Re-irradiation of Recurrent Pineal Germ Cell Tumors with Radiosurgery: Report of Two Cases and Review of Literature

Primary intracranial germ cell tumors are rare, representing less than 5% of all central nervous system tumors. Overall, the majority of germ cell tumors are germinomas and approximately one-third are non-germinomatous germ cell tumors (NGGCT), which include teratoma, embryonal carcinoma, yolk sac tumor (endodermal sinus tumor), choriocarcinoma, or mixed malignant germ cell tumor. Germ cell tumors may secrete detectable levels of proteins into the blood and/or cerebrospinal fluid, and these proteins can be used for diagnostic purposes or to monitor tumor recurrence. Germinomas have long been known to be highly curable with radiation therapy alone. However, many late effects of whole brain or craniospinal irradiation have been well documented. Strategies have been developed to reduce the dose and volume of radiation therapy, often in combination with chemotherapy. In contrast, patients with NGGCT have a poorer prognosis, with about 60% cured with multimodality chemoradiation. There are no standard approaches for relapsed germ cell tumors. Options may be limited by prior treatment. Radiation therapy has been utilized alone or in combination with chemotherapy or high-dose chemotherapy and transplant. We discuss two cases and review options for frameless radiosurgery or fractionated radiotherapy.


Introduction And Background
Primary intracranial germ cell tumors (IGT) are rare, representing less than 5% of all central nervous system tumors in Western series [1][2] but may be more common in East Asia [3][4]. These tumors most commonly occur in the suprasellar cistern and pineal gland and have a male predominance. Overall, the majority of germ cell tumors are germinomas and approximately one-third are non-germinomatous germ cell tumors (NGGCT), which include teratoma, embryonal carcinoma, yolk sac tumor (endodermal sinus tumor), choriocarcinoma, or mixed malignant germ cell tumor. Embryonal or endodermal sinus tumors are more common in adolescence and young adulthood [3]. Germ cell tumors may secrete detectable levels of proteins into the blood and/or cerebrospinal fluid (CSF), and beta-human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) are used for diagnostic purposes and monitor tumor recurrence. Pure germinomas may have elevated HCG [5]. Elevated serum or CSF HCG > 50 mIU/mL and/or elevated AFP are generally considered consistent with NGGCT and biopsy is not required.
Germinomas have long been known to be highly curable with radiation therapy (RT) alone. However, the late effects of whole brain or craniospinal irradiation (CSI) have been well documented, with adverse impacts on hearing, endocrine regulation, neurocognitive function, and risk of secondary malignancies [6][7][8]. To mitigate these risks, strategies have been developed to reduce the dose and volume of radiation therapy, often in combination with chemotherapy. In contrast, only about 20-45% of patients with NGGCT can be cured following radiation therapy alone, though results are improved to about 60% with multimodality chemoradiation [1].
The focus of this paper is to discuss treatment options for locally relapsed IGT without dissemination and to investigate patient and/or tumor characteristics that may affect the choice of re-irradiation modalities, such as stereotactic radiosurgery (SRS), hypofractionated fractionated stereotactic radiotherapy (FSRT), or full dose re-irradiation with external beam RT.

