Reversed sequence radiation therapy for treatment of primary central nervous system choriocarcinoma prioritizing for bleeding control: A case report

Background

Primary central nervous system (CNS) choriocarcinoma is a malignant, aggressive tumor arising from non-germinomatous germ cells and comprises up to 5% of all CNS germ cell tumors. ¹ Common locations include suprasellar or pineal locations, with others including the basal ganglia, lateral ventricles, and thalamus.^1,2 Associated symptoms include hemorrhage, polydipsia, precocious puberty, headache, nausea, and visual disturbances. ² Workup includes beta-human chorionic gonadotropin and alpha-fetoprotein levels, lumbar puncture, and imaging including brain magnetic resonance imaging (MRI). ¹

Treatment regimens are made by teams with surgical, medical, and radiation oncologists. If surgical resection is feasible, maximally safe resection is completed prior to chemotherapy and/or radiation.^1,2 While there are no guidelines highlighting an optimal regimen, neoadjuvant or adjuvant chemotherapy occurring before radiation therapy (RT) is the usual sequence.^3,4 Most commonly, RT is performed with craniospinal irradiation (CSI) with subsequent tumor bed/gross tumor boost. ⁴ Here, we present a case of an adult male with primary CNS choriocarcinoma who underwent reversed sequence RT with tumor bed boost before CSI with subsequent chemotherapy. This case highlights the feasibility of reversed sequence RT in controlling hemorrhages when urgently indicated and treating primary CNS choriocarcinoma effectively for consideration in future treatment paradigms.

Case presentation

A 21-year-old Caucasian male with past medical history of anxiety had a sudden onset of double vision 1 year before clinic. As per ophthalmologist recommendations, brain MRI and lab testing for myasthenia gravis were conducted, with MRI showing a possible cavernoma. His diplopia resolved but recurred in the following weeks with headache, nausea, and vomiting. Repeat MRI showed a tectal mass causing intracranial hydrocephalus due to mass-effect on the cerebral aqueduct; the mass was also associated with acute to subacute hemorrhage (Figure 1).

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Figure 1.

Brain MRI showing tectal mass contributing to hydrocephalus and hemorrhage in the brain.

As such, neurosurgery conducted an endoscopic third ventriculostomy with right burr hole evacuation. Ophthalmology was consulted for concerns of Parinaud syndrome, where upward gaze is impaired due to dorsal midbrain disruption from tumor mass effect. The patient also had binocular horizontal diplopia and uppercase paresis; recommendations were to patch either eye for treatment.

Four weeks later, the patient had subtotal surgical resection. Pathology revealed a high-grade malignant neoplasm, favoring choriocarcinoma likely of pineal origin. The patient had a chemotherapy port placed and continued to experience fatigue, vomiting, and nausea. Head computed tomography (CT) scan obtained prior to starting chemotherapy showed a new episode of thalamic hemorrhage extending into the right ventricle. Afterward, the patient was admitted to the intensive care unit. MRI of the cervical, thoracic, and lumbar spines were negative for disc herniation, canal stenosis, or spinal canal enhancement. Lumbar puncture yielded craniospinal fluid with elevated protein at 69 mg/dL and elevated white blood cell (WBC) count at 95/cmm; 30% of WBCs were polymorphonuclear cells, 44% were lymphocytes, and 26% were monocytes and histiocytes. After surgery, the patient had no progression of neurological symptoms or intracranial hemorrhage (ICH), decisions were made to initiate chemotherapy with no steroids. He was discharged home after starting carboplatin and etoposide alternating with ifosfamide and etoposide. Referral was placed to consult radiation oncology to plan for adjuvant RT sequentially after chemotherapy.

At the radiation oncology clinic 3 weeks after discharge for the initial consult visit, the patient had completed his first round of chemotherapy, which started 3 weeks after surgery. He noted continued diplopia, but denied darkened vision, heat or cold intolerance, seizures, or sexual dysfunction. Positron emission tomography–CT and testicular ultrasound were negative for metastases. MRI showed no tumor growth or hemorrhage. Plans involved CSI following six cycles of chemotherapy. Two days later, the patient had a worsening headache. Head CT revealed an acute hemorrhage in the right lateral ventricle atrium. The patient was hospitalized with close neurological checks.

Due to having multiple ICHs and a new acute hemorrhage episode despite starting chemotherapy, treatment recommendations were changed after multidisciplinary discussion, with recommendations to start RT immediately for bleeding control. The patient received 1800 centi-gray (cGy) of radiation in 10 fractions over 14 days to the tumor bed with volumetric-modulated arc therapy (VMAT) of photon therapy, stopping ICH. Referral to an outside facility for proton CSI was initiated prior to VMAT and completed during the treatment. Four days after completing tumor bed RT, the patient started on a proton therapy regimen with a total dose of 3600 cGy equivalent in 20 fractions after traveling to an outside institution with no significant delay in proton therapy. He completed chemotherapy after radiation.

Since treatment, the patient follows with his oncologist with brain and spine MRIs. He most recently followed up with imaging 4.75 years following completion of radiation, with no evidence of progression or ICH (Figure 2). On the most recent examination, the patient was alert to person, place, and time; fluent speech, symmetrical facial features, normal muscle tone with intact muscle strength, intact sensation and proprioception, and normal gait were noted. He had persistently large bilateral pupils that remained minimally reactive to light as well as mild palsy with upward gaze, which is stable since prior to RT. After completion of all therapies, the patient expressed concerns about failing two classes, prompting neuropsychology evaluation 3 years following his treatment course. At his neuropsychology evaluation, he noted difficulties with skills including multitasking, focusing, and depth perception; these changes remained stable since then. The patient continues to be employed with a full-time job with good performance despite the neurocognitive deficits.

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Figure 2.

T1 post-contrast Brain MRI, cervical spine MRI, thoracic spine MRI, and lumbar spine MRI (from left to right as shown below) following completion of radiation therapy and chemotherapy that were negative for malignancy recurrence.

Discussion

Traditional approaches for treating CNS non-germinomatous germ cell tumors (NGGCTs) including choriocarcinoma involve maximally safe resection followed by chemotherapy and radiotherapy.^1,2 Localized CNS NGGCTs are frequently treated with CSI. ⁵ Proton beam RT (PBRT) is preferred particularly in pediatric and young adult patients to reduce the risk for long-term sequelae, in particular neurocognitive dysfunction and secondary malignancies. However, the higher cost of PBRT compared to photon therapy, concerns regarding accessibility due to limited proton centers nationally, and complexity of the planning process often result in delayed start of treatment.^6,7 This is in line with the initial treatment sequence prescribed for our patient. However, this treatment sequence was recommended prior to his recurrent hemorrhages, which are known vascular outcomes of choriocarcinomas.^8,9 RT has been routinely used for achieving hemostasis as a noninvasive and very effective palliative care for cancer-related bleeding. ¹⁰ In the setting of recurrent hemorrhage, treatment recommendation to our patient was changed to urgent start of RT for bleeding control. Due to the challenges to start him on proton beam CSI on time, our patient received reversed sequence radiation with boost RT to his primary tumor site with photon therapy prior to proton beam CSI. Current standard paradigms often involve CSI prior to tumor bed boost to potentially reduce risks for neuroaxis disease dissemination, relapses within brain, and/or spinal recurrence. ⁴ However, CSI planning, especially with PBRT, can be delayed by factors such as proximity of proton centers, cost of PBRT requiring clearance of insurance approval as well as difficulties in treatment planning.^11,12 Our patient received radiation in a timely manner with focal radiation by photon VMAT planning prior to proton beam CSI, resulting in rapid and long-term control of hemorrhages. His outcome was not compromised in that he has no disseminated disease more than 4 years posttreatment. Within the literature, there is a paucity of information regarding the sequencing of CSI and local boost RT in similar cases to that of our patient. Thus, our case possesses clinical value in suggesting reversed sequence RT as a safe and reasonable option for NGGCT patients requiring CSI, particularly those with choriocarcinoma who are at high risk of ICH or in urgent need of acute ICH control.

Furthermore, our patient received his chemotherapy regimen, that is, a six-cycle regimen of carboplatin and etoposide alternating with ifosfamide and etoposide per the Phase II study ACNS0122, a study developed by the Children’s Oncology Group, albeit with radiotherapy preceding chemotherapy completion in a reversed sequence from standard-of-care. ⁴ To our knowledge, there are no prospective studies that have examined chemotherapy first versus RT first regimens or whether patients who respond well to neoadjuvant RT prior to chemotherapy could receive de-escalated chemotherapy; these are questions that would be of interest to answer in the future. Currently, our patient’s case indicates that starting RT prior to chemotherapy is reasonable, particularly for tumors with high risk of bleeding or recurrent bleeding. However, we do acknowledge that performing RT first before chemotherapy may potentially lose the option of de-escalation of RT dose or field size per treatment response by doing chemotherapy first. Although CSI for NGGCTs has been consistently demonstrated to be superior to whole ventricle RT (WVRT) by preventing spine metastases even in patients who responded well to chemotherapy (i.e. partial response (PR) or complete response (CR)), current ongoing trials such as ACNS2021 are testing a new regimen of WVRT plus spinal canal irradiation for its equivalency to CSI with potentially less neurocognitive toxicities for patients who respond well (CR or PR) to neoadjuvant chemotherapy before RT.^5,13,14 These uncertainties indicate the ongoing and needed work in the field to continue to clarify sequencing of RT in relationship to chemotherapy for NGGCT treatment.

Conclusion

While primary CNS choriocarcinomas have been routinely treated with sequential chemotherapy followed by RT (CSI followed by boost RT to residual tumor/tumor bed) per NGGCT protocol, challenges exist for choriocarcinoma-induced ICH despite surgery and chemotherapy. Although RT has been known to be an effective and noninvasive therapy for rapid and durable control of tumor-related hemorrhages, there is very limited information of the feasibility regarding early sequencing of RT. Our patient received prompt early/urgent RT by reversing the sequence of RT, that is, with boost RT first to residual tumor/tumor bed via rapid photon planning preceding proton CSI and by receiving the entire RT course preceding completion of chemotherapy. The durable control of ICH and tumor more than 4 years after treatment suggests that early RT is feasible; thus, our report contributes to the medical literature in this area. Our patient’s case also demonstrates utility of combining photon beam boost RT with proton beam CSI for treating CNS choriocarcinomas and the reversed sequence radiotherapy in controlling ICHs prior to initiation of a wider field of treatment. Further investigation by prospective trials of the sequence changes, both for boost RT versus CSI and for RT overall versus chemotherapy, may help define standard-of-care for CNS choriocarcinomas, or by large, NGGCT.