PCI in the elderly
Elderly patients are a rather interesting subgroup of SCLC patients. The proportion of elderly among all cases of SCLC has increased over the past 40 years.33 According to the Surveillance, Epidemiology, and End Results (SEER) database, elderly patients (>70 years) among all cases of SCLC increased from 23% in 1975 to 44% in 2010. In general, elderly could be characterized by a lower performance status, higher comorbidity index, reduced organ function and less bone marrow reserve. Earlier studies have shown that elderly have significantly worse outcome compared to younger SCLC patients.34,35Also, a large cohort study regarding therapeutic whole-brain irradiation reported significant toxicity such as neurocognitive dysfunction with memory loss in patients older than 70 years.36 In this context, elderly patients are the focus of research to reduce treatment-related toxicity of cranial irradiation and improve prognosis.
Historical studies reported that older patients (>60 years) experience a greater risk of acute and chronic neurotoxicity after PCI, as well as patients treated with higher total dose (>30 Gy) or concurrent chemotherapy.37–39 Previous data from randomized trials and a meta-analysis4,6,11,18included a varying number of older patients, which should be taken into consideration.
The landmark study by Aupérin et al evaluated 987 patients from 7 studies focusing on oncologic outcome of PCI.4 Over 25% of all analyzed patients could be defined as elderly patients (≥65 years). In the study by Le Péchoux et al, age (≤60 vs. >60 years) was a stratification factor for randomization.11 Unfortunately, the percentage of older patients in the analysis was not reported. Slotman et al included patients older than 75 years in their study, which represented over 7.5% of all participants.17
The SEER database analysis (1926 patients) published by Eaton et al focusing on elderly SCLC patients aged ≥75 years confirmed application of PCI as an independent predictor of overall survival.40However, the study did not report toxicity data for this patient subgroup.
A retrospective analysis of 658 LS SCLC patients from MD Anderson Cancer Center revealed that PCI conferred no survival benefit for patients aged ≥70 years and explained it with an increased risk of death from other comorbidities and extracranial disease progression.36
In Takahashi et al’s study, about 47% of patients in the PCI group and 46% in the observation group were aged 70 years or older.18 Takahashi et al found no overall survival benefit when administering PCI versus observation. Their suggestion is that PCI in patients with extensive-disease SCLC and confirmed absence of BM should be judged carefully because of the risk of declining cognitive function. Especially older patients appear to be at a higher risk of neurocognitive decline.
In summary, there is inconsistent data for PCI in elderly. The usage of PCI in this subgroup should be critically evaluated according to the stage of disease, treatment response to initial therapy, performance status, and existing general and neurological comorbidities. Data on the survival benefit of PCI in elderly are rather limited due to underrepresentation of this subgroup in prospective clinical trials.41
PCI in resected early-stage SCLC
Another relevant issue worth addressing is the issue of PCI in resected p-stage I SCLC.
The NCCN and European Society for Medical Oncology guidelines recommend adjuvant chemotherapy and PCI for early-stage SCLC, irrespective of primary treatment approach. We previously addressed this issue in two previous communications.42,43
Stahl et al demonstrated in an analysis of the National Cancer Data Base (NCDB) a surge in the utilization of surgery in 2004 vs. 2013, up from 14.9% to 28.5%.44 The paucity of evidence suggests that surgery is feasible in clinical stage I disease. However, careful selection of candidates including rigorous preoperative staging should be performed (positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-d-glucose integrated with computed tomography, endobronchial ultrasound-guided transbronchial needle aspiration and/or mediastinoscopy, comprehensive brain imaging using contrast-enhanced MRI) in order to ascertain stage I disease.
Current evidence supports adjuvant chemotherapy following surgery and is endorsed by another NCDB analysis by Yang et al in patients with pT1-2N0M0 disease, which demonstrated that these patients had inferior outcomes than those who underwent resection with adjuvant treatment.45
Regarding PCI in these patients, there is some evidence albeit retrospective data suggesting omission of PCI exclusively in the group of patients with p-stage I disease as various studies have shown a relatively low cumulative incidence of BM, in the order of 10%.42 However, due to the paucity of data and expected discrepancies in the prevalence of BM, this recommendation does not extend to patients with clinical stage I disease.
PCI in ES-SCLC
The most intense debate recently has centered on universal delivery of PCI particularly in ES-SCLC. In an era in which there was a paucity of data regarding PCI delivery in these patients, the EORTC study by Slotman et al in 2007 demonstrated a reduction in risk of BM in the PCI group, cumulative risk of BM within 1 year of 14.6% and 40.4% in the PCI vs. control group, 1-year survival rate of 27.1% vs. 13.3% in the PCI vs. control group, association of PCI with an increase in median disease-free survival from 12.0 weeks to 14.7 weeks and an increase in median OS from 5.4 months to 6.7 months from randomization.6
However, the recently published Japanese study by Takahashi et al has sparked renewed debate. The study randomized 224 patients between 2009 and 2013 to PCI vs. observation. In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of PCI, being superior to observation, was 0.011%, resulting in early termination of the study due to futility. In the final analysis, median OS from randomization was 11.6 months in the PCI group vs. 13.7 months in the observation group. The authors concluded that PCI could be omitted in therapy responders under the premise that these patients be followed up comprehensively by serial brain imaging and radiotherapy be deferred till onset of BM.18
Both studies have been studied methodically and defining shortcomings have been leveled against both studies, which have been discussed extensively in various previous publications,18,46–49particularly in the original publication by the Japanese group18 as well as a recently published review article by the same group.48
Most noteworthy was the mandated comprehensive brain imaging scheduling in the Japanese study, whereas in the EORTC study, CT/MRI of the brain was only performed in symptomatic patients. As such, only 29% of randomized patients in the EORTC study received brain imaging at diagnosis, and the number of patients who received repeat brain imaging prior to PCI is unclear.
Critics of the EORTC study partly attribute the survival benefit to the possible presence of subclinical BM before randomization, ascribing improved median OS to cranial irradiation. In addition, it is unclear what proportion of patients in the EORTC trial received platinum-based chemotherapy as mandated in the Japanese trial.
Moreover, various fractionation schedules at the discretion of the participating centers were adopted in the EORTC study with the predominant schedule being 20 Gy delivered in five fractions in 88/143 patients. By contrast, 25 Gy was universally delivered in 10 daily fractions in the Japanese trial.