Case 1
A 16-year-old Hispanic male without prior health problems presented with gradual memory loss and severe headache; an MRI brain with gadolinium revealed an enhancing 3.5 x 3.4 x 3.7 cm pineal gland tumor ( Figure 1). His serum AFP was 49.3 ng/mL and CSF AFP was 33.9 ng/mL ( Figure 2). Both serum and CSF HCG were negative. An MRI spine and CSF cytology were negative. He had hydrocephalus and an intratumoral hemorrhage following a ventriculostomy and ventriculoperitoneal (VP) shunt placement ( Table 1). His neurological status deteriorated and he became unresponsive. Because of his intratumoral bleed and performance status, he was treated with systemic chemotherapy as per the Children's Oncology Group (COG) Trial ACSN0122 with alternating carboplatin/etoposide and ifosfamide/etoposide. Following his first cycle of chemotherapy, he began to neurologically recover and his tumor markers normalized after two cycles of chemotherapy. After six cycles of chemotherapy, his serum and CSF tumor markers remained undetectable with a residual 1.3 x 2.1 x 1.3 cm enhancing pineal gland mass. About six weeks post-chemotherapy and before RT, his serum AFP rose to 8.9 ng/mL (institutional high normal: 7.3 ng/mL). MRI of the spine was negative. Although concerned about relapse, we began whole ventricular irradiation (WVI) and intensity-modulated radiation therapy (IMRT) with an intended dose of 30.6 Gy ( Figure 3). Two weeks after starting WVI, his serum AFP increased to 23.9 ng/mL, and five days later was 15.3 ng/mL. With this AFP elevation, we changed his WVI to 36 Gy and subsequently completed an IMRT boost to the pineal gland to a cumulative total dose of 54 Gy. After peaking at 23.9 ng/mL early during RT, his serum and CSF AFP became undetectable one-month post-RT. His MRI brain showed a continued mild decrease in the size of enhancing residual tissue. Unfortunately, three months after RT, his CSF AFP was elevated at 11.4 ng/mL (serum 5.4 ng/mL), and MRI of the brain showed an interval increase in the size of enhancing tissue of the pineal gland. He was enrolled in a clinical trial of gemcitabine, paclitaxel, and oxaliplatin (GemPOx), and his CSF AFP became undetectable. After three cycles of GemPOx, he proceeded to consolidation chemotherapy with carboplatin, etoposide, and thiotepa, followed by autologous hematopoietic stem cell rescue (ASCR). He tolerated the transplant well and was discharged on Day 20. He was subsequently referred for stereotactic radiosurgery at an adult hospital where he received treatment on Day 97 ( Table 2). He was treated with Gamma Knife (Elekta, Stockholm, Sweden) SRS to 18 Gy in one fraction ( Figure 3, Table 3). With 34 months of follow-up post-SRS, his tumor markers remain normal with a stable MRI of the brain.

Case 2
A 17-year-old Hispanic male without prior health problems presented with headaches and multiple episodes of vomiting. He had an MRI of the brain, which showed a pineal gland tumor with hydrocephalus ( Figure 1). Upon transfer to our institution, he had an endoscopic third ventriculostomy and biopsy, which revealed a mixed malignant germ cell tumor (80% yolk sac and 20% germinoma). His serum AFP was 755 ng/mL, a normal serum HCG, and the CSF AFP was 350 ng/mL (CSF HCG: 13). An MRI of the brain revealed a 1.5 x 1.3 x 1.3 cm T1-enhancing pineal region mass. An MRI of the spine and CSF cytology were negative. He was also treated as per COG ACNS0122 with six cycles of chemotherapy. His serum AFP reached a nadir of 7 ng/mL and CSF AFP was 17.4 ng/mL; serum and CSF HCG were negative. MRI of the brain showed only a small residual enhancement in the region of the pineal gland. About six weeks after chemotherapy and before his planned RT, his serum AFP rose to 17.8 ng/mL and the CSF AFP rose to 26.5 ng/mL (see inset graph on Figure 2). Instead of proceeding to RT as in Case 1, our patient was enrolled on the GemPOx clinical trial; after four cycles, his serum and CSF AFP decreased to 4.6 and 5.2 ng/mL, respectively, ( Table 1). With post-chemotherapy serum and AFP stable at 5.2 and 6.8 ng/mL, respectively, he proceeded to consolidation chemotherapy with ASCR. After he recovered from the transplant, he started RT with 36 Gy CSI with TomoTherapy® (Accuray, Inc., Sunnyvale, CA) followed by an IMRT boost to the pineal gland for a cumulative dose of 54 Gy (Figure 4). One month post-RT, his serum and CSF AFP became undetectable. He was then followed for 16.5 months, after which he was lost to follow-up. He returned almost one year later with morning headaches and an MRI of the brain showed a large partially hemorrhagic, enhancing pineal region mass measuring 3.6 x 3.1 x 3.4 cm ( Figure 1). He had a markedly elevated serum AFP, and CSF AFP was over 3,000 ng/mL ( Figure 2). MRI of the spine was negative for leptomeningeal metastases with negative CSF cytology. He was salvaged with systemic chemotherapy (cisplatin, ifosfamide, etoposide for five cycles with one intervening cycle of BCNU, etoposide, and cisplatin). Initially, his serum AFP rapidly declined with chemotherapy but plateaued with a mean of 268 ng/mL. Because of prior treatment, his hematopoietic cell recovery was prolonged. After the sixth cycle of chemotherapy, his serum AFP rose to 490 ng/mL. At this point, he was considered for re-irradiation with SRS. MRI of the brain demonstrated a residual enhancing mass measuring 1.7 x 1.7 x 1.4 cm intimately associated with the thalamus, tectum, and midbrain. With a history of prior RT and involvement of brainstem and thalamus, we decided to offer fractionated stereotactic radiotherapy rather than single fraction SRS. The patient underwent CT simulation with a vacuum-assisted mouthpiece head immobilization system with 1.5 mm slice spacing and intravenous contrast. A gadolinium-enhanced MRI of the brain with 1 mm spacing was obtained and rigidly registered with the simulation CT scan. The gross target volume (GTV) was defined by a team of radiation oncologists, a neuroradiologist, and a neurosurgeon. A 1 mm margin was added to create the planning target volume. A dose of 25 Gy in five fractions was prescribed with a constraint of 20 Gy to the brainstem ( Table 3). Dose-painting IMRT (Figure 4) was planned with the Eclipse treatment planning system, version 13.6 (Varian, Palo Alto, CA), and delivered on a Varian TrueBeam with a PerfectPitch™ 6-DOF (degrees of freedom) couch (Varian, Palo Alto, CA) with kVue couch top (Qfix, Avondale, PA). Cone beam CT (CBCT) daily image guidance was used for alignment to the calcified portion of the residual tumor. Intrafraction real-time optical surface monitoring system (OSMS) was performed with surface imaging using AlignRT (VisionRT, London, UK). The patient tolerated FSRT well with Grade 2 fatigue. At the start of the FSRT, his serum AFP was 656 ng/mL, peaked at 832 ng/mL, and decreased by 40% two weeks after FSRT. Oral etoposide and thalidomide were then added, and 2.5 months post-treatment, the serum AFP fell to 6.9 ng/mL.

