Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group Study.

PURPOSE: To prospectively analyze the outcome of patients with Stage A neuroblastoma (NB) treated with surgery alone, especially with regard to the prognostic significance of age, tumor site, MYCN copy number, tumor cell ploidy, and histology. PATIENTS AND METHODS: The clinical course of 329 patients with Stage A disease registered on the POG NB Biology Study #9047 between February, 1990 and October, 1997 were evaluated. Age, tumor site, MYCN copy number, tumor cell ploidy, and histology were analyzed for their impact on event-free survival (EFS) and survival (S). RESULTS: The 5-year estimated EFS and S rates for the 329 patients were 91% (+/-3%) and 96% (+/-2%), respectively. The EFS rate was similar for infants younger than 12 months and children age 12 months or older, but age older than 12 months was predictive of lower S rates (P = 0.044). Patients with adrenal, abdominal non-adrenal, thoracic, and cervical tumors had similar S rates. The majority of patients had tumors with favorable biologic features, and only 3% had MYCN amplification. For infants with diploid tumors, the EFS rate was 82% (+/-16%), but effective therapy yielded an S rate of 100%. Rate of S was 80% (+/-26%) and 64% (+/-27%) for patients with unfavorable tumor histology and MYCN-amplified tumors, respectively. CONCLUSION: The outcome for patients with Stage A NB treated with surgery alone is excellent. Although EFS and S rates were significantly worse for patients with MYCN-amplified tumors, a subset achieved long-term remission after surgery alone. For patients with Stage A and MYCN amplification, additional factors are needed to distinguish the patients who will achieve long-term remission with surgery alone from those who will develop recurrent disease.

Lymph node sampling in localized neuroblastoma: a Pediatric Oncology Group study.

BACKGROUND/PURPOSE: Lymph node (LN) sampling was required by the Pediatric Oncology Group (POG) staging for neuroblastoma and currently is required as a part of the International Neuroblastoma Staging System (INSS). This retrospective study of planned lymph node sampling in patients with localized neuroblastoma was carried out with the intent of assisting surgeons in carrying out this procedure. The report documents the POG experience where LN, both uninvolved and involved with tumor, were found based on site of primary. METHODS: From 391 patients with localized neuroblastoma of the abdomen, chest, and neck, 238 patients had LN sampling at the primary operation, and these patients constitute the major part of the study. In addition, 89 patients had a carefully documented search for LN, and 64 had neither search nor biopsy. The operative note, pathology report, and surgical study sheet were used in the 238 patients based on the site of the primary tumor to determine which nodal groups or basins underwent biopsy, and in which groups tumor was found. RESULTS: The pattern of drainage, based on the primary site of abdominal tumors, favored an arterial rather than venous pathway. Primary tumors and metastatic LN were more numerous on the left side. The abdominal drainage followed three pathways: (1) infrarenal tumors from the left and midline were associated with paraaortic LN; (2) right infrarenal tumors were associated with LN in the paracaval basin; (3) with suprarenal primaries and with both adrenals, the superior mesenteric-portal-celiac basins were most productive for nodal sampling. Tumor was found most frequently in the left adrenal-renal basin and in the paraaortic basin. The actual number of LN sampled in a single case varied from 1 to 19 LN, with a mean number of LN based on stage and primary from one to seven LN. The tumor spread in LN was consistent with a "watershed" course, but this was not statistically significant. Patients for whom LN were sought had a better outcome, contrasting with the patients in whom LN were not sought or in whom nodal sampling was not possible. CONCLUSIONS: The experience in this study is consistent with previous descriptions of the lymphatic drainage of the retroperitoneal area. Delineation of the various basins as they relate to the site of the primary tumor should assist the surgeon in lymph node sampling. The role of LN involvement still remains unclear in the light of current studies of biological factors and histopathology as determinants of "risk groups." It is hoped that this study will enable ongoing and future studies to clarify this problem. The adult experience with breast cancer and with melanoma has indicated a continued importance of anatomic factors (including LN status) along with biological factors.

Bioethics in pediatric neuromuscular disease.

The increasing frequency with which bioethical issues arise in the medical care of pediatric patients with neuromuscular disease suggests a need for a working knowledge of the field for the clinical physician, Institutional Bioethics Committees are multidisciplinary groups that include medical, nursing, social service, legal, religious or chaplaincy, and community representation. The role and functioning of these committees vary widely according to institution. Inherent in the process of consent is that it must be an Informed consent. This requires that the person consenting has been given adequate information to understand and to appreciate the benefits and risks of the treatment. There are some instances in which consent by minor patients is necessary.

Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience--a pediatric oncology group study.

PURPOSE: Although a high rate of spontaneous regression is observed in infants with stage D(S) neuroblastoma (NB), survival is not uniform. To determine the prognostic relevance of age at diagnosis, therapy, and tumor biology in infants with stage D(S) NB, we reviewed the Pediatric Oncology Group (POG) experience. PATIENTS AND METHODS: A review of patients diagnosed with stage D(S) NB registered on POG protocols was performed. Survival according to age at diagnosis, treatment, and tumor biology was determined. RESULTS: Between 1987 and 1996, 110 infants with stage D(S) NB had an estimated 3-year survival rate of 85% +/- 4%; survival rate was 71% +/- 8% for infants 2 months of age or younger, and 68% +/- 12%, 44% +/- 33%, and 33% +/- 19% for patients with diploid, MYCN-amplified, and unfavorable histology tumors, respectively. Survival rates were similar for patients who received adjuvant chemotherapy versus those who did not (82% +/- 5% v 93% +/- 6%, respectively; P = .187). Furthermore, there was no statistical difference in survival rate for patients who underwent complete resection of their primary tumor compared with those who underwent partial resection or biopsy only (90% +/- 5% v 78% +/- 7%, respectively; P = .083). CONCLUSION: Our review confirmed that the survival of infants with stage D(S) NB is excellent. However, subsets of patients with poor prognosis can be identified by young age and unfavorable biologic factors. More effective therapy is needed for the group of stage D(S) infants who show unfavorable clinical and biologic features.

The risk of nephrectomy during local control in abdominal neuroblastoma.

METHODS: Eight hundred sixty-eight children presenting from 1981 to 1991 were treated on five multiagent chemotherapy protocols by members of the Pediatric Oncology Group for advanced-stage neuroblastoma with large primary tumors crossing the midline or distant metastasis. Of these children, 696 had abdominal (adrenal or paravertebral) primary tumors. One hundred sixteen children underwent greater than 50% surgical resection of these abdominal primary tumors before chemotherapy, and 233 underwent similar surgery after induction chemotherapy. RESULTS: Among the 349 who underwent surgical resection, 52 children (14.9%) had nephrectomy or renal infarction during surgery for local control. There was a 25% incidence among those with initial resection (29 patients) and a 9.9% incidence in the postchemotherapy resections (23 patients). Reasons for nephrectomy given by the surgeons included direct involvement of the kidney by adjacent tumor (17 children), clinical impression that the tumor was a Wilms' tumor (11 children), renal vessels could not be separated from the tumor (10 children), extensive tumor surrounding the kidney (8 children), postoperative renal infarction (4 children), marked decrease in unilateral renal function after chemotherapy (1 child), and position of the tumor posterior to the kidney and vena cava making resection without nephrectomy impossible (1 child). Of the patients undergoing nephrectomy, four children had an upper pole nephrectomy in conjunction with their adrenalectomy and resection of the tumