Keywords Glioblastoma multiforme - GammaTile therapy - microvascular free flap - Multidisciplinary
management - recurrent brain tumor - scalp reconstruction - brachytherapy - oncologic
integration - tissue viability
Introduction
Glioblastoma multiforme (GBM) is the most prevalent malignant primary brain tumor
in adults, characterized by an incidence rate of 3.2/100,000.[1 ] The standard management of GBM involves a multimodal strategy, including neurosurgical
resection followed by the administration of concurrent chemoradiation therapy typically
initiated 4 to 8 weeks after the initial surgery.[1 ]
[2 ]
[3 ]
[4 ] Despite these interventions, GBM is notorious for its aggressive local progression
and poor prognosis, with tumor recurrence inevitably occurring, especially near the
surgical resection cavity or in immediately adjacent regions where the density of
microscopic residual tumor cells is highest. Notably, 50 to 70% of glioblastoma patients
experience tumor regrowth adjacent to the resection cavity during the critical 4 to
8-week recovery period before postoperative radiation begins.[1 ]
Several clinical trials have explored the impact of increasing radiation doses directed
at the treatment cavity on controlling GBM regrowth. However, while these studies
showed only marginal improvements in survival, they also demonstrated a significant
increase in radiation-induced adverse effects.[5 ] To augment the radiation dose directed at the resection bed while mitigating adverse
effects to adjacent healthy tissue, various brachytherapy approaches have been explored
both for primary and recurrent diseases.
GammaTile therapy, or surgically targeted radiation therapy (STaRT), is designed to
address the aggressive recurrence of tumors like GBM directly at the source.[2 ] This Food and Drug Administration (FDA)-licensed device utilizes cesium-131 (Cs-131)
seeds encased in a resorbable collagen matrix, forming a tile that is implanted immediately
after tumor resection.[3 ] The cesium-131 isotope is favored due to its relatively short half-life of 9.7 days,
compared to 59.4 days for iodine-125, which has also been used in brain brachytherapy.[1 ]
[2 ]
[4 ] This shorter half-life allows for a potent dose of radiation to be delivered directly
to the tumor bed, reducing the potential for radiation damage to surrounding healthy
tissues.
Each GammaTile measures 2 cm × 2 cm and contains four radioactive seeds. This modularity
and the pliability of the collagen matrix ensure conformal radiation delivery, making
surgical implantation quicker and aiding in precise dosimetric planning.[3 ] The design includes a tissue offset of 3 mm, which minimizes the risk of focal necrosis
around the radioactive sources. GammaTile delivers 120 to 150 Gy at the cavity surface
and maintains 60 to 80 Gy up to 5 mm depth, which is 1.5 to 2× the standard dose delivered
by external beam radiation therapy (EBRT).[1 ]
[2 ]
The implementation of subsequent surgeries as well as standard adjuvant chemoradiation
therapy and surgically targeted radiation therapy can negatively impact the integrity
of the scalp soft tissues and can compromise the ability to achieve primary closure
over the surgical site. In these circumstances, complex reconstruction with free tissue
transfer may be necessary.
Free flaps are often utilized in complex reconstructive surgeries, particularly in
cases where large defects are created after tumor resection, such as in head and neck
cancers or soft tissue sarcomas.[6 ]
[7 ]
[8 ] These flaps of well-vascularized tissue are essential in covering defects and promoting
healing in previously irradiated or compromised tissues. However, postoperative complications
such as wound dehiscence, fistula formation, and flap necrosis can pose a significant
risk, especially when combined with postoperative radiation therapy or brachytherapy.[6 ]
[7 ]
[8 ]
[9 ] Studies have demonstrated complication rates as high as 38.33% in patients undergoing
microsurgical free flap reconstruction with intraoperative brachytherapy, with the
most frequent issues being wound dehiscence and delayed flap necrosis.[7 ]
[9 ] Additionally, patient-related factors such as smoking, diabetes, high BMI, prolonged
operative time, anemia, atherosclerotic calcifications, serum creatinine, and prealbumin
levels, and extensive intraoperative resuscitation have been associated with an increased
risk of flap failure.[10 ]
[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ] Despite these risks, free flaps continue to play a crucial role in improving surgical
outcomes by providing adequate coverage for large defects and facilitating healing,
particularly when combined with careful perioperative management.
Case Presentation and Surgical Course
Case Presentation and Surgical Course
A 37-year-old woman diagnosed with GBM (IDH wild-type, WHO grade 4) initially underwent
a right temporal craniotomy and tumor resection. Postoperative pathology confirmed
high-grade glioma with vascular proliferation, geographic necrosis, and palisading
necrosis, consistent with GBM. Molecular testing also revealed that the tumor was
IDH1 negative. The patient underwent postoperative adjuvant chemotherapy and intensity-modulated
radiation therapy (IMRT). Three months after completing IMRT, she presented with wound
induration which was initially managed with incision and drainage of underlying purulent
material. All microbiological examinations, including wound collection cultures, yielded
negative results.