Review
These two cases contribute insight to the series demonstrating that recurrent germ cell tumors can be sensitive to chemotherapy and re-irradiation [9][10][11][12]. In the series described by Zissiadis, et al. [9], one patient with NGGCT recurred after subtotal resection, chemotherapy, and CSI.
That patient, who subsequently received high-dose chemotherapy with ASCR and 15 Gy SRS, was alive at 32 months post-salvage therapy. Modak, et al. [10] described 21 relapsed IGT patient treated with high-dose chemotherapy and ASCR. There were five survivors among the twelve patients with NGGCT, and of those survivors, two had RT and one was treated focally, but not with SRS. Hasegawa, et al. [11] successfully salvaged a patient with chemotherapy and Gamma Knife SRS. In contrast, chemotherapy alone is not likely to be effective up front [1,[13][14][15] or at relapse [16], and avoiding RT with high-dose chemotherapy and ASCR is uncertain [10,12,17].
Consideration for re-irradiation must take into account size and location of tumor recurrence, prior treatments, the time interval from prior radiation therapy, the proximity of organs-at-risk (OAR), and the need for anesthesia. Not all patients are candidates for single fraction radiosurgery. In cases where re-irradiation has been performed with curative intent for medulloblastoma or ependymoma, brainstem toxicity has been an issue [18][19][20][21][22]. Less toxicity has been described with FSRT or conventional fractionation [23][24], and thus, these may be safer techniques. Effective palliation in children with recurrent or metastatic tumors with frameless SRS or FSRT can be achieved with attention to cumulative doses to critical structures [25]. Similarly, palliation in adults with brainstem metastases with the CyberKnife SRS/FSRT has been described with limited acute brainstem toxicity [26].
Our second case highlights some of the potential advantages of frameless radiosurgery, which include increased patient comfort, ability to fractionate treatment, greater time for the multidisciplinary team review of imaging, contours, and dosimetry, and shorter daily treatment appointments. For children, frame placement may be a higher risk due to their thinner and softer skulls and need for sedation, so frameless FSRT can be more a more acceptable option. When re-irradiation is planned, a diagnostic MRI should be obtained within two weeks of the simulation scan [27].
There are three main types of frameless immobilization: thermoplastic mask, open thermoplastic mask with or without bite block, and upper jaw fixation devices (bite block or vacuum-assisted mouthpieces) [28]. These devices are commonly used in conjunction with custom cushions conformed to the head or head and shoulder. Thermoplastic masks and vacuum-assisted mouthpiece systems seem to have similar accuracy and precision [29][30][31], although masks tend to be less rigid. In addition, some investigators have found the mask to be more comfortable [29]. However, in our experience over the past decade, children by far chose the mouthpiece system over a closed thermoplastic mask, which was described as "scary" and "too tight." We have used the vacuum-assisted mouthpiece with high accuracy in infants or edentulous patients [32].
Treatment delivery can be accomplished on a variety of different platforms with different equipment, including linear accelerators, Gamma Knife, CyberKnife, TomoTherapy, or protons ( Table 4). Some consider frameless immobilization systems to be less precise, even though patients can shift within frames and most frame-based systems ignore rotational shifts. To address this concern, orthogonal or stereoscopic kilovoltage (kV) or CBCT imaging guidance can permit shifts to correct for setup or immobilization inaccuracies. The time required for image guidance (acquisition, review, and adjustment) in the second case was a mean of 9 minutes (range: [4][5][6][7][8][9][10][11][12][13] and was reasonable and comparable to other investigators [34,41]. Our workflow was similar to that described by Li, et al. [29]. In some centers, as a proxy for intrafraction motion, post-treatment imaging is often performed. More recently, real-time intrafraction monitoring can be performed with surrogate markers or the body surface and can interrupt treatment when movement exceeds a predefined tolerance (1-2 mm and 1°) [29,[41][42]. At our institution, we conducted a phantom study, which demonstrated the variability of the OSMS when the region of interest was decreased in size and as the couch angle changed ( Figure 5). Based on these results, we utilized an intermediate patch monitoring the forehead and temples which were not obscured by the mouthpiece system. Over five treatments, the patient had very small intrafraction shifts (     Some common features of the latest equipment for radiosurgery include: higher mechanical precision, higher dose rate, smaller collimators, image guidance, intrafraction motion detection, and robotic 6DOF couches. Several investigators have performed end-to-end accuracy tests [43][44] and have found the equipment to be highly accurate and suitable for frameless SRS, with GTV-PTV margins of 1-2 mm [31,34,41]. By comparison, an end-to-end test with older equipment utilizing 10 mm MLC leaves without 6-DOF couch advocated a GTV-PTV margin of 2.8 mm [45].

