Prophylactic Cranial Irradiation (PCI) in Extensive Stage Small Cell Lung Cancer (ES-SCLC) (EORTC 22993-08993)

Reviewer: Charles B. Simone, II, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 29, 2007

Presenter: Bernard J. Slotman, MD, PhD
Presenter's Affiliation: VU University Medical Center, EORTC Radiation Oncology and Lung Cancer Groups
Type of Session: Scientific


  • At the time of diagnosis, approximately 20% of patients with small cell lung cancer (SCLC) have brain metastases, and at least 50% will develop brain metastases at two years.
  • Brain metastases have a major impact on physical and psychological functioning.
  • Patients with SCLC historically have had a poor response to systemic therapy and brain radiotherapy once they develop brain metastases.
  • Prophylactic cranial irradiation (PCI) has been established to reduces the risk of brain metastases in patients with limited stage (LS) SCLC.
  • The Prohylactic Cranial Irradiation Overview Collaborative Group (Auperin A, et al. N Engl J Med. 1999;341(7):476-84.) and other investigators have shown that PCI improves disease-free survival and overall survival in LS-SCLC patients in complete remission following local therapy.
  • The EORTC Radiation Oncology and Lung Cancer Groups conducted this study to determine if PCI impacts outcomes in patients with extensive stage (ES) SCLC after chemoradiotherapy.

Materials and Methods

  • Patients aged 18 to 75 years with WHO ≤2 and confirmed ES-SCLC with no evidence of brain or leptomeningeal metastases who had a significant reduction of their thoracic disease following four to six cycles of chemotherapy were randomized to observation versus PCI.
  • PCI doses ranged from 20 to 30 Gy in five to 12 fractions.
  • Patients were stratified by performance status and institution.
  • PCI was administered four to six weeks after the completion of chemotherapy.
  • The primary endpoint of the study was the cumulative incidence of symptomatic brain metastases.
  • Brain imaging with CT scan or MRI was not required prior to randomization and was performed if at least one pre-defined “key symptom” that is suggestive of brain metastasis was presents. Such symptoms included headache, nausea or vomiting, signs of increased intracranial pressure, cognitive and/or affective disturbances, seizures or focal neurological symptoms.
  • Quality of Life data were collected among study participants, with primary QoL endpoints including global health status, alopecia, fatigue, and cognitive and emotional functioning.


  • 286 patients were enrolled in this randomized trial between February 2001 and March 2006.
  • At the time of randomization, there was no significant difference in the percentages of patients who had persistent primary disease (75.5% vs. 76.9%) or metastatic disease (69.2% vs. 72.7%) among the PCI group and observation group.
  • Baseline characteristics were well balanced between the two groups. 
  • 94% of patients who were randomized to the PCI group received irradiation and only three percent had treatment interruptions. 
  • Approximately two-thirds of patients in the PCI group received 20 Gy in five fractions, while the remainder of patients received 30 Gy in 10 fractions or 24 to 30 Gy in eight to 12 fractions.
  • PCI significantly reduced the risk of symptomatic brain metastasis, with the cumulative one-year incidence of 14.6% in the treated arm versus 40.4% in the control arm (HR 0.27, p<0.001).
  • PCI did not have a significant impact on extra-cranial progression rates (p>0.1).
  • PCI was shown to significantly improved progression-free survival (p=0.0218, HR 0.76).
  • One-year overall survival in the PCI group was significantly higher (27.1% vs. 13.3%, p=0.0033, HR 0.68) when compared to the observation group.
  • Acute toxicity was generally mild in the PCI arm, with headache, nausea and vomiting, fatigue, and skin reactions being the most common. Acute Grade 3 toxicity of headache was seen in 3% of patients.
  • Late radiation toxicities were seen in 35% of patients, including 21.6% with Grade 1 toxicity, 11.2% with Grade 2 toxicity, and 2.2% with Grade 3 toxicity (headache).

Author's Conclusions

  • PCI significantly reduces the risk of symptomatic brain metastases.
  • There is no difference in the time to extra-cranial progression with PCI.
  • PCI significantly prolongs progression-free survival and overall survival.
  • Patients with ES-SCLC who respond to chemotherapy should routinely be offered PCI.

Clinical/Scientific Implications

This trial was previously presented at the Plenary sesssion of the American Society of Clinical Oncology in June 2007 and reported on ( OncoLink).  The authors presented a well-designed randomized phase III evaluating the impact of PCI on outcomes in patients with ES-SCLC after chemoradiotherapy.  Prior investigations have demonstrated a clear survival benefit to PCI in patients with LD-SCLC, but little data exists regarding the role of PCI for ES-SCLC.  Patients with extensive stage disease have historically had very poor outcomes with systemic therapy for their primary disease. This trial clearly demonstrates a survival benefit with PCI, as patients receiving prophylactic radiation had more than twice the rates of one year survival as patients in the control arm. Additionally, the authors found that PCI was well tolerated among study participants, with low rates of both acute and late Grade 3 toxicity. Rates of toxicity might be further reduced by using more protracted radiation schedules that the 20 Gy in five fractions regimen used primarily in this investigation.  This trial should change the standard of care in this disease, as patients with ES-SCLC who respond to systemic therapy should routinely receive PCI.

Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.