Treatment reduction for neuroblastoma (2004)

In the absence of MYCN amplification, cortical bone metastases, and bone marrow involvement, infants and children (though not adolescents or adults) with neuroblastoma (NB) have an excellent prognosis with little or no chemotherapy or radiotherapy. The challenge in these patients—a heterogeneous group comprising ∼50% of the NB population and encompassing all stages—is defining how little therapeutic intervention (if any) is needed to preserve the very high cure rate. Reducing or completely eliminating cytotoxic therapy has proved satisfactory for low-stage NB 1-3 and for biologically favorable stage 3 NB 4. A more recent interest is in avoiding or delaying surgery—hence, the report by Fritsch et al. on the “wait-and-see” approach in a small subset of patients, viz., infants with incidentally detected adrenal masses. Questions that arise are: how valid (i.e., safe) is “expectant observation” in these babies and is that approach applicable in other clinical situations? The fundamental rationale underlying this “backing off” from active treatment is the realization that MYCN-nonamplified NB in some patient subsets has limited proliferative (and metastatic) potential. This major insight into the natural history of NB derives from several observations: (1) survival is excellent when microscopic or, more remarkably, grossly visible disease is left untreated after surgery on local-regional NBs 1-3; (2) spontaneous regression of widespread soft tissue disease, as well as of bone marrow involvement, is common in infants (stage 4S) 5-8; and (3) population-based NB screening studies of newborns and of well babies up to 12 months old indicate that spontaneous regression or size-stabilization of tumor occurs in many infants 9-12. These findings, which are certainly not characteristic of cancer in general, account for NB's renown as an “enigmatic” entity and provide persuasive evidence that only rarely does a favorable NB evolve into a lethal metastatic form. Most low-stage NBs are asymptomatic and/or are discovered incidentally and can be managed without cytotoxic therapy. Those that do cause major clinical problems—e.g., airway deviation from a cervico-mediastinal tumor or spinal cord compromise from a paraspinal mass—are sometimes best managed with chemotherapy. Continuing chemotherapy beyond the one or two cycles needed for clinical stabilization should be avoided. The extent of tumor response (shrinkage) and the possibility of regrowth or regional extension causing major morbidity (e.g., paraplegia) will then be key factors in determining the advisability of surgery to reduce residual disease. In some circumstances, although a tumor appears to be resectable in its entirety, a complete resection might not be justified if it would entail significant morbidity such as nephrectomy or brachial or sacral plexopathy. One patient in the report of Fritsch et al. was doing well after tumor debulking. With MYCN-nonamplified stage 4S, surgical resection of the primary tumor at diagnosis may not be necessary 5,6 since these masses rarely endanger vital structures, usually regress, and, consistent with one view of stage 4S 13, may merely represent one of many lesions of multifocal disease and consist of tumor cells that are unlikely to metastasize 5. Stage 4S is notable not only for an unusual pattern of involvement (including bulky distant lesions), but also for a waxing and waning clinical course. Indeed, it may present as a localized tumor with asymptomatic new lesions emerging two-to-three months later 2; sometimes this sequence is called “progressive disease” and prompts the (unwarranted) initiation of chemotherapy. Enlarging liver tumors, however, can be life-threatening (usually in babies <2–3 months old). If treatment with one or two cycles of low-dose chemotherapy and/or modest doses of radiotherapy achieves clinical improvement, additional cytotoxic therapy is not needed, since residual disease, even if extensive, is likely to regress. Biologic markers, which can be obtained without major surgery (e.g., by percutaneous biopsy of liver), have not to date proved helpful in predicting massive progression of NB in liver (insights can be expected with increasingly sophisticated biologic analyses of tumor tissue). Nevertheless, risk-related treatment guidelines call for multiple cycles of chemotherapy for MYCN-nonamplified stage 4S with diploidy or unfavorable histology 14. This approach is not universally accepted. For example, the German Society of Pediatric Oncology and Hematology recommends no cytotoxic therapy in the absence of clinical deterioration 7—an approach that our team too has taken in these rare cases. The German group also advocates a wait-and-see approach for asymptomatic infants with MYCN-nonamplified NB that, by strict criteria, represents stage 4 7. This subset includes asymptomatic infants who lack the