Contents
References . . . 291
A hallmark of neuroblastoma (NB) is heterogeneity, with a wide spectrum of clinical behavior which varies according to age at diagnosis, the stage of dis- ease, and tumor biology (Brodeur 2003). This hetero- geneity is most evident in the numerous transforma- tion-linked genetic changes identified in cell lines and tumors. Some of these aberrations are predictive of treatment response and outcome (see Chap. 4).
Nevertheless, it is increasingly clear that despite such tissue heterogeneity, the clinical biology of NB is gen- erally predictable. By and large, patients with stage- 4S and local–regional tumors are curable with mini- mal or no therapy, whereas children with distant metastatic disease pose an enormous clinical chal- lenge. Only small subsets of patients have elusive risk identities at diagnosis. Modern treatments stratify- ing patients according to both clinical and biological factors are now the standard (see Chap. 7). At the present time, because of disparities in classification and treatment approaches, it remains difficult to compare the results of clinical trials conducted in dif- ferent regions of the world; however, efforts are cur- rently underway to develop an International NB Risk Group (INRG) System.
All of the current risk grouping systems utilize age at diagnosis ( £vs >1 year), INSS stage, and tumor MYCN status. The COG Risk Classification System also includes tumor histology and ploidy, whereas other cooperative groups have incorporated the pat- tern of metastatic disease, tumor resectability, and the presence or absence of threatening symptoms (see Chaps. 7 and 11). As currently defined, each of the risk-classification systems has limitations. Small subsets of patients classified as low- or intermediate risk at diagnosis have acted clinically as aggressive
Perspectives
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290 N.-K. V. Cheung · S. L. Cohn
disease, whereas other children, currently classified as high risk, have favorable outcomes and may not require the dose-intensive therapeutic approach presently prescribed. Some genetic abnormalities and molecular markers not utilized in the current classification schemas may help refine the definition of risk groups (see Chap. 4–5), and prospective stud- ies investigating their clinical significance are ongo- ing. In addition, new techniques, such as comprehen- sive gene expression profiling, are being utilized to molecularly classify NB tumors (see Chap. 9). These studies are likely to lead to a refinement of the cur- rent risk-group classification systems and an im- provement in risk-group based treatment strategies.
Although substantial progress has been made in the treatment approach toward patients with low- and intermediate-risk NB, the cure rate for metastat- ic NB in children remains unsatisfactory. As de- scribed in Chap. 11, most low-risk patients are suc- cessfully treated with surgery alone, and some infants do not require any treatment because their tumors have a high frequency of spontaneous regression (Chap. 2). Even for infants with stage 4 NB, >90%
long-term survival is typical if the tumor MCYN oncogene is not amplified. Similarly, among patients with intermediate-risk tumors, >90% survival is ex- pected following moderate-dose chemotherapy and surgery. In contrast, outcome remains poor for chil- dren older than 1 year with metastatic NB, with or without MYCN amplification, and during the past decade there has been only a modest improvement in cure. This small gain is due to intensification of in- duction chemotherapy, megatherapy consolidation, biological/immunological therapy and improved supportive care. Several clinical trials, including the large prospective randomized CCG-3891 study which demonstrated superior outcome for patients ran- domized to myeloablative therapy and bone marrow transplant vs chemotherapy during consolidation (Matthay et al. 1999), support the hypothesis that dose intensification is an important component to achieve successful treatment of metastatic NB (Che- ung and Heller 1991).Whether intensification is most beneficial during induction or during consolidation remains controversial. Although promising results have also been observed in recent pilot studies test-
ing tandem cycles of high-dose therapy plus stem- cell rescue (Grupp et al. 2000; Kletzel et al. 2002) (Chap. 11), further dose escalation is likely to be un- acceptable. In addition, despite achieving complete clinical remission, the majority of children with high- risk disease will relapse due to drug-resistant resid- ual disease. Eradication of refractory microscopic disease remains the most significant challenge in the treatment of metastatic NB. The paradigm of “more is better” should be questioned and additional high- risk trials testing biological and targeted agents need to be designed (Chap. 11).
