|Year : 2021 | Volume
| Issue : 1 | Page : 2-5
Hippocampal avoidance prophylactic cranial irradiation in small cell lung cancer: Ready for prime time?
Department of Radiation Oncology, ACTREC/TMH, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
|Date of Submission||24-Nov-2021|
|Date of Acceptance||25-Nov-2021|
|Date of Web Publication||06-Jan-2022|
Dr. Tejpal Gupta
Department of Radiation Oncology, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Kharghar, Navi Mumbai 410210, Maharashtra.
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gupta T. Hippocampal avoidance prophylactic cranial irradiation in small cell lung cancer: Ready for prime time?. Bengal J Cancer 2021;1:2-5
Small cell lung cancer (SCLC) is an aggressive disease characterized by rapid progression and early dissemination with resultant poor survival outcomes., It is associated with an increased propensity for brain metastases leading to significant neurological morbidity and mortality. Prophylactic cranial irradiation (PCI) is the contemporary standard of care for patients with limited-stage SCLC following definitive thoracic chemoradiation and is often employed as a treatment option for extensive-stage disease responsive to induction therapy., Although PCI significantly reduces the risk of brain metastases and improves overall survival,, it is typically associated with progressive and irreversible neurocognitive decline with potential detrimental impact upon health-related quality of life., Hippocampus is a small structure located in the ventromedial part of both temporal lobes in the brain that is considered integral to the regulation of learning, memory encoding, and memory consolidation. Experimental and clinical data, have shown a good correlation of radiation dose received by the neural stem-cell compartment particularly the hippocampus with such cognitive toxicity. With technological advances in radiation planning and delivery, it is now possible to irradiate the whole brain while sparing the hippocampus [Figure 1]. Prospective data including a large cooperative group pivotal phase III randomized controlled trial (RCT) have clearly shown that hippocampal avoidance (HA) whole-brain radiation therapy (WBRT) reduces the incidence and severity of neurocognitive dysfunction compared to conventional WBRT without increasing the risk of peri-hippocampal metastases in patients with brain metastases.,
|Figure 1: Typical dose-wash (axial, coronal, and sagittal section) of hippocampal avoidance prophylactic cranial irradiation on 6MV linear accelerator using volumetric modulated arc therapy. Note the whole brain planning target volume (in red) covered by 95% of the prescription isodose, while both hippocampi (left, in pink and right, in green) with respective hippocampal avoidance zones (in yellow, 3 mm planning at risk volume margins) are spared to reduce neuro-cognitive impairment|
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The success of HA-WBRT in brain metastases prompted the neuro-oncology community to test the HA-PCI paradigm in the curative-intent management of SCLC. Two recently reported multicentric phase III RCTs, in this space have sparked global debate,,, due to conflicting and contradictory results. Key study characteristics, endpoints, and outcomes from both these trials are compared and contrasted for similarities and differences [Table 1] for the benefit of the reader. The first such trial from the Netherlands Cancer Institute (NKI) compared HA-PCI to standard PCI in 168 SCLC patients using a primary endpoint of ≥5 points decline (from baseline) on total recall of the Hopkins Verbal Learning Test-Revised (HVLT-R) at 4 months after cranial irradiation. The Dutch trial found no significant differences (P = 1.0) in the decline of total recall on HVLT-R at 4 months between standard PCI (29%) versus HA-PCI (28%). There were no significant differences in other cognitive secondary endpoints such as memory, executive function, attention, motor function, and processing speed raising questions about the efficacy of HA-PCI in preserving neurocognitive function in patients with SCLC. Treatment with HA-PCI was however deemed to be safe with no differences in the incidence of brain metastases and overall survival between the two arms. The PREMER trial of the Oncologic Group for the Study of Lung Cancer – Spanish Radiation Oncology Group (GICOR-GOECP-SEOR) randomized 150 SCLC patients to HA-PCI or standard PCI using ≥3 points decline (from baseline) of delayed free recall (recent memory) on the Free and Cued Selective Reminding Test (FCSRT) at 3 months as the primary endpoint. The Spanish trial found significantly lesser decline (P = 0.003) of delayed free recall on the FCSRT at 3 months associated with HA-PCI (5.8%) compared to standard PCI (23.5%). Additional analyses found lesser decline in learning at 3, 6, and 24 months and delayed free recall at 6 months after HA-PCI compared to standard PCI affirming the efficacy of hippocampal sparing. Overall survival, incidence of subsequent brain metastases, and patient-reported outcomes were not significantly different between the two arms.
|Table 1: Randomized trials comparing hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) versus standard PCI in small cell lung cancer (SCLC)|
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So how do we reconcile such divergent cognitive outcomes in two remarkably similar trials [Table 1] conducted in a very similar patient population using the same standard dose (25 Gy in 10 fractions over 2 weeks) of PCI. Both studies reported comparable overall survival outcomes and similar rates of subsequent brain metastases development with no increase in isolated hippocampal failures with HA-PCI thereby establishing oncological safety. We need to be cognizant of the fact that the magnitude of anticipated difference between treatments, test battery, timing of assessment, and choice of primary endpoint for neurocognitive function can impact analyses, inferences, and conclusions. Both these trials used different instruments for neurocognitive assessment. FCSRT is a validated, well-established measure that has many similarities and some differences with HVLT-R, a cognitive test frequently used in neuro-oncology trials. One potential difference could be the relative specificity of the FSCRT tool (used in the Spanish study) for monitoring hippocampal-related function, whereas the HVLT-R test (used in the Dutch study) may be more vulnerable to effects of attention on memory and may represent global neurocognitive status not restricted to hippocampal function. The hippocampus dose constraints in the Spanish trial were similar to the Radiation Therapy Oncology Group (RTOG) 0933 study that limited hippocampus D100% to ≤9 Gy (optimum) and ≤10 Gy (acceptable) with Dmax ≤16 Gy (optimum) and ≤17 Gy (acceptable), respectively. The Dutch trial used more stringent criteria with a mean hippocampal dose of ≤8.5 Gy (6.1 Gy biological dose, α/β = 2 Gy) and Dmax not exceeding 10 Gy. Stricter dose-volume constraints to the hippocampus in the Dutch trial may have been associated with greater dosimetric heterogeneity and dumping of higher doses to other critical areas of the brain somewhat negating the benefit of hippocampal sparing. There was a central review of hippocampus contouring and plan quality in the Spanish trial that allowed for meaningful change if required, whereas no such quality control and central review was employed in the Dutch trial. Robust quality assurance for advanced irradiation techniques such as HA-PCI assumes greater importance as we start to plan and deliver such treatments in clinical practice to ensure optimum or at least acceptable plan quality. Finally, there was significant attrition in either arm in both trials (more in the Dutch than the Spanish trial) for assessment of primary endpoint reducing statistical power and rigor., It is quite possible that both the trials were underpowered and may not have enough patients or events to robustly detect or negate a significant difference in neurocognitive outcomes. However, whether these minor differences are enough to explain the conflicting results remains debatable.
So, is HA-PCI in SCLC ready for prime time? Should we routinely start to spare the hippocampus during PCI in SCLC henceforth? Although based on the above results as well as by extrapolation of data from other randomized trials of HA-WBRT in brain metastases, it is oncologically safe to offer HA-PCI to patients with SCLC, its efficacy for better preservation of neurocognitive function compared to standard PCI is yet to be shown unequivocally. We also need to remember that HA-PCI is a resource-intensive strategy with resultant logistic and cost implications, particularly in a low–middle-income country settings including India with a perennial shortfall of contemporary linear accelerators, capable of delivering such treatments. We would need to await the results of a larger ongoing multicenter cooperative group trial (National Research Group-NRG CC003) with a target accrual of 392 patients and inbuilt central quality assurance of HA-PCI treatment plans, before adopting HA-PCI as standard of care treatment. In summary, the role of PCI in SCLC continues to evolve with opportunities to prevent irradiation-associated neurocognitive toxicity through improvements in treatment planning and delivery. Ongoing and planned trials incorporating rigorous scientific methodology and deeper insights from cognitive neurosciences are likely to further refine our therapeutic armamentarium for expectant and prophylactic management of brain metastases in patients with SCLC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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