However, the publication by Takahashi et al is not without its flaws. It is inevitable to question whether careful patient selection might have played a role as previously described in a previous communication by Slotman.46 On an average, participating centers enrolled only one patient per year and the high proportion of patients who received second-, third- and fourth-line chemotherapy is incongruent with previously published data49 and might reflect this assumption. In addition, in stark contrast to the EORTC trial, a higher proportion of patients received radiotherapy in the observation arm of the Japanese trial (25% vs. 58%). Le Péchoux et al described extensively similar 1-year survival rates in the subgroup analysis of ES-SCLC patients of the landmark PCI meta-analysis published in 1999.4,49Differences in survival outcome between both studies were also attributed to several factors including eligibility criteria, patient selection, treatment regimens (chemotherapy and PCI fractionation), demographics as well as possibly related to host-related genetic differences in SCLC between Asian and non-Asian populations.49
However, a retrospective study emanating from Germany demonstrated a stark improved median overall survival after PCI in ES-SCLC patients in comparison to the EORTC trial (12 vs. 6.7 months) and similar to the results of the Japanese trial.50 However, as the authors duly noted, according to institutional policy, the study population comprised a select group of patients with relatively good performance status (median ECOG 1) with exclusion of older patients and patients at high risk for cognitive decline.
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PCI vs. active MRI surveillance with access to stereotactic radiotherapy (SRT)
Based on the conflicting results of the EORTC and Japanese trials, the NCCN softened its latest recommendation for PCI in ES-SCLC to “consider”. However, in patients not receiving PCI, a comprehensive MRI surveillance program in accordance with the above-mentioned study is paramount.
Furthermore, there is uncertainty regarding use of SRT for brain relapse (single or multiple) in SCLC. There are some retrospective data supporting its use.
A secondary analysis of the Japanese trial noted that 25/54 (46%) patients in the PCI arm received repeat radiotherapy with stereotactic radiosurgery (SRS) the preferred modality as is popularly adopted in the authors’ country of origin.51
In a recent NCDB analysis of 5952 SCLC patients by Robin et al, upfront SRS was associated with improved median OS vs. upfront WBRT +/− SRS (10.8 vs. 7.1 months, HR 0.65, 95% CI 0.55–0.75, p<0.001), which persisted on multivariate analysis controlling for comorbidities, extracranial metastases, age, race/ethnicity and sex (HR 0.70, 95% CI 0.60–0.81, p <0.001). However, the results must be interpreted with caution as the SRS arm was underpowered with 200 vs. 5752 patients in the WBRT arm.52
Also in patients with single brain metastasis, Bernhardt et al recently described prognostic factors and demonstrated in a retrospective analysis of 52 patients that, prior surgery, synchronous as opposed to metachronous metastasis and response to primary chemotherapy was associated with improved OS.53
Currently, a Phase 2 study in Germany comparing WBRT alone to SRS for SCLC patients is recruiting to this effect (NCT03297788) and might provide a basis for further investigation of this strategy within the ramifications of a Phase 3 study.
CONCLUSION
It is imminently paramount that the TNM classification according to the UICC 8th edition is universally adopted for SCLC.54 Subsequently, survival benefit conferred by PCI in LS-SCLC could be further elucidated.
Since its initial proposal for SCLC in 1973 and recommendation in 1999, PCI has been the topic of recurring interest and debate. It is inevitable that we are slowly arriving at a defining crossroad as new data emanating from studies in the current MRI era and ubiquity of comprehensive brain imaging suggest that the modest survival benefit alluded to PCI may be less than previously anticipated, especially in ES-SCLC. Thus, further studies are urgently required to dispel these uncertainties.
However, the best strategy moving forward is probably integrating hippocampal avoidance and drug neuroprotection to minimize neuropsychological sequelae. Additionally, regarding the question of PCI in the elderly, there are some question marks that remain but, in our opinion, shared decision making is the pinnacle of patient-centered care. Subsequently, the next step, strictly hypothesis-generating would be evaluating possible dose de-escalation in elderly patients.
Disclosure
The authors report no conflicts of interest in this work.
Farkhad Manapov,1,2 Lukas Käsmann,1 Olarn Roengvoraphoj,1 Maurice Dantes,1 Nina-Sophie Schmidt-Hegemann,1 Claus Belka,1,2 Chukwuka Eze1
1Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany; 2Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany
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Source: Lung Cancer: Targets and Therapy.
Originally published August 16, 2018.
