Whole-Brain Radiotherapy for Brain Metastases: Is the Therapeutic Window Enlarging?

WBRT: Historical Context

Prior to the 1950s, the treatment of intracranial metastases was supportive care alone. demonstrated significant symptomatic improvement in 63% of brain metastases patients treated with WBRT. This original study showed that there was minimal morbidity and toxicity with WBRT and that tumors responded equally well irrespective of the “radiosensitivity” of the primary tumor. Chao and colleagues’ technique initially utilized two opposed lateral fields with fractions starting at 0.5–1 Gray (Gy) increasing to 3.5–4 Gy as tolerated for a total dose of 30 Gy, although they acknowledged that palliative benefit may be obtained at a total dose as low as 20 Gy. With improvements in surgical and radiosurgical techniques, the role of WBRT has evolved to be used not only for symptom relief as originally described but also in conjunction with more focused techniques.

Palliative Benefit

Palliation of symptoms from intracranial metastases is the most studied and best established role of WBRT. originally described the effects of brain metastases as “disabling and distressing” including “headache, vomiting, inability to communicate, paralysis, and incontinence” and showed improvement, albeit in an uncontrolled series, in a majority of patients, justifying their recommendation of palliative WBRT. Since then, controlled studies carried out by the Radiation Therapy Oncology Group (RTOG) trials 6901 and 7361 reported that 43–64% of patients had a positive clinical response after 2 weeks of treatment. The median survival for patients treated with WBRT was three times longer (3–6 months vs. 1–2 months) compared to those treated without radiation ( ).

Subsequent studies over the last several decades have reported similar results to RTOG 6901 and 7361. demonstrated a 25% complete radiographic response rate 3 months after WBRT with 30 Gy in 10 fractions. Thirty-five percent of patients achieved partial radiographic response and no change was observed in 39%, with only 2% showing progressive disease. Importantly, complete or partial radiographic response at 3 and 6 months following WBRT correlated to a 38% and 42% improvement in overall survival respectively across multiple cancer types ( ). Likewise, tumor response to WBRT was associated with preservation of neurologic function with stable intracranial lesions shown by to correlate with stable Mini Mental Status Exam scores at 3 months while progressive lesions correlated to an average drop of 6 points at 3 months.

Although 30 Gy in 10 fractions is considered the most common dosing schedule for palliative WBRT, a number of groups have investigated alternative dosing schedules. Both RTOG 6901 and 7361 included an optional arm to investigate hypofractionated doses of either 10 Gy in one fraction or 12 Gy in two fractions versus regimens with smaller fraction sizes (20–40 Gy in 5–20 fractions) and found no major differences between these various schedules except for an increased risk for cerebral edema in the hypofractionated regimen.

Conversely, evaluated the impact of dose escalation over a longer period in a retrospective analysis of patients with multiple brain metastases treated with 30 Gy in 10 fractions versus 45 Gy in 15 fractions or 40 Gy in 20 fractions and found no apparent survival or local control benefit. In fact, most studies that have investigated alternative dosing schedules have shown no significant improvement over 20–37.5 Gy in 5–15 fractions, respectively, which allows tailoring around 30 Gy in 10 fractions for shorter or longer treatment courses depending on patient life expectancy.

Primary Treatment of Multiple Brain Metastases

Advances in SRS and neurosurgical technique have reduced the use of WBRT as a primary treatment modality. However, WBRT is still the primary technique for certain clinical situations such as lesions that are too large for radiosurgery, lesions not amenable to surgical resection, if the burden of metastatic disease is large, or if there is a high risk of microscopic disease such as with small-cell lung cancer.

A number of studies have examined whether WBRT alone is sufficient to control intracranial disease or whether it should be augmented with either resection or radiosurgery. reviewed seven different studies specifically looking at the advantage of adding resection prior to WBRT to WBRT alone. Of these seven studies, three were prospective randomized control trials, two of which concluded there was a survival advantage to surgical resection of 40 versus 15 weeks in one series and 10 versus 6 months in another series favoring postoperative WBRT compared to WBRT alone. The third prospective trial failed to find any benefit from resection. In this study, however, the inclusion criteria allowed for a higher proportion of patients with systemic disease and lower performance scores resulting in more deaths from systemic disease than the other two trials ( ).

Surgical resection is recommended with postoperative WBRT in patients with good performance status and surgically amenable lesions. The optimum treatment is less clear in patients with extensive systemic disease as the long-term benefit of resection may not be realized before they succumb to extracranial disease. Likewise, in patients with poor performance scores or multiple brain metastases, the risk of surgery may not justify the benefits.

SRS is another technique used to boost the dose to metastatic brain lesions following WBRT. The advantage here is that both WBRT and SRS are noninvasive and that conventional WBRT doses can be boosted without undue deposition of radiation dose to unaffected brain areas. evaluated the benefit of adding SRS to standard WBRT in patients with 2–4 brain metastases. The trial was stopped at the interim evaluation because the local failure at 1 year in the WBRT alone group was 100% but only 8% in the group treated with SRS in addition to WBRT. The RTOG trial 9508 tested WBRT with or without SRS in 333 patients with one to three brain metastases. All patients received WBRT at 37.5 Gy in 15 fractions and half were randomized to receive an additional 15–24 Gy boost to the metastatic lesion(s) depending on size. reported that the median survival of patients with a single brain metastasis improved from 4.9 to 6.5 months ( p = 0.04) with the addition of SRS. Additionally, patients treated with WBRT and SRS were more likely to have stable or improved Karnofsky performance status at 6 months (43% vs. 27%, p = 0.03) and better control of the treated tumors at 1 year (82% vs. 71%, p = 0.01).

Multimodal Treatment with Radiosensitizing Agents

A classic radiosensitizing agent increases the radiation-induced tumor cell kill without significant corresponding increase in normal tissue cell death, and on its own, the agent has almost minimal to no direct cell kill effect. Various agents have been explored to sensitize target cells to the effects of radiation. These so called radiosensitizers limit the tumor cells’ ability to respond to damage from radiation. Historically, these agents fell into three main categories: hypoxic sensitizers such as hyperbaric oxygen, or the imidazoles which could mimic the effect of oxygen to “fix” (make permanent, in this context) radiation-induced DNA damage, or perfluorochemicals or efaproxiral (RSR-13), which could increase oxygen-carrying capacity; S-phase sensitizers such as halogenated pyrimidines, which increased DNA double-strand breaks, such as iododeoxyuridine (IUdR) and bromodeoxyuridine (BUdR); and hypoxic cytotoxins which would have a localized cytotoxic effect only within a hypoxic environment. Several of these agents, such as IUdR, BUdR, misonidazole, etanidazole, Fluosol, RSR-13, etc., have demonstrated preclinical radiosensitization, but have failed to achieve significant clinical improvements in clinical trials.

More recently, redox-modulating agents such as motexafin gadolinium (MGd), which disrupts the redox balance in cancer cells by catalyzing the oxidation of intracellular reducing metabolites rendering the cell vulnerable to reactive oxygen species, and reducing a cell’s inherent repair capacity, have been tested. The efficacy of MGd was assessed in the Phase III SMART trial that compared WBRT with or without the agent in patients with brain metastases. Although the study failed to show a significant benefit for overall survival or time to neurologic progression, it did prompt a follow-on study based on subset analysis showing significantly longer time to neurologic progression in patients with non-small cell lung cancer (NSCLC) ( ). The follow-on Phase III study included 554 patients with brain metastases from NSCLC treated with WBRT with or without MGd and showed a trend toward improved time to neurologic progression (10.0 vs. 15.4 months) in the MGd group that, however, was not statistically significant ( p = 0.122). Subset analysis in this study showed a significant improvement in time to neurologic progression in North American patients treated with MGd shown in Figure 3.1 which reflected prompter WBRT after diagnosis compared to other geographic regions. Reanalysis of the entire cohort showed that if WBRT was given within 28 days of diagnosis, the time to neurologic progression was significantly prolonged with the use of MGd ( ).

Multimodal Treatment with Systemic Chemotherapeutics

There are a number of chemotherapeutics that potentially sensitize cells to the effects of radiation including alkylating agents such as temozolomide (TMZ), topoisomerase inhibitors, taxanes, and platinum agents. Unlike conventional sensitizers, these agents also possess direct antitumor cytotoxicity, and are often simply additive rather than synergistic with radiation. Unfortunately, there is a lack of robust Level 1 evidence to support the use of conventional chemotherapy, concomitantly with WBRT in the setting of brain metastases. Many of the agents used have poor blood–brain barrier permeability, making it difficult to achieve therapeutic levels in the metastatic lesion.

The most widely studied agent in the brain metastases context is TMZ, an alkylating agent with excellent blood–brain barrier penetration and the potential to be safely combined with radiotherapy. Structurally a pro-drug, it is metabolized in systemic circulation to a cytotoxic alkylating agent that delivers a methyl group to purine bases, causing purine methylation, and disrupting DNA transcription, resulting in cell death.

A number of Phase II studies over the last decade have suggested improved response rates with the addition of TMZ; however, no large prospective clinical trial has shown convincingly that a survival benefit accrues. showed that the addition of TMZ to WBRT produced a significantly higher radiographic partial response rate 2 months after the completion of radiation of 96% versus 67% with WBRT alone. A second study reported by showed improved progression-free survival at 90 days of 72% versus 54% ( p = 0.03) when TMZ was added to WBRT. Most recently, reported similar results with significantly better objective response (78.6% vs. 48.1%) and median progression free survival (11.8 vs. 5.6 months) favoring the addition of TMZ to WBRT. None of these studies, however, showed a significant improvement in overall survival.