cortical bone metastases and extensive bone marrow invasion of classic stage 4, but have unresectable primary tumors, NB in distant or bilateral lymph nodes, and/or NB in distant atypical sites (e.g., pleura). Our team has also managed such patients with observation alone, though sometimes with resection of the primary tumor 15. Regarding MYCN-nonamplified classic stage 4, infants do well with low-dose chemotherapy 16, and low- or moderate-dose chemotherapy might also suffice for selected patients diagnosed just beyond their first birthday (e.g., up to 15-to-18 months of age) 17,18. Localized NBs discovered by chance carry a particularly good prognosis. The report by Fritsch et al. highlights a number of issues related to the management of the small subset of these patients who are infants with an adrenal NB. Regarding natural history, small asymptomatic adrenal masses incidentally detected pre/perinatally might have a greater propensity to regress spontaneously (3/3 in this report) than those detected beyond the first months of life (2/2 without regression in this report). However, especially for clinically inapparent tumors detected pre/perinatally, some enlargement before regression should not cause alarm. Rapid or life-threatening tumor enlargement is unlikely, consistent with the generally favorable serum (low ferritin, lactate dehydrogenase, and neuron-specific enolase), urine (VMA:HVA ratio >1), and tumor (nonamplified MYCN, hyperdiploidy) prognostic markers in these cases 19-22; hence, performing urine studies and abdominal ultrasonography monthly suffices for monitoring. Surgery carries substantial risks in this very young population 10,21; if surgical intervention is eventually deemed necessary (as it did in one patient in this report), the procedure will be at an older, less vulnerable age. Criteria for observation include small size and low urine catecholamine levels, but guidelines for proceeding with surgical resection are not well established. In the report of Fritsch et al., one enlarging tumor was debulked and another was left alone. Doubling of tumor size and/or of urine catecholamine levels points to a need for surgical intervention, but these criteria (used in screened populations 9,10) allow for continued observation despite some tumor growth if major organs remain unaffected and the baby continues to be asymptomatic. As noted, the five cases described by Fritsch et al. all had adrenal NBs and the same holds for the few reported unscreened patients whose incidentally detected NBs were not immediately resected 19,23. Indeed, the Childrens Oncology Group is conducting a study of the wait-and-see approach for small adrenal masses detected at ≤3 months of age. One argument in favor of limiting observation alone to small adrenal masses is that some of these, especially when a cystic component is present, might represent NB-in-situ which is viewed as a benign variant in the development of normal adrenal glands 24. (The presence of triploidy, however, is evidence against that possibility in many cases since normal tissue would be diploid.) In contrast, expectant observation has been advocated for small NBs detected by screening in the first year of life (not just in the perinatal period) regardless of tumor location because masses typically either regressed spontaneously or had favorable biology when resected 10. That there may be little reason to limit the wait-and-see approach to adrenal masses in very young babies is further supported by evidence that extra-adrenal NBs are more likely than adrenal NBs to regress spontaneously 25 and by the fact that some apparently stage 1 extra-adrenal NBs are actually stage 4S, with liver lesions (not visible in imaging studies) only seen at the time of surgery. Monitoring should include sonography for infradiaphragmatic tumor or magnetic resonance imaging for supradiaphragmatic tumor, the aim being to avoid unnecessary exposure to radiation. In summary, treatment reduction possibilities should be considered for infants and children with MYCN-nonamplified NB. Some of these patients require no therapeutic intervention of any sort, others need surgery but no chemotherapy, while still others require chemotherapy due to tumor location or osteomedullary involvement but may not need prolonged or intensive therapy even if complete remission is not achieved. A very large past experience documents the overwhelming association of good prognosis, absence of MYCN amplification, and local-regional as well as stage 4S disease in infants; hence, the risks of major surgery in some of these cases may not be justified. In contrast, much more clinical experience (as in group-wide studies), correlated with comprehensive biologic studies, is needed for MYCN-nonamplified stage 3 in older children and stage 4 subsets (including patients up to 15-to-18 months of age) where preliminary results support treatment reduction.