Patterns of care with regard to whole-brain radiotherapy technique and delivery among academic centers in the United States

We used the chi-square test for linear trends to assess for a relationship between years of practice and whether respondents deviated from their typical method of WBRT therapy when treating more radioresistant tumors (melanoma, renal cell carcinoma). Respondents were classified by years in practice: 0-5, 6-10, 11-20, and >21 years. The results showed a linear association, with those in practice for longer periods more likely to use SRS alone, P = .027 (Figure 1).

The Jonckheere-Terpstra test was used to assess the linear trend of years of practice on the median rankings of the SRS- and WBRT-related factors. The Kendall tau-b was performed to assess the effect sizes for these analyses. The analysis revealed that younger practitioners ranked the status of extracranial disease for SRS alone as increasingly more important than older practitioners (effect size, 0.26; P = .010, Figure 2), and older practitioners ranked the histopathology as increasingly more important (effect size, -.30; P = .002, Figure 3).

With regard to WBRT reirradiation, the Kruskal-Wallis test showed differences among how long respondents had been in practice and the importance placed on brain tumor histology when considering treatment (P = .02). The Mann-Whitney U post hoc test showed that practitioners who had been in practice for 21 years or more placed more importance on histology than did younger practitioners (Table 3, p. 93; Figure 4).

There was no significant difference between physicians who are board certified and those who are not with regard to treatment technique and delivery. Likewise, no associations were found between what region of the country the academic physician practiced in and their treatment technique and delivery.

Discussion

The incidence of brain metastases is increasing because of improvements in diagnostic imaging techniques and advancements in systemic therapy control of extracranial disease but not of intracranial disease or metastasis, because therapies do not cross the blood-brain barrier.^11,12 Brain metastases are the most common type of brain tumor. Given that most chemotherapeutic agents cannot cross the blood-brain barrier, radiotherapy is considered a means of treatment and of controlling brain metastases. Early data from the 1950s¹³ and 1960s¹⁴ have suggested clinical improvement with brain radiation, making radiotherapy the cornerstone for treatment of brain metastases.

The Radiation Therapy Oncology Group (RTOG) has evaluated several fractionation schedules, with 5 schemas evaluated by the RTOG 6901 and 7361 studies: 30 Gy in 10 fractions, 30 Gy in 15 fractions, 40 Gy in 15 fractions, 40 Gy in 20 fractions, and 20 Gy in 5 fractions. The combined results from these two trials showed that outcomes were similar for patients treated with a shorter regimen than for those treated with a more protracted schedule. In our study, respondents reported that they most frequently treated brain metastases to a total dose of 30 Gy in 10 fractions. Given the results of the aforementioned RTOG trials and practice patterns among academic physicians, we recommend all practitioners consider a shorter hypofractioned course when treating brain metastases with WBRT. This will also reduce delays for patients who are likely to benefit greatly from earlier enrollment into hospice care, because protracted radiation schedules typically are not covered while a patient is in hospice.

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Pharmacologic management for patients with brain metastases is important for symptomatic improvement. Glucocorticoids are important for palliation of symptoms from edema and increased intracranial pressure.¹⁵ However, steroids have a multitude of side effects and their use in asymptomatic patients is unnecessary. Improvements in imaging and detection¹¹ have allowed us to find smaller and asymptomatic brain tumors. In our survey, it was promising to see a change in former practice patterns, with only 8% of academic practitioners regularly prescribing steroids to all of their patients receiving whole-brain radiation.

Diminished cognitive function and short-term memory loss are troublesome side effects of WBRT. As cancer patients live longer, such cognitive dysfunction will become more than just a nuisance. The RTOG has investigated the use of prophylactic memantine for patients receiving whole-brain radiation to determine if it would aid in the preservation of cognition. It found that patients who received memantine did better and had delayed time to cognitive decline and a reduced rate of memory decline, executive function, and processing speed.¹⁶ In our study, about a third of practitioners prescribed memantine and it was reserved for patients who had an otherwise favorable prognosis.

The RTOG has also investigated adjusting treatment technique for patients who receive WBRT. RTOG 0933 was a phase 2 trial that evaluated hippocampal avoidance during deliverance of WBRT with intensity-modulated radiation therapy (IMRT). Results showed that avoiding the hippocampus during WBRT was associated with improved memory preservation and patient quality of life.¹⁷ In a survey of practicing radiation oncologists in the US, most reported that they did not use memantine or IMRT for hippocampal sparing when delivering whole-brain radiation.¹⁸ Given the positive results of RTOG 0933 and 0614, the NRG Oncology research organization is conducting a phase 3 randomized trial that compares memantine use for patients receiving whole-brain radiation with or without hippocampal sparing to determine if patients will have reduced cognitive decline. All patients receiving WBRT should be considered for enrolment on this trial if they are eligible.

The delivery of brain radiation has continued to change, especially with the introduction of SRS. Recent publication of a meta-analysis of three phase 3 trials evaluating SRS with or without WBRT for 1-4 brain metastases showed that patients aged 50 years or younger experienced a survival benefit with SRS, and the omission of whole-brain radiation did not affect distant brain relapse rates. ¹⁹ The authors recommended that for this population, SRS alone is the preferred treatment. In our study, physicians who had been in practice for a longer time were more likely to treat using SRS alone. The results showed a linear association, with those in practice for a longer time being more likely to use SRS alone compared with those practicing for a shorter time (P = .027). Accordingly, 67% of respondents (8 of 12) who had been in practice for 11 or more years used SRS alone, whereas 24% (14 of 58) who had practiced for 0-5 years and 42% (5 of 12) who had practice from 6-10 years used SRS alone (Figure 1). When treating with SRS, younger practitioners placed more importance on the status of extracranial disease, whereas older practitioners placed more importance on tumor histopathology.

The use of repeat whole-brain reirradiation is more controversial among practitioners.^20-22 Son and colleagues evaluated patients who needed whole-brain reirradiation after intracranial disease progression.²² The authors noted that patients with stable extracranial disease benefited from reirradiation. In our study, we found that when considering whole-brain reirradiation, older practitioners placed more importance on tumor histology than other factors.

As far as we know, this is the first study evaluating the practices and patterns of care with regard to the delivery of brain radiation in academic centers in the US. We found that time in practice was the most significant predictor of treatment technique and delivery. We also found that older practitioners place more importance on tumor histopathology compared with younger practitioners. A limitation of this study is that we had contact information only for program coordinators at ACGME-accredited programs. As such, we were not able to assess practice patterns among community practitioners. In addition, it seemed that residents and junior faculty were more likely to respond to this survey, likely because of the dissemination pattern. Given the evolution and diversity of treatment regimens for brain metastases, we believe that patients with brain metastases should be managed individually using a multidisciplinary approach.