Recently, the differentiation agent 13-cis retinoic acid was shown to be clinically effective when ad- ministered in the setting of minimal residual disease in the randomized CCG 3891 clinical trial (Matthay et al. 1999) (reviewed in Chap. 15). This seminal study demonstrated that a biological agent was capable of impacting outcome in high-risk NB. The COG is cur- rently conducting a randomized prospective study comparing the efficacy of anti-GD2 ch14.18 antibody plus cytokines and 13-cis retinoic acid vs 13-cis retinoic acid alone in the setting of minimal residual disease. Clinical trials have also been developed in Europe to test immunotherapy in high-risk NB, and a single-arm study investigating the efficacy of the anti-GD2 antibody 3F8 plus GM-CSF, is ongoing at Memorial Sloan-Kettering Cancer Center. Additional phase-I and phase-II studies are testing other target- ed therapies (see Chap. 12). As outlined in Chaps.
14–17, preliminary studies suggest that several im- munotherapeutic molecules, new retinoids, anti-an- giogenic agents, and other experimental therapeutics have activity against refractory disease.
As reviewed in Chap. 18, a variety of acute and late complications from NB and its treatment may occur;
these include late effects of chemotherapy, radiation
therapy, and surgery. High-risk patients are at great-
est risk because of the intensive multi-modality treat-
ment strategies that are currently utilized. Reliable
identification of the subset of patients currently clas-
sified as high risk who do not require intensive ther-
apy would significantly decrease long-term morbidi-
ty and treatment-related mortality for these very
young patients. For example, data from both the POG
and CCG indicate that toddlers 12–18 months of age
Chapter 19 291 Perspectives and Future Directions
with favorable biology stage-4 tumors may not re- quire the current intensive high-risk treatment regi- men to be cured (Schmidt et al. 2003; George et al.
2003); however, ultimate improvements in survival and reductions of late effects may require more tar- geted therapies. Research aimed at discovering new genes and pathways critical to NB tumorigenesis and drug resistance should be prioritized. It is hoped that these biologically based treatment approaches will prove to be more effective and less toxic than the cur- rent regimens.
We have learned important lessons from NB. The clinical biology of stage-4S and local-regional NB, when combined with the findings of the screening study (Chap. 2), have challenged accepted oncologi- cal principles. If clinical progression from local re- gional small NB to metastatic disease does not gener- ally occur, adjuvant cytotoxic therapy is probably not necessary for the majority of these patients. On the other hand, despite general sensitivity of NB to chemotherapy, curing minimal residual metastasis remains difficult. Research focused on its measure- ment, control, or eradication should be emphasized.
Most important of all, with the growing list of prom- ising therapies, efforts devoted to their timely and ef- fective integration into an overall curative strategy should have high priority.
References
Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203–216
Cheung NK, Heller G (1991) Chemotherapy dose intensity cor- relates strongly with response, median survival, and medi- an progression-free survival in metastatic neuroblastoma.
J Clin Oncol 9:1050–1058
George RE, London WB, Maris JM, Cohn SL, Diller L, Brodeur GM, Castleberry RP, Look AT. Hyperdiploidy plus Non-am- plified MYCN Confers a Favorable Prognostic Group in Children 12 to 18 Month of Age with Disseminated Neuro- blastoma: A Pediatric Oncology Group Study. J Clin Oncol (in press)
Grupp SA, Stern JW, Bunin N, Nancarrow C, Ross AA, Mogul M, Adams R, Grier HE, Gorlin JB, Shamberger R, Marcus K, Neuberg D, Weinstein HJ, Diller L (2000) Tandem high- dose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol 18:2567–2575
Kletzel M, Katzenstein HM, Haut PR,Yu AL, Morgan E, Reynolds M, Geissler G, Marymount MH, Liu D, Kalapurakal JA, Shore RM, Bardo DM, Schmoldt J, Rademaker AW, Cohn SL (2002) Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chica- go Pilot II Study. J Clin Oncol 20:2284–2292
Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB, Reynolds CP (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis- retinoic acid. N Engl J Med 341:1165–1173
Schmidt ML, Lal A, Seeger RC, Maris JM, Shimada H, O’Leary M, Gerbing RB, Matthay KK. Favorable prognosis for pa- tients ages 12–18 month with stage 4 MYCN-nonamplified neuroblastoma. J Clin Oncol (in press)