Conclusions
Overall, intracranial germ cell tumors are rare. There are no standard approaches for patients with recurrent germ cell tumors. Curative options are limited by prior treatment. For patients with pure germinomas treated initially with either radiation or chemotherapy [36,46], high salvage rates are achieved. However, for patients with prior chemoradiation or those with relapsed NGGCT, sustained responses to commonly used salvage chemotherapy regimens are difficult to achieve. To date, cure rates of about 50% have been achieved using a salvage paradigm with an initial intensive chemotherapy to achieve minimal residual tumor, followed by high-dose chemotherapy with ASCR. However, compared to germinomas, relapsed NGGCT patients have a worse prognosis with two-thirds progressing within 18 months of treatment.
When re-irradiating recurrent IGT, the cumulative dose to the optic apparatus or brainstem will often be an issue since these tumors tend to occur in the suprasellar cistern or pineal gland. Data from re-irradiation of pediatric posterior fossa tumors or radiosurgery of lesions near critical structures can inform us about radiobiological dose constraints and guide treatment planning [47][48]. Fractionated treatments may have a lower risk of toxicity.
Frameless immobilization is the best choice for multiple repeated treatments. With our current technology and policies and procedures, we can safely and accurately deliver either SRS or FSRT. With short follow-up, decrement in the tumor markers in our second patient indicated a partial response, although further follow-up is needed to assess response and toxicity.

Conflicts of interest:
The authors have declared that no conflicts of interest exist.