Radiation Oncology/NSCLC/PCI

Prophylactic cranial irradiation (PCI)

 * Currently not considered standard of care due to neurotoxicity of WBRT
 * RTOG 02-14 opened (Stage IIIA/B, PCI vs. observation)

Randomized
 * Netherlands NVALT-11/DLCRG-02 (2009 - 2015)
 * Randomized. 175 patients, Stage III NSCLC after concurrent/sequential chemoRT with/without surgery, negative brain imaging. Chemo was platinum combo 79%, platinum singlet 16%. Arm 1) observation vs Arm 2) PCI (36/18 or 30/12 or 30/10). Primary outcome symptomatic brain mets
 * Primary Result; 2018 PMID 29787357 -- "Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study." (De Ruysscher, J Clin Oncol. 2018 Aug 10;36(23):2366-2377. doi: 10.1200/JCO.2017.77.5817. Epub 2018 May 22.) Median F/U 48 months
 * Outcome: Symptomatic brain metastases 27% PCI vs 7% OBS (SS). PCI also increased time to symptomatic mets (HR 0.2, SS). Median OS 22 months vs 24 month (NS)
 * Toxicity: At 3 months, PCI worse (SS), with memory impairment (8% vs 30%) and cognitive disturbance (3% vs 19%). But at 6, 12, and 18 months no difference (NS).
 * Conclusion: PCI significantly decreased symptomatic brain mets rate, with increase in low-grade toxicity


 * RTOG 02-14
 * Stage III randomized after treatment (RT or surgery +/- chemo) without disease progression. PCI 30 Gy in 15 fractions vs observation.
 * Closed early due to slow accrual. 356 pts (340 eligible) enrolled out of targeted 1058.
 * 2011 PMID 21135270 -- "Phase III Comparison of Prophylactic Cranial Irradiation Versus Observation in Patients With Locally Advanced Non–Small-Cell Lung Cancer: Primary Analysis of Radiation Therapy Oncology Group Study RTOG 0214" (Gore EM, J Clin Oncol. 2011 Jan 20;29(3):272-8.)
 * 1 yr OS 75.6% vs 76.9% (NS), DFS 56.4% vs 51.2% (NS). Decrease brain metastases 7.7% at 1 yr vs 18.0% (OR 2.52).
 * Conclusion: PCI decreased the rate of brain metastases but did not improve OS or DFS.
 * 2011; Neurocognitive/QOL PMID 21135267 -- "Phase III Trial of Prophylactic Cranial Irradiation Compared With Observation in Patients With Locally Advanced Non–Small-Cell Lung Cancer: Neurocognitive and Quality-of-Life Analysis" (Sun A, J Clin Oncol. 2011 Jan 20;29(3):279-86.)
 * No statistically significant differences at 1 yr between the 2 arms for any component of the QOL, MMSE, or ADLS. Trend for greater decline (for PCI) in pt reported cognitive function. In the HVLT, greater decline in immediate and delayed recall.
 * Conclusion: Significant decline in memory (HVLT) at 1 yr but no significant differences in global cognitive function (MMSE) or QOL after PCI.


 * German Multicenter (1994-2001)
 * Terminated early due to slow accrual after benefit of adjuvant chemo shown.  Randomized. 112 patients with operable Stage IIIA NSCLC based on mediastinoscopy staging. Arm 1) primary resection + adjuvant RT 50-60 Gy vs. Arm 2) preoperative chemo (cisplatin/etoposide x3 cycles) + concurrent chemo-RT (cisplatin/etoposide RT 45 Gy in 1.5 Gy BID) + definitive surgery + PCI 30/15
 * 2007 PMID 17971598 -- "Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial." (Pottgen C, J Clin Oncol. 2007 Nov 1;25(31):4987-92.)
 * 5-year outcome: brain first failure PCI 8% vs no PCI 35% (SS); any brain failure 9% vs. 27% (SS)
 * Toxicity: no difference; slightly decreased neurocognition in both groups compared to age-matched controls
 * Conclusion: PCI effective in preventing brain mets after trimodality therapy


 * RTOG 84-03 (1984-?)
 * 187 pts. Adeno or large cell. Confined to the chest. Randomized to thoracic RT alone vs thoracic RT + concurrent PCI.
 * PMID 1651304, 1991 &mdash; "Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group." Russell AH et al. Int J Radiat Oncol Biol Phys. 1991 Aug;21(3):637-43.
 * PCI did not decrease the incidence of brain mets (9% vs 19%, p=0.10) but did delay their development. No difference in OS.

Non-randomized
 * Essen, 1999 (Germany) PMID 10561344 -- "Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects." (Stuschke M, J Clin Oncol. 1999 Sep;17(9):2700-9.)
 * Phase II, nonrandomized. Trimodality for IIIA/IIIB NSCLC, PCI offered. RT 30/15 starting 1 day after last chemo
 * PCI reduced brain mets as first site at 4 years: 30% to 8% (SS), brain mets overall 54% to 13% (SS)
 * Effect seen especially in CR/PR group: 23% to 0% (SS) at 4 years
 * Toxicity: Late toxicity in both +PCI and -PCI patients. MRI more white matter abnormalities with +PCI
 * Conclusion: PCI reasonable in intense protocols for locally advanced NSCLC, especially in favorable prognosis