Neuroblastoma

Neuroblastoma is the most common malignancy of infancy, with 50% of patients presenting before age two and 75% of patients presenting before age four. It affects boys and girls equally and is responsible for 15% of all childhood cancer deaths. While some subsets of patients have enjoyed improved survival, outcomes of those with high-risk tumors have only improved modestly. Both CT and magnetic resonance imaging (MRI) are useful in evaluation of the primary lesion and metastases. Current COG protocols stratify tumors into low-, intermediate-, and high-risk groups based on International Neuroblastoma Staging System (INSS) stage, patient age, Shimada evaluation of histopathology, DNA index, and MYCN amplification. MYCN amplification has proven to be an important prognostic marker, and a recently completed COG trial will assess its impact among patients with low- risk disease.¹⁴ Low-stage (stage 1—localized, stage 2— local lymph node involvement, not crossing the midline) neuroblastoma responds to surgery with an 80% survival rate, and chemotherapy is unnecessary.¹⁵ Unfortunately, high-stage neuroblastoma (stage 3— bilateral lymph nodes, stage 4—distant metastases) responds poorly to standard chemotherapy, with a 10–40% survival. Most patients with stage IV-S disease (stage I or II with skin, liver, bone marrow metastases) can expect spontaneous regression, with a five-year 92% survival rate. For high-stage neuroblastoma, high-dose chemotherapy (cyclo- phosphamide, ifosfamide, cis-platinum, carbo- platinum, and doxorubicin) followed by autologous bone marrow transplant is used, but there is a significant mortality (5% to 10%) and relapse rate (60% at four years).16 New approaches are currently being evaluated by COG, including observation for select perinatally diagnosed tumors, monoclonal antibodies directed to tumor-associated antigens, such as disialoganglioside GD2, and new chemotherapy agents, such as topotecan and irinotecan. Other experimental approaches, including the use of differentiating agents such as retinoids, antisense oligonucleotides, and immunotherapy, are being investigated.¹⁷

RMS

RMS is the most common soft tissue sarcoma, of which 20% involve the bladder, prostate, or paratesticular area. RMS has two peaks, ages two to four and ages 15 to 19. Similar to Wilms’ and neuroblastoma, a risk-based stratification system is used.Tumors of the paratesticular area are by definition favorable risk, whereas bladder and prostate primaries are intermediate risk. Paratesticular primaries usually present as a painless scrotal mass. Bladder and prostate tumors may present with difficulty urinating or gross hematuria. Ultrasound is usually performed first, followed by CT or MRI scan of the chest, abdomen, and pelvis to determine the extent of the disease. Bone scan and bone marrow biopsy are also necessary.

Positron emission tomography (PET) scan can also be used to detect metastases.¹⁸ The IRS IV have shown that initial biopsy, followed by chemotherapy, can successfully preserve pelvic organs while maintaining a high survival rate. Patient survival was 86% in IRS IV, which used vincristine, dactinomycin, cyclo- phosphamide (VAC) chemotherapy. Exenterative procedures are currently reserved for tumors unresponsive to chemotherapy. In IRS IV,VAC was shown to be as effective as two other three-drug regimens (VIE/VAE—ifosfamide, etoposide).¹⁹ Owing to the fact that cyclophosphamide is cheaper and has lower toxicity, VAC is the current standard chemotherapy. IRS-V was designed to evaluate new agents such as topotecan for advanced disease while attempting to decrease cyclophosphamide and RT dosing for low-risk patients.²⁰ Bladder and prostate primaries are initially diagnosed by endoscopic, open, or transrectal biopsy after CT reveals the mass in the affected organ. IRS III included intensified chemotherapy (dactinomycin,VP-16) and six weeks of RT increasing the functional bladder salvage rate from 25% to 60%.²¹ In IRS IV, half of patients were managed with biopsy, 37% had partial cystectomy, and 13% had prostatectomy.²¹ Renal function as assessed by serum BUN and creatinine was normal in 95%.22 ‘Normal’ bladder function was maintained in only 40% of the entire group of patients.²³ A more objective evaluation of the success of functional bladder salvage using urodynamic studies will hopefully be included in future RMS studies undertaken by the COG.²⁴

Paratesticular tumors may mimic testicular tumors, so serum beta human chorionic gonadotrophin (`HCG) and alpha-fetoprotein (AFP) are obtained pre- operatively. The tumor is resected by inguinal orchiectomy, and post-operatively a CT scan of the chest, abdomen, and pelvis is obtained. Depending on age and stage, retroperitoneal lymph node dissection (RPLND) may be recommended. In IRS III, all patients underwent RPLND, which was not recommended if the CT scan was negative in IRS IV.

This led to a significant understaging of disease, and some patients with radiologically normal retroperitoneums did not receive chemotherapy, leading to a decrease in failure-free survival. Of those patients who required retreatment, 30% had negative CT scans and were over 10 years of age.²⁵ For IRS V, patients under the age of 10 with negative CTs and patients over the age of 10 with negative RPLNDs receive vincristine, dactinomycin (VA) chemotherapy.

Patients under the age of 10 with positive CTs and all patients over the age of 10 undergo RPLND.Those with negative retroperitoneal lymph nodes undergo VA chemotherapy, whereas those with positive LNs have VAC (vincristine, dactinomycin, cyclophos- phamide) and RT.²⁵

Other complications of therapy included sex hormone replacement being required in 29% of patients, and 11% were shorter than expected.22 RT increases the risk of a secondary neoplasm, often another sarcoma. Complications specific to surgical treatment from 1972–1984 include intestinal obstruction, anejaculation, and lower extremity edema after RPLND.26 However, with newer surgical techniques designed to preserve ejaculation, better outcomes are expected.

The role of VEGF and other pro-angiogenic molecules, such as basic fibroblast growth factor and interleukin (IL)-8, are currently being explored. Anti-VEGF antibodies have a dramatic effect on RMS growth in animal models.^27,28 COG is currently studying the use of anti-sense therapy directed at the proto-oncogene B-cell (BCL)-2, in conjunction with chemotherapy for children with relapsed solid tumors.