Because of the heterogeneity of disease presentation and tumor stage, no single treatment regimen can be used to effectively treat all neuroblastomas. Patient management should be individualized and protocol based using risk-group stratifications and the biologic characteristics of the tumor as predictors of outcome. An even greater challenge for clinicians is the fact that more than 50% of children will have locally advanced or metastatic disease at the time of diagnosis. Therefore, a comprehensive therapeutic protocol is directed towards complete reduction of primary tumor burden and elimination of metastatic disease using a combination of surgery, chemotherapy, radiation therapy, and bone marrow/stem cell transplantation.
The role of surgery in the treatment of neuroblastoma is based on INSS staging as well as the associated risk-group stratification. A surgical procedure may be used not only as primary therapy, but also for diagnostic and staging purposes. Although the timing of operation has been debated in “intermediate-” and “high-risk” groups of patients with neuroblastoma, it is generally accepted that surgical resection alone is the treatment of choice for a “low-risk” category of disease. For early-stage cancers (I, IIA, and IIB), complete surgical excision of the primary tumor is recommended as the initial treatment, and often it may be the only therapy that is required. A complete curative resection based on fundamental surgical oncology principles should always be the goal. In “low-risk” patients, survival correlates with the ability to maintain local control. The ability to obtain a complete gross resection, which is defined by the macroscopic removal of all visible tumor and clinically abnormal regional lymph nodes, distinguishes stage I from stage IIA. The presence of residual microscopic tumor does not preclude a complete gross excision. A near-complete excision is defined as excision of the tumor with minimal residual macroscopic disease, which corresponds to stage IIA. Stage IIB is defined by complete gross or near-complete excision of the primary tumor with the presence of infiltrated regional ipsilateral lymph nodes. For localized disease that is limited to stages I and IIB, treatment with resection alone has yielded promising results. Multiple studies have shown that a “surgery-only” approach is safe for low-risk tumors. In further evaluating “surgery-only” for INSS stage I disease, other studies have found a 2-year survival rate of nearly 90%, even when microscopic residual disease is present. Another study comparing complete vs. subtotal resection of localized, non-metastatic tumors determined 2-year disease-free survival to be 93% in the complete resection group vs. 54% in the subtotal resection group. Interestingly, studies have also shown that local recurrence following resection of stage I neuroblastoma can be safely treated with re-excision and rarely requires additional therapy.
The timing of operation and the degree of resection vary with stage III and IV tumors. These lesions often involve multiple contiguous structures along with a component of metastatic disease. For intermediate-risk patients, surgical management consists of complete tumor resection if possible, including all regional lymph nodes, while preserving major vascular structure and vital organ function. In stage III tumors, it has been shown that significant improvement in overall survival can be observed when gross surgical resection corresponds to microscopic completeness. Performing a complete or near-complete gross resection may be technically difficult, and thus, an incomplete excision corresponds to a situation in which gross macroscopic disease remains, or when contralateral lymph nodes are positive despite a complete gross excision. Incomplete resections can be further classified into subtotal resection (STR; removal of >50% but <95% of the visible tumor) or less than STR (removal of <50% of the visible tumor). In 1 study, stage III patients with no MYCN amplification were successfully treated with operation without the need for radiotherapy or chemotherapy, as reflected by a 10-year EFS and overall survival (OS) of 74.9 ± 16.9% and 92.6 ± 5.5%, respectively. For those with MYCN amplification, a multimodal treatment consisting of chemotherapy, surgery, and radiotherapy was associated with improved complete response (CR) or very good partial response (VGPR) of 81% as well as 10-year EFS and OS (75 ± 10.8%). Since most intermediate-risk patients receive neo-adjuvant chemotherapy, identifying tumors with favorable biologic features pre-operatively allows for a higher rate of gross total resection in this group.
Although chemotherapy is the mainstay of treatment for advanced, high-risk neuroblastoma, operative therapy still has a definitive role. Early surgical intervention for advanced disseminated disease should focus on obtaining an adequate volume of tissue for cytogenetic and pathologic analysis, while documenting the degree of metastases if present. Studies have shown that tumor volume reduction is greatest between the second and fourth cycle of chemotherapy, and therefore, operative intervention for primary tumor resection is usually timed after the fourth or fifth cycle of induction chemotherapy. While it is generally agreed that “operation post-chemotherapy” approach to advanced disease offers the greatest chance for local control and possibly improved survival, the extent of surgical resection has been debated. However, most agree that complete gross resection of all macroscopic disease is appropriate in the vast majority of cases, citing that resection correlates with a reduced risk of local recurrence, especially in combination with induction chemotherapy and local radiotherapy. It has been suggested that there may be some survival benefit for attempting complete gross resection at the initial operation in stage IV neuroblastomas, though the numbers have not been significant and this approach carries an increased risk of patient morbidity. An exception to the management paradigm of stage IV disease is in infants with stage IVS neuroblastoma. Surgical resection is not recommended given the propensity for these tumors to spontaneously differentiate and regress.
