risk for failure in the brain. On the other hand, the standard therapy for ES-SCLC has been primarily chemotherapy only.
However, a randomized trial by Slotman and colleagues assessing the addition of PCI after chemotherapy in patients with ES-SCLC patients suggested that it confers a survival benefit for patients showing any response to their initial chemotherapy. Thereafter, PCI became a frequent recommendation for these advanced patients.
This trial was critiqued for the absence of mandated pre-PCI brain imaging that might have biased the results, and so a phase 3 study with a primary endpoint of OS for further validation was carried out in Japan by Takahashi and colleagues, in which brain MRI imaging was carried out prior to study entry. This study failed to confirm a survival benefit, although it continued to show benefit with respect to improving local control in the brain.
Given that this trial suggested there was no extension of survival by the addition of PCI in patients with ES-SCLC — and that there were concerns regarding the addition of central nervous system toxicity in this population — there has been debate regarding PCI’s role. The current abstract from Gjyshi and colleagues addresses this controversy by looking at the change in practice resulting from the Takahashi findings. They conducted an anonymous survey of 205 attending radiation oncologists who specialize in the treatment of thoracic malignancies from 105 academic centers, and their results showed a decrease in PCI utilization for ES-SCLC from 78% to 38% following publication of this trial.
What is the impact of these significant findings? This abstract reveals that clinicians are less inclined to use an intervention when there is no demonstrated survival benefit, especially in incurable patients. On the question on whether prevention of failure in the brain — which is clearly an effect of PCI — is justifiable even without a survival benefit, the results suggest many clinicians would prefer close imaging for observation to using PCI.
However, the study did not address how clinicians see PCI’s role for improving quality of life by preventing brain failure as opposed to quality-of-life changes that may come from the therapy itself. It would have been of interest for this study to determine if clinicians would still consider participating in ongoing clinical trials such as NRG CC003 that are looking at hippocampal-avoidance whole-brain radiotherapy to reduce potential cognitive side effects.
References:
Slotman B, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa071780.
Takahashi T, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30230-9.
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Charles B. Simone, MD
Although older trials have demonstrated a survival benefit from the addition of PCI in patients with extensive-stage small cell lung cancer, clinical practices since then have evolved, including the now more widespread use of MRI brain imaging and advanced chest imaging for assessing the thoracic response to frontline chemotherapy.
Also, as a more recently published Japanese trial did not show a survival benefit to PCI, the current clinical practices of providers in the United States are unclear.
Gjyshi and colleagues conducted surveys of thoracic radiation oncologists and the general ASTRO membership assessing the impact of the Takahashi trial finding on the delivery of PCI. Not surprisingly, physicians are now more likely to defer PCI and instead perform MRI brain surveillance for patients.
Knowledge of these current clinical practices may help to inform future clinical trials investigating or even incorporating the long-standing practice of routine PCI delivery.
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