Randomized Trial of Standard Versus Higher Dose Prophylactic Cranial Irradiation (PCI) in Limited Stage Small Cell Lung Cancer (SCLC) Complete Responders (CR): Primary End Point Analysis (PCI99-01, EORTC 22003-08004, RTOG 0212)

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2008

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Presenter: Le Pechoux C.
Presenter's Affiliation: Institute Gustav Roussy, Villejuif, France
Type of Session: Scientific

Background

  • The use of prophylactic cranial irradiation (PCI) in patients with limited stage small cell lung cancer (SCLC) has been shown to provide an overall survival benefit (3-year overall survival of 20.7% with PCI versus 15.3% without) in a large meta-analysis (Auperin A., NEJM 1999).
    • There were a variety of doses and fractionation schemes used in the above mentioned meta-analysis. 
    • When the total dose was examined, it appeared that there was a trend towards decreased brain metastasis with higher doses of PCI.
  • PCI has also been shown to provide a survival benefit in patients with extensive stage SCLC who have a response to systemic therapy (Slotman B. et al. NEJM 2007).
  • Neurotoxicity is a concern with PCI and requires closer investigation. However, it can often be difficult to determine if changes are due to PCI or other factors, such as neurocognitive changes due to chemotherapy.
  • The present study is a randomized trial comparing standard dose PCI with high dose PCI.

Materials and Methods

  • Patients with histologically confirmed limited stage SCLC who had a complete response were randomized to one of two different radiation doses:
    • Standard arm: Patients were treated to a total PCI dose of 25 Gy in 10 2.5 Gy fractions over 12 days. 
    • High Dose arm: Patients were treated to a total dose of 36 Gy using either conventional fractionation or hyperfractionated radiation:
      • Patients treated with conventional radiation therapy were treated daily with 2 Gy fractions for a total of 18 treatments over 24 days.
      • Patients treated with hyperfractionated radiation therapy were treated with 1.5 Gy fractions twice a day for a total of 24 fractions given over 16 days. 
  • The primary endpoint for this study was the development of brain metastasis. Secondary endpoints of this study were survival, quality of life, and late treatment-related toxicity. The secondary endpoints were assessed yearly.
  • Patients underwent brain imaging, neurological assesment, and quality of life evaluation at baseline. 
  • The number of patients required to demonstrate a 15% decrease in brain metastasis at two years with a power of 90% and a type I error of 5% was calculated to be 700 patients. 

Results

  • From September 1999 to December 2005, a total of 720 patients were randomized to either standard or high dose PCI. 360 patients were randomized to each arm.
  • Median follow up was 38 months.
  • Patient Characteristics:
    • Median age was 60 yo
    • 64% of patients were male
    • Demographics and tumor characteristics were well balanced between the two arms of the study. 
  • Toxicity was similar between the two arms and has been reported previously (Le Pechoux et al. J Thor Onc 2007). 
  • The two-year risk for developing brain metastasis, other metastasis, chest relapse and overall survival are presented below.   Hazard ratios are also presented:
 
 
Standard Dose (95% CI)
High Dose (95% CI)
p-value
HR (95% CI)
Brain Metastasis
30% (25%-36%)
24% (18%-30%)
0.13
0.77 (0.55-1.08)
Chest Relapse
40% (34%-46%)
48% (42%-54%)
0.02
1.32 (1.04-1.69)
Other metastasis
41% (35%-47%)
42% (37%-48%)
0.16
1.19 (0.93-1.52)
Overall Survival
42% (37%-48%)
37% (32%-42%)
0.03
1.22 (1.02-1.47)
  • Sensitivity and competing risk analysis was performed, and these analyses did not change the results noted in the table above.

Author's Conclusions

  • The present study did demonstrate a slight decrease in the rate of brain metastasis in the patients in the high dose arm. However, this difference was not significant. 
  • There was a significantly higher rate of chest relapse and mortality in the higher dose arm. The authors did not have a biologically plausible explanation for these results. It may be a false positive result. 
  • There was comparable toxicity between the standard dose and the high dose treatment arms.
  • At present, 25 Gy remains the standard dose for PCI based on the results of this study.

Clinical/Scientific Implications

  • Brain metastases are often present at the time of diagnosis in SCLC patients, and the brain is a frequent site of relapse. The optimal dose for PCI has not yet been clearly defined. Furthermore, given that twice-a-day dosing of the primary appears to improve local control and overall survival, it seems reasonable that twice-a-day dosing may be effective in PCI. The results from the present study suggest that there is a modest benefit from higher dose PCI, either with daily dosing or hyperfractionation, although this benefit is not significant. It is possible that the 15% decrease in brain metastasis at two years may have been too ambitious of a change to expect from simply increasing dose. It is possible that with a larger cohort of patients, a difference in the rate of brain metastasis may have been seen. In the present study, even though there was an improvement in the rate of brain metastasis, there was a decrease in overall survival with high dose PCI. The authors report that the toxicity was similar between the two arms, and that this decrease in overall survival did not appear to be related to increased toxicity in the high dose arm. There was also an increase in the chest relapse rate which could not be explained.
 
  • Taken together, these results present a confusing picture regarding the use of higher doses of PCI in patients with SCLC who have a complete response to systemic therapy. It is unlikely that another large study of high dose PCI will be undertaken. Given the size of this study and the modest decrease seen in the rate of brain metastasis, a very large study would be needed to detect an overall survival benefit, which itself would most likely be a small benefit. There remains the possibility that there is unknown toxicity associated with PCI that is contributing to the early mortality. Until and unless these factors are further elucidated, at present, “standard dose” radiation therapy remains the gold standard by which patients should be treated.

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News
ASTRO: Radiation Beneficial in Non-Small Cell Lung Cancer

Dec 21, 2014 - In patients with non-small cell lung cancer, prophylactic cranial irradiation may help prevent brain metastases, and stereotactic radiotherapy may arrest the growth of lung cancer in frail patients, according to research presented at the 51st Annual Meeting of the American Society for Radiation Oncology, held from Nov. 1 to 5 in Chicago.


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