Intracranial Neoplasms: The Evolution of Radiotherapies
CURRENT STANDARD OF CARE FOR BRAIN TUMORS
The current initial standard of care for aggressive brain tumors—whether they are primary brain tumors (ie, tumors that originate in the brain), or metastatic tumors from cancers that started outside of the brain—is resection. After surgery, a follow-up treatment, also referred to as adjuvant treatment, is often recommended to help eliminate any residual traces of the tumor.1 In the case of brain tumors, more often than not, adjuvant therapy involves using radiation, in part because few chemotherapy agents reliably cross the blood brain barrier.
Adjuvant radiation is used either alone or in combination with chemotherapy, and the most common method of radiation treatment is external beam radiation therapy (EBRT).1,2 For EBRT, a large machine generates radiation beams and focuses them inward to travel through the skin, then through the skull, and finally, into the brain.2 Radiation therapy including EBRT works by creating double-strand breaks in cellular DNA, which interferes with the reproductive integrity of the cells.3 Radiation primarily impacts cells that are rapidly undergoing cellular division, which is why it is useful for arresting aggressive tumor development. However, it can also stop the normal cellular replication that takes place as part of the body’s healing and repair process after surgery. For this reason, external beam radiation treatments are often delayed for 2 to 3 weeks or longer after a surgery.
EBRT FOR BRAIN TUMORS As noted above, postsurgical wound healing must occur prior to the initiation of EBRT, leaving a large window of time for unchecked tumor cell replication.4,5 Additionally, EBRT regimens for primary brain tumors (ie, fractionated EBRT) are often time and resource intensive (typically requiring daily visits from Monday through Friday for 4 to 6 weeks), which poses a significant burden on these vulnerable patients and their caregivers.3 With stereotactic radiosurgery (SRS), a type of EBRT, it is sometimes possible to truncate the treatment period to a total of 1 to 5 treatments. Involving multiple focused radiation beams, SRS is used for both metastasis and for relatively small primary brain tumors with well-defined borders.2 As with standard fractionated EBRT postsurgery, these treatments must also be delayed for a few weeks to allow for postsurgery wound healing. For primary brain tumors (gliomas, meningiomas, and similar tumors), adjuvant fractionated EBRT is administered to a limited region of brain; typically, the tumor bed plus a zone around the bed to encompass possible tumor spread (FIGURE 1). For the treatment of a single or a limited number of brain metastases (4 or fewer), SRS delivered in 1 to 5 treatments is often used.3 When more than 4 brain metastases are present, whole-brain radiation therapy (WBRT), given daily over 2 to 4 weeks, is often recommended.
KEY TAKEAWAYS
- The standard of care for aggressive brain tumors is resection.1
- Adjuvant therapy (chemotherapy or radiation) is recommended when surgery is unable to remove all traces of a tumor.1,3
- The most common method of adjuvant radiation treatment is fractionated EBRT.1,3
- Radiation travels from outside of the body through the skull and into the brain, exposing healthy tissue.
- EBRT typically involves a 2- to 3-week treatment delay to allow for postoperative wound healing, and the treatment regimen is time and resource intensive (typically requiring daily visits from Monday through Friday for 4 to 6 weeks).3
RECURRENT BRAIN TUMORS AND THE UNMET CLINICAL NEED FOR A NEW POSTOPERATIVE ADJUVANT THERAPY When an aggressive tumor returns, resection alone is not usually curative, but it can provide symptom relief, and the extent of resection correlates with the likelihood of longer-term control.6 Thus, whenever feasible, recurrent brain tumors are treated by combining maximum safe surgical resection with an adjuvant therapy.1 As noted previously, few effective chemotherapies cross the blood brain barrier, and even fewer are available for recurrent tumors.1 Additionally, for many patients, repeating adjuvant EBRT is often not an option, as they received a maximum safe dose of EBRT during their initial treatment.7 If EBRT is repeated, the radiation will pass through the same (or nearby) skin, skull, and normal brain tissue that were impacted previously. The risks of injury from radiation to healthy tissues increases with the repeated radiation dose and the total irradiated brain volume treated.8 Consequently, to keep the risk of injury from escalating, we must either lower the radiation dose and/or lower the volume of brain treated.8 The problem is we know that lower treatment doses are potentially less effective, and minimizing the treatment volume can lead to missing tumor cells (FIGURE 2A–C). Since EBRT comes from the outside inward, it typically exposes a large volume of normal brain tissue in proportion to the actual area in need of treatment.9 As volume has 3 dimensions (H x W x L), even a seemingly small increase in any one of these measurements can lead to a large increase in the end volume. To avoid toxicity with EBRT, clinicians use treatments in the lower dose range of the highest safe doses.1,8 These lower radiation doses are temporarily helpful in many cases, but rarely enough to produce reliable tumor control. Hence, there is a critical need for a new radiation paradigm for recurrent brain tumors.
Determining the precise treatment zone with postoperative imaging can be an additional challenge, and as mentioned previously, leaving the residual tumor cell replication unchecked for several weeks until the wound from the operation has healed is a suboptimal necessity of EBRT.4,5,10 Thus, although many recurrent aggressive brain tumors may be technically resectable, surgery is frequently not offered at recurrence because: 1) resection alone is unlikely to remove all tumor cells, and 2) no repeat safe and effective adjuvant therapy has historically been available to prevent any tumor cells missed at surgery from regrowing.11 For these reasons, effective re-treatment options are extremely limited, and there is no clearly established standard of care.1,12
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