Introduction

Neuroblastoma is a common extracranial childhood solid tumor seen most commonly below 5 y of age. This is probably the only tumor which has vastly divergent clinical behavior depending on the age at which it occurs. It can regress spontaneously, or can mature into a benign lesion with or without treatment, or progress and metastasize rapidly with poor outcomes despite aggressive treatment. What is mindboggling is the fact that neuroblastoma remains undetected till late stages. In spite of dramatic improvements in the outcomes of children with solid tumors from <50 % to more than 80 % overall, outcome of neuroblastoma has not yet reached that level. The reasons for these are multifactorial, most important being the fact that most of the tumors (upto 60 %) are detected in advanced stages [1, 2]. The tumors, once diagnosed, are risk stratified and based on the stage and the grade of the tumor, further therapy is planned. The management of the advanced stage disease is difficult even in the West; in developing countries like ours, it poses a major therapeutic challenge. This article attempts to understand the management and outcome of this puzzling tumor.

Development of Neuroblastoma Treatment

The main highlights in the history of development of neuroblastoma treatment are as follows:

  • The first description of abdominal tumor termed then as "glioma” occurred in 1864 by German physician Rudolf Virchow [3].

  • 1891: Tumor characteristics were described by German Pathologist Felix Marchand [4].

  • 1901: 4s tumor presentation was described by William Pepper.

  • 1910: The tumor was named Neuroblastoma by James Homer Wright.

  • 1982–1985: Study of affectivity of melphalan and bone marrow transplant in high risk tumors was done by European Neuroblastoma Study Group (ENSG1) [5].

  • 1990–1999: Another study by the European group (EU-20592 or CCLGNB-1990-11), enrolling 262 high risk patients for effectiveness of rapid sequence induction cycle over 10 d instead of standard induction cycle over 21 d [6].

  • 1991–1996: Clinical trial by CCG (Children’s Cancer Group 3891) with four arms proved the efficacy of myeloablative therapy with total body radiation and 13-cis-retinoic acid for high risk disease [7].

  • 1996–2003: German neuroblastoma study (GPOH NB 97) proved that stem cell transplant is superior to consolidation chemotherapy in 295 high risk neuroblastomas [8].

  • 2000–2006: Study by COG (COG-A3973) on purged stem cell transplant failed to prove its efficacy [9].

  • 2000–2012: Ongoing study to study the effect of antibody ch14.18 in the treatment of neuroblastoma.

  • 2002–2008: Joint study of SIOP and European SIOP Neuroblastoma Group (ESIOP NB) for treatment of high risk neuroblastoma with rapid COJEC cycle [9].

  • 2005–2010: German study group NB2004 with 642 patients have randomized MIBG therapy and topotecan for all risk groups [10].

  • 2007: COG study which is ongoing with the aim to compare single versus tandem transplants [11].

Risk Stratification

Comparable to Wilms’ tumor, several co-operative groups exist for the management of neuroblastoma which have different philosophies and disparate risk stratification factors [12]. The several co-operative groups are the COG(Children’s Oncology Group) from North America and Australia, SIOPEN (Society of International Oncology in Pediatrics Europe Neuroblastoma) from Europe, GPOH (German Pediatric oncology and Hematology Group) from Germany, the JANB (Japanese Advanced Neuroblastoma Study Group) and JINCS (Japanese Infantile Neuroblastoma Co-operative Study Group) both from Japan, and another group from China.

The discussion of all the different co-operative groups and trials is beyond the scope of this article. Discussed herein are the 2 main important protocols of management and the outcomes – the COG and the SIOPEN.

COG: Children’s Oncology Group

To decide the modality of treatment one needs to define the risk group the child belongs to. As per the COG in America, the risk grouping is dependant on stage of the disease as per the INSS, age of the patient, and tumor biology. As per the COG, which believes in upfront surgery similar to Wilms’s tumor as in NWTSG (COG), the tumors have to be resected and an adequate amount of tissue sent for histopathological studies for assessment of tumor biology. The risk assignment is thus low, intermediate and high risk groups. To simplify matters, stage 1 and stage 2a are the only tumors in low risk category, rest all being intermediate or high risk groups.