Thorough preoperative planning is crucial prior to any operation for neuroblastoma. Multidisciplinary collaboration should be obtained to formulate a comprehensive treatment plan. Tumor features such as size, extent of adherence and/or extension into adjacent structures, and the likelihood of “operation-only” cure should be considered carefully. As with all cancer operations, dependable IV access is important since neuroblastomas can be highly vascular making the risk for blood loss substantial. Reliable, size-appropriate modalities for hemodynamic monitoring should be used given the potential for significant alterations in hemodynamics as a result of intraoperative catecholamine extravasation during tumor manipulation. Because neuroblastomas can arise in multiple anatomic locations, the surgical approach and technique will vary based on the primary tumor. More than half of all neuroblastomas arise from the retroperitoneal portion of the abdominal cavity. Given that visceral and/or vascular tumor involvement is likely, the need for wide exposure is usually necessary and facilitated by patient size. Standard midline or transverse abdominal incisions are frequently used with some surgeons preferring bilateral subcostal (chevron) incisions for access to the upper retroperitoneum. For tumors involving major midline vessels, particularly on or near the celiac axis and diaphragm, a thoracoabdominal approach maybe best suited. For example, large right-sided tumors adherent to the diaphragm will require a wide exposure that can be optimally obtained through a thoracoabdominal approach. This affords the surgeon the ability to visualize and obtain control of major blood vessels, including the aorta, inferior vena cava, and renal vessels, which is of particular importance with encasing tumors (Fig. 89-5). Exploration of the abdominal cavity should be performed to assess the primary tumor, lymph nodes, and other involved structures. Dissection is often tedious and should be approached with meticulous caution to prevent hemorrhage, since it is generally acceptable to leave residual tumor if it avoids bleeding complications. As part of the dissection, the renal vein and artery should be mobilized and controlled. A dissection plane should be established between the tumor and the IVC, and proper exposure and ligation of the right adrenal venous drainage to the IVC and left adrenal venous drainage to the left renal vein is imperative. A nephrectomy should be avoided unless substantial tumor burden will be left behind. En bloc resection of adjacent organs is rarely needed unless significant tumor involvement is encountered.
Thoracoabdominal exposure with mobilization of the kidney out of the renal fossa to expose tumor along the lateral border of the aorta. The spleen and pancreas were previously mobilized.
Laparoscopic adrenalectomy in adults and children with benign disease has become the standard of care, yet the role of the laparoscopic approach in children with malignant tumors remains controversial. The use of laparoscopic approach for smaller periadrenal neuroblastomas is growing in certain centers along with the employment of minimally invasive techniques for the initial management and diagnosis of primary tumors. Laparoscopic biopsy of infiltrating abdominal lesions is becoming more common as well. A retrospective review from a single institution analyzing 7 consecutive laparoscopic adrenalectomies for small neuroblastic tumors over a 1-year period was recently reported. All tumors were well-circumscribed and noninfiltrating with an average tumor size of 2.8 cm. Three of the patients were INSS stage I while the other 4 were INSS stage IV (all 4 patients received preoperative chemotherapy). There were no deaths or late complications and the average hospital stay was 3 days. Other groups have reported similar results related to the feasibility of the laparoscopic approach for small, well circumscribed, non-invasive adrenal neuroblastomas.
Multiagent chemotherapy is the basis of all treatment regimens for advanced stage and high-risk neuroblastomas. In spite of advances in combination therapy, a well-defined, proven chemotherapeutic regimen capable of achieving complete remission in these patients has not been found. Initial tumor response to induction chemotherapy demonstrates a 50% to 80% CR or VGPR to dose-intensive, multiagent regimens. The most commonly used agents are cyclophosphamide, doxorubicin, cisplatin, melphalan, carboplatin, etoposide, topotecan, ifosfamide, and vincristine. The most important therapeutic goal is local disease control. Unfortunately, tumor resistance to chemotherapeutic agents is common with disseminated disease, as exhibited by aggressive neuroblastoma phenotypes with high rates of relapse. To decrease the risk of developing tumor resistance to chemotherapy, it is recommended that surgical resection of any primary or local–regional disease is performed as soon as there is radiographic evidence of resectability, even if the patient has not completed their full course of induction therapy. The rationale for this approach is based on the hypothesis that chemotherapeutic agents with different mechanisms of action are most effective when given together against the most-minimal volume of tumor burden possible.
Recent estimates are that 50% to 60% of children with high-risk neuroblastoma will develop a recurrence. The management scheme in these patients has traditionally been induction chemotherapy followed by myeloablative consolidation therapy with stem cell rescue. A multicourse regimen of 13-cis-retinoic acid (RA) then follows for eradication of residual disease. Any persistent disease, or recurrence, is treated with multiagent chemotherapy, though these are likely to be clonally selected aggressive phenotypes, and the long-term survival in this population is poor. Stem cell harvesting is performed during induction chemotherapy, usually after the 2nd cycle, while surgical resection of the primary tumor and any metastatic disease is done after the 5th cycle of chemotherapy or when there is radiographic evidence of resectability.