The patient continued to experience intermittent yellow drainage and scab formation
at the incision site, indicating a persistent wound complication. Blood tests and
cultures ruled out systemic infection. At this stage, she was treated conservatively
with empiric antibiotics. However, due to the concerns about local infection spread
and to rule out the formation of an epidural or intracranial abscess, a follow-up
MRI was performed. The imaging showed a small extradural collection sub-adjacent to
the craniotomy characterized by restricted diffusion, likely related to the underlying
blood product. Also, a postcontrast enhancing nodule in the posterior region of the
operative cavity was noted. This finding was neuroradiologically consistent with either
tumor recurrence or radionecrosis ([Fig. 1 ]).
Fig. 1 (A ) Preoperative axial MRI demonstrating the right temporal GBM, highlighting the extra-axial
infection as well as the recurrent tumor's location and extent before surgical intervention.
(B ) Postoperative axial MRI. (C ) Postoperative axial CT illustrating the integration of titanium mesh following craniotomy.
Given the suspicion of the presence of an epidural infection, approximately 1.5 months
after wound incision and drainage, the patient underwent a revision craniotomy. Purulent
material was confirmed in the epidural space and after removal of the infected bone
flap and debridement of the epidural space collection, a titanium mesh cranioplasty
was performed. A temporoparietal fascial flap was used both for hardware coverage
and primary scalp closure was achieved. No tumor resection was performed during this
procedure. Wound cultures returned positive for Staphylococcus aureus. The patient
was then started on a 6-week course of Cefazolin administered via a PICC line, followed
by suppressive therapy with oral cefadroxil.
Approximately 3 weeks following surgery, the patient's right temporal scalp skin became
dehiscent with exposure of the underlying temporoparietal flap ([Fig. 2 ]). A follow-up MRI was performed and did not reveal any sign of residual infection
but showed a volumetric progression of the nodular enhancing areas with a mild increase
in the extent of heterogeneous enhancement.
Fig. 2 Right temporal wound dehiscence with exposure of underlying temporoparietal flap.
In response, a conscious craniotomy was performed for recurrent tumor resection followed
by the placement of 3 GammaTiles along the resection bed. Intraoperatively, pathology
confirmed viable residual high-grade glioma in the brain surface, midportion, and
deeper sections of the right temporal region. Given the poor condition of the patient's
temporal scalp skin, she underwent excisional debridement leaving a sizeable full-thickness
scalp defect overlying the resection site. To achieve wound closure and dural coverage,
a fasciocutaneous anterolateral thigh free flap was harvested and the pedicle was
anastomosed to the right facial artery and common facial vein. [Fig. 3 ] demonstrates the pre-and postoperative imaging findings.
Fig. 3 (A ) Preoperative MRI showing nodular enhancement in recurrent neoplasm before resection,
GammaTile placement, and free flap. (B ) Postoperative MRI after surgery with free flap intact.
At the conclusion of the surgery, the radiation physicist assessed radiation exposure
at different distances from the surgical site ([Fig. 4 ]). The dose measured at the right side of the patient's head, at a distance of 3
inches from the surgical cavity, resulted in 125 mR/hour. This provided the most accurate
estimate of the minimal dose the free flap received, though the actual dose to the
flap would have been much higher given that the GammaTiles sit closer than 3 inches
to the reconstructed tissue. This close proximity increases radiation exposure, raising
concerns about the long-term effects on tissue viability. Additionally, the musculocutaneous
perforators that perfuse the skin were small in caliber (1–2 mm) and located adjacent
to the resection cavity. Despite these challenges, the free flap remained viable in
the immediate postoperative period, suggesting that GammaTile therapy can potentially
be safely integrated with reconstructive procedures. However, further research is
necessary to fully understand the effects of such high, localized radiation doses
on free flaps.
Fig. 4 Radiation exposure (mR/hour) at varying distances from the GammaTile.
Postoperative Course
Postoperatively the patient had an uneventful course of recovery. She remained in
hospital for 7 days and the free flap demonstrated no evidence of arterial ischemia
or venous congestion. The incision lines also remained intact and the patient had
an excellent neurological outcome with no deficits.
At over 9 months from surgery, the free flap has now completely healed, providing
soft tissue coverage of the right temporal region with an excellent aesthetic outcome
([Fig. 5 ]). This integrated approach of single-stage GammaTile therapy for GBM with free flap
reconstruction is the first of its kind reported.
Fig. 5 Right scalp free flap reconstruction 9 months following surgery.