As per the INSS, Stage 3 is unresectable tumor and Stage 4 is metastatic disease. When the tumor is unresectable, to study the tumor biology, it becomes mandatory to achieve adequate tissue from the tumor either by a closed or an open biopsy method so that appropriate risk stratification is done. The chemotherapy schedules have to be planned as per the intermediate or high risk groups.

INRG: International Neuroblastoma Risk Group

The INRG [13] is a new risk stratification developed by the SIOP with the joint effort of COG and several other co-operative groups in the year 2004. The need for a new risk stratification was felt because the COG system is a post-surgical system and entirely dependant on the surgical excision which decides the stage of the disease. Also standardization and comparison of the results were not reliable because of variations in the surgical techniques from one center to another, thus categorizing a similar tumor in different stages in different centers. Hence, a pre-surgical staging for risk stratification was discussed and finalized in 2005 with the objective of having a uniform assessment of the pretreatment extent of the disease. Since 1994, SIOPEN protocols categorized neuroblastomas as resectable or non-resectable for all stage 1, 2 and 3 tumors (the non-metastatic tumors). The decision was taken on imaging; defined as surgical risk factors and later modified to Image Defined Risk Factors (IDRF). The image defined risk factors are provided in detail in the SIOP booklet [14].

As per the International Neuroblastoma Risk Group Staging System (INRGSS), four stages have been proposed [15].

  • Stage L1 is defined as a locoregional tumor without risk factors identified on imaging.

  • Stage L2 is defined as a locoregional tumor with at least one risk factor identified on imaging, such as tumor encasement of blood vessels.

  • Stage MS identifies metastatic disease confined to the skin, liver or bone marrow.

  • Stage M identifies all other distant metastases.

After formulation of the new staging system, it was imperative to test its efficacy, which was done by studying 661 European patients in whom image defined risk factors were known. The authors [12] found this system to be much more reliable in comparison to the risk based clinical trials all over the world. The limitation of this staging and risk stratification is that it cannot be applied post-treatment. In 2007, another study conducted by joint co-operative groups on 8,800 children with neuroblastoma for assessing the efficacy of the newly developed INRGSS concluded that since INRG is a standardized approach, it can facilitate international collaborative studies and comparisons of outcomes of several risk-based treatment protocols, which was otherwise not feasible [15]. A comparison of both the INSS and the INRGSS staging systems as well as features for risk stratification are depicted in Tables 1 and 2.

Table 1 Comparison of staging in INSS and INRGSS
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Table 2 Comparison of the Risk Stratification of INSS and INRGSS
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Management

Unlike Wilms’ tumor, there are many modalities for treating neuroblastoma, though the mainstay modalities are surgery, chemotherapy and radiotherapy. Also, since this is an elusive tumor with wide variations in clinical behavior and response to therapy, the major co-operative groups have their own policies regarding the chemotherapeutic drugs, the timing of surgery, the timing of stem cell collection, type of radiotherapy used, and use of alternate forms of treatment. Both the national and international co-operative groups have continued efforts to improve on the survival rates which are still at par with wilms’ tumor [16].

The various treatment approaches are summarized in Table 3, as detailed discussions on the so many different modalities is beyond the scope of this article.

Table 3 Treatment guidelines for all stages of neuroblastoma
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In low risk groups, all patients need not be given chemotherapy. Surgery alone is sufficient. An expectant line of management may be undertaken depending on the selection criteria [18]. Chemotherapy is reserved for those children with spinal cord compression or those respiratory compromise from massive hepatomegaly due to hepatic infiltration in stage 4s tumors. The chemotherapy given is carboplatin, cyclophosphamide, doxorubicin and etoposide.

In intermediate risk group, patients undergo upfront surgery, resection of tumor followed by 12–24 wk of chemotherapy same as in low risk group [19]. Those who have unfavourable tumor biology, undergo chemotherapy for twice the duration i.e., 24–48 wk with the same agents.

High risk groups have a much more intense chemotherapy protocol with multiagent dose intensive schedules. The chemotherapeutic drugs used are carboplatin, cyclophosphamide, doxorubicin, etoposide, cisplatin high dose, and ifosfamide. The high risk induction protocols vary not only in the use of chemotherapeutic drug but also in the doses of similar drugs. A synopsis of the various protocols can be accessed [16], wherein even the variable timings of surgical intervention are provided. Following the induction chemotherapy, surgical excision must aim to remove all the residual disease [20], though there are conflicting reports in the literature regarding the extent of surgical resection in high risk neuroblastoma [21, 22]. Myeloablative chemotherapy must follow with an autologous stem cell transplantation to control the progression or recurrence.

Outcome

Antenatally detected neuroblastomas deserve a short mention here as the management of these tumors differ from country to country and thus the outcome. The 3 options practiced in these type of neuroblastomas are as follows:

  1. 1.

    Observation – for spontaneous regression

  2. 2.

    Surgical excision

  3. 3.

    Chemotherapy + surgery

Since there are no definite guidelines, expectant treatment only is followed in very few centers [23]; most of them agree that the criteria for adopting this line of treatment should be followed only if the tumors are small, and the urinary VMA levels are normal at birth and at serial follow-up. Most of the centers use a combination of the above options. Surgical option has been followed in most of the series and case reports [24]. The outcome of the children with antenatally detected neuroblastoma is usually very good [25]. Granata et al. reviewed the Italian neuroblastoma registry wherein all patients underwent surgical excision of the tumor and reported a 5 y survival of 14/17 patients [26]. A 10 y review showed a 92 % survival, with antenatally detected tumors in all stages including dumbbell tumors [27]. A study conducted on 55 patients with antenatal detection reported 90 % survival 2–120 mo post-treatment [28]. 95 % of these patients had undergone surgical excision. Most of the reports adopted the surgical option for treatment [29–32].

Most of the centers report excellent outcomes for the low risk tumors between 90 and 100 % [33]. But the results of treatment for advanced stage and high risk neuroblastomas are still poor even in the Western world, inspite of the recent advances which are inadequate or ineffective in decreasing the mortality [34]. An Egyptian institute based retrospective analysis showed majority of patients (68 %) in high risk group. The overall outcome reflected the risk groups thus showing only 21 % of 3 y survival [35]. As per a study by the Japanese study group, the overall survival for 5 y was 47.8 %. The 5 y survival of stage 3 tumors was 58.8 % and that of stage 4 was 20 % [36]. The Children’s Cancer Group Study reported an event free survival at 4 y of 90–100 % with favourable histology including infantile and neuroblastomas at all ages, but the survival rates plunging to 54 % for stage 3 tumors with unfavorable histopathology [37].

The results of Polish Study group also indicated that the high risk neuroblastoma accounts for more than 50 % of all neuroblastomas and only about one-third of them can be cured. This study group also compared the results of treatment of stage 4 by the European HR-NBL-1/ESIOP protocol. The results were better but not statistically significant in this group, 5 y EFS being 31.1 %, than those treated by other treatment protocols where 5-y EFS was 16.4 % [38].

In spite of all the advances and research in the management of high risk neuroblastoma and with many clinical trials conducted in several different study groups with variable number of patients, the outcome for this group of the disease has not changed much. In the Indian context, a retrospective analysis from one of the major Pediatric Oncology centers in North India revealed that the overall outcome profile is much more dismal [39], with only 8.7 % TFS at 16.5+/−6.7 mo. A 10 y review from a large center in South India reported a very large subgroup (>80 %) of children with advanced disease with only 27.7 % for stage 3 and a meager 9 % survival for stage 4 disease over long term [40]. Another study from Mumbai reviewed infantile neuroblastomas and concluded that the survival of infants with advanced stage disease, stage III and IV disease was 60 % and 25 % respectively [41].

Conclusions

To improve the outcome of neuroblastomas in our Indian subcontinent, it is imperative that we focus on proper risk stratification and appropriate therapy as per the risk. Even if the results for high risk neuroblastoma may not improve dramatically till we find a better treatment modality, the outcome in terms of event free and tumor free survival for low-risk tumors can be improved in most of the centers in developing countries.