After induction, treatment is consolidated with 1 or more courses of high-dose chemotherapy to eradicate minimal residual disease, but this unavoidably induces bone marrow ablation, which necessitates autologous stem cell transplant (ASCT). Rescue is not without risk since the presence of tumor contamination of the bone marrow graft can contribute to relapse. Complications of such a transplant include growth failure, endocrinopathy, and the occurrence of secondary malignancies. Finally, maintenance therapy may be incorporated to target minimal residual disease. Unfortunately, relapse and poor survival are common in high-risk patients, as evidenced by event-free and overall survival rates of 26% and 37%, respectively, in stage IV patients undergoing chemotherapy/ASCT. Upon completion of chemotherapy, patients may receive six courses of RA to eradicate residual disease that may still be present despite meeting imaging criteria for complete remission. This treatment is based on reports that high-dose therapy with RA given after chemoirradiation significantly improved overall survival in high-risk neuroblastoma (59% vs 37% at 5 years). Side effects, such as skin dryness and cheilitis, are the dose-limiting factor; and consequently, RA therapy consists of 2-week courses alternating with 2 weeks for mucocutaneous recovery.
Trials involving myeloablative chemotherapy and 131I-MIBG have been underway in an effort to minimize adverse side effects by making therapies more targeted. Previous studies have shown that 131I-MIBG exhibits activity against refractory neuroblastoma with response rates ranging from 10% to 50%. In a phase I trial of 131I-MIBG therapy for relapsed neuroblastoma, myelosuppression was the most significant toxicity at doses >15 mCi/kg, with nearly half of the patients requiring hematopoietic cell transfusion. Despite this, the response rate (36%), event-free survival (18% at 1 year), and overall survival (49% at 1 year; 29% at 2 years) were found to be significantly higher in patients older than 12 years and those who had fewer than three prior treatment regimens. Subsequently, a phase I dose escalation study of 131I-MIBG with myeloablative chemotherapy and stem cell rescue reported a significant response rate of 25% in patients with primary refractory disease. Given these findings, 131I-MIBG may prove to be useful in conjunction with other treatment modalities.
Despite using independent prognostic variables to tailor treatment, many high-risk neuroblastomas have developed resistance to chemotherapeutic agents, making the likelihood of relapse quite high. The total length of therapy averages nearly 1 year and most treatment failures are due to minimal residual disease that was not eradicated following high-dose chemotherapy. While the aim of further treatment is remission, prolonged disease stabilization is usually the reality, and most patients who relapse eventually die from disease progression. Even patients who achieve a cure with initial therapy remain at risk for developing long-term complications related to treatment, including hearing loss, infertility, and second malignancies.
External-beam radiotherapy (EBRT) is an important part of the treatment paradigm in both intermediate and high-risk neuroblastomas. As a radiosensitive malignancy, neuroblastoma cells can be targeted at sites of residual primary tumor, regional lymph node involvement, and metastatic beds. For intermediate-risk disease, radiotherapy is typically reserved for unresectable or residual disease following chemotherapy and/or surgery, or in the case of tumors with unfavorable prognostic features/histology. Nearly all patients with intermediate-risk or high-risk disease receive focused radiotherapy to the primary tumor site for increased local control. Several institutional retrospective studies have reported improved local control rates employing 21 Gy or more to the primary site. Though not statistically significant, a small retrospective study found that in the absence of EBRT to the primary tumor site, 44% of patients recurred locally, whereas none of the patients who received 20 Gy to the primary tumor site experienced a primary relapse. This suggests that radiation of the primary tumor in patients with gross residual and microscopic residual disease may be of value. EBRT has also been shown to improve response rates and event-free survival in children with regional lymph node metastases.
Some advocate the use of intraoperative radiation therapy (IORT), which allows higher doses of irradiation to be applied under direct visualization. This technique has the benefit of minimizing irradiation effects to nearby, uninvolved structures by either displacing or shielding them at the time of resection. Furthermore, it can deliver high-radiation doses to both areas of residual tumor and microscopic disease, while reducing the risk of irradiation toxicity to uninvolved structures such as the spinal cord. In 1 retrospective study, stage IV neuroblastoma patients who underwent chemotherapy, resection, and IORT had similar recurrence rates to their stage I, II, or III counterparts while their survival remained quite poor. With stage III or less, the overall survival rate was 78% at 2 and 5 years, but with stage IV, the overall survival rate was 71% and 21% at 2 and 5 years, respectively. The local recurrence rate with stage III or less was 31% at 5 years, while it was 33% at 2, 5, and 10 years with stage IV. Thus, IORT appears to promote local control in advanced neuroblastoma.