Neuroblastoma

Background

Clinical KeyNeuroblastoma is a neuroendocrine tumor that arises from neural crest tissue of the sympathetic ganglia or the adrenal medulla. It is the most common solid neoplasm outside of the central nervous system in children and the third most common cancer overall, with 50% diagnosed before age 2 and 90% before age 5. The most common primary site for this tumor is the adrenal glands; however, it can arise anywhere from the neck to the pelvis.

Neuroblastoma is known for being a diverse disease – varying in location, appearance, and in clinical characteristics. The symptoms of neuroblastoma depend primarily on tumor location, neuroendocrine function of the tumor, and presence of metastatic disease. The majority of children present with vague symptoms such as fever, weight loss, and fatigue. Depending on tumor location, additional symptoms may include abdominal swelling/constipation, difficulty breathing, bone/joint pain, and pallor from anemia secondary to bone marrow infiltration or chronic disease.

More than 600 cases of neuroblastoma are diagnosed in the United States each year, accounting for approximately 15% of all pediatric cancer deaths.

Current Treatment

Neuroblastoma is classified into three risk categories: low, intermediate, and high risk based on factors such as disease stage, patient age, tumor histologic appearance, and molecular/genetic features of the tumor.

  • Low Risk: Surgical resection alone may be curative, but some children may need additional chemotherapy.
  • Intermediate Risk: Primary treatment approach is surgery combined with chemotherapy, prior to resection.
  • High Risk: Most patients require multi-modal therapy – surgery, irradiation, chemotherapy, stem cell transplant, and biologic/immunologic therapy.

Focused Ultrasound Research

The mainstay of treatment for neuroblastoma is surgical resection coupled with chemotherapy. However, many patients with high-risk disease do not respond adequately to chemotherapy and commonly relapse. Furthermore, most long-term survivors who had low or intermediate-risk disease suffer long-term effects from their treatment.

One method of enhancing tumor response to chemotherapy involves creating a state of local hyperthermia, which increases blow flow to the tumor—thus enhancing local delivery of chemotherapy via the blood stream. This process of inducing hyperthermia in a tumor is known as sensitization and has already been proven effective in the clinical setting. Through this mechanism, physicians can enhance the effects of chemotherapy or achieve the same therapeutic outcome with lower doses of chemotherapy, thereby minimizing the adverse effects. Focused ultrasound (FUS) provides a radiation free, non-invasive method of inducing local hyperthermia. FUS is an optimal approach for inducing hyperthermia because the ultrasonic beam can be conformed to a wide variety of shapes and sizes. The FUS may also be able to ablate or kill tumors that are not amenable to surgical resection. Furthermore, tissue temperature can be monitored real-time using magnetic resonance imaging, making FUS an excellent complement to drug therapy.

In addition, pre-clinical studies have already begun examining the effect of high-intensity FUS in the treatment of neuroblastoma. In one study, mice with neuroblastoma were treated with chemotherapy, FUS+chemotherapy, or FUS alone. Following treatment, 53% of mice treated with FUS and 80% of mice treated with FUS+chemotherapy were cured with no evidence of tumor at 200 days, versus 100% fatality at 45 days in the control group and in mice treated with just chemotherapy. This early data suggests that FUS may play have a beneficial role in the treatment of unresectable neuroblastoma.

A clinical report of the ability to target metastatic or recurrent pediatric sarcoma and neuroblastoma cases showed that the primary tumor was targetable 64% of the time for sarcomas and 25% for neuroblastoma. The metastatic tumors (at diagnosis) or relapses were less than 20% targetable for both sarcomas and neuroblastomas. The conclusion is that many sarcomas are targetable at diagnosis. Some recurrent neuroblastomas will be targetable, but few newly diagnosed neuroblastomas will be amenable to focused ultrasound.

Notable Papers

Shim J1, Staruch RM2,3, Koral K2, Xie XJ4, Chopra R2,5, Laetsch TW6,7. Pediatric Sarcomas Are Targetable by MR-Guided High Intensity Focused Ultrasound (MR-HIFU): Anatomical Distribution and Radiological Characteristics. Pediatr Blood Cancer. 2016 Oct;63(10):1753-60. doi: 10.1002/pbc.26079. Epub 2016 May 19.

S. Wang, V. Frenkel, and V. Zderic, “Optimization of pulsed focused ultrasound exposures for hyperthermia applications.,” J. Acoust. Soc. Am., vol. 130, no. 1, pp. 599–609, Jul. 2011. 

H. Matsumoto, “Revisiting sensitization mechanisms in cancer thermochemotherapy.,” Fukuoka igaku zasshi = Hukuoka Acta medica, vol. 100, no. 4, pp. 95–103, Apr. 2009.

Yang R, Reilly CR, Rescorla FJ, Sanghvi NT, Fry FJ, Franklin TD Jr, Grosfeld JL. Effects of high-intensity focused ultrasound in the treatment of experimental neuroblastoma. J Pediatr Surg. 1992 Feb;27(2):246-50


 

     

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