Discussion
The management of GBM presents ongoing challenges due to its aggressive nature and
high likelihood of local recurrence. This case report presents an innovative approach
in which GammaTile therapy and free flap scalp reconstruction can be integrated simultaneously
to address both oncological and reconstructive needs in GBM treatment. By integrating
GammaTile therapy into the surgical procedure, the patient benefits from immediate
localized radiation, which is crucial given the rapid proliferation typical of GBM.
This method could potentially reduce the window for tumor regrowth that is usually
observed during the delay before starting conventional EBRT.[3 ] GammaTiles also enhance the precise targeting of remnant tumors and reduce radiation
exposure to normal brain regions. The customization aspect of placement intraoperatively
also presents an advantage in delivering precise, targeted therapy, which is particularly
helpful in eloquent brain regions.[2 ]
Brachytherapy has historically been associated with an increased risk of complications,
particularly in patients undergoing microvascular free tissue transfers. Traditional
brachytherapy can exacerbate the risk of wound dehiscence and fistula formation, crucial
considerations in surgeries involving extensive tissue manipulation.[2 ]
[6 ]
[8 ]
[9 ] Radiation from brachytherapy can also damage the blood vessels that perfuse free
flaps, resulting in tissue ischemia and necrosis, further complicating the recovery
process.[7 ] Beyond radiation exposure, factors such as smoking, diabetes, elevated BMI, prolonged
operative time, anemia, atherosclerotic calcifications, serum creatinine, and prealbumin
levels, and extensive intraoperative resuscitation have been identified as potential
contributors to flap failure.[10 ]
[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ] However, the impact of these factors may vary depending on the type of free flap
and the surgical context.[19 ]
Given the complexity of this case, alternative reconstructive options were considered.
Local rotational flaps, such as the temporoparietal or pericranial flaps, were deemed
inadequate due to prior radiation exposure, wound dehiscence, and the need for durable
soft tissue coverage over the GammaTiles. Skin grafting was not a viable option as
it would not have provided the necessary bulk and vascularity to cover the exposed
hardware. A regional island flap using the trapezius was deemed inappropriate for
several reasons. First, the location of the defect in the temporal scalp would be
difficult to reach with either an upper or lower trapezius island flap unless an atypically
long flap was harvested which would put the vascularity of the most distal aspect
of the flap (arguably the most crucial for reconstruction) at risk. Second, the trapezius
island flaps would result in suboptimal aesthetic outcomes for the patient as they
are bulky and must remain attached to their vascular pedicle.[20 ] Ultimately, an ALT flap was chosen for its reliable vascular supply, sufficient
soft tissue bulk, and flexibility in contouring to the defect. Free tissue transfer
also allowed for optimal revascularization, reducing the risk of further wound breakdown
and necrosis in a previously compromised surgical field.[6 ]
[7 ]
[8 ]
A multidisciplinary team approach was crucial in developing and executing a comprehensive
treatment plan. This patient's care was coordinated through a multidisciplinary tumor
board involving neurosurgery, neuro-oncology, neuroradiology, head and neck reconstructive
surgery, and radiation oncology. The treatment plan was developed through discussions
at a multidisciplinary tumor board to ensure optimal oncologic control and reconstructive
feasibility. Collaborative decision-making focused on preoperative imaging, prior
radiation effects, and flap selection to minimize complications and promote long-term
healing.
The success of this approach can likely be attributed to the specific characteristics
of the Cs-131 used in GammaTiles. Cs-131 is a low-energy emitter with a short half-life
of 9.7 days, allowing for a quicker and more concentrated delivery of radiation.[1 ]
[2 ]
[4 ] This impacts the efficacy and safety of radiation delivery because after placing
the tiles into the operative bed, they instantly deliver a uniform radiation dose
to the target area.[3 ] Fifty percent of the therapeutic dose is delivered in the first 10 days after surgery
to help deter residual tumor cells from multiplying, and 88% of the therapeutic dose
is delivered within 30 days, with over 95% of the dose delivered within 6 weeks.[3 ] This rapid and focused delivery reduces the duration of radiation exposure and could
decrease potential tissue toxicity. Crucially, the highest doses are delivered during
the most critical healing period for free flaps, raising concerns about wound complications.
Despite this, we noted no issues with flap necrosis, fistula formation, or wound infection
in the 9 months following surgery.
Conclusion
This case report demonstrates a pioneering approach in the treatment of GBM by integrating
GammaTile therapy with microvascular free flap reconstruction. This approach highlights
the possibility of meeting complex reconstructive needs without forgoing the ability
to address the aggressive nature of GBMs, providing immediate, localized radiation
to reduce tumor recurrence risks while preserving surrounding healthy tissues. The
utilization of Cs-131 in GammaTiles minimizes radiation-induced toxicity, enhancing
patient recovery and improving quality of life through better aesthetic and functional
outcomes. This novel approach could potentially set new standards for treating GBM
and similar cancers, highlighting its significance for future clinical practices and
research in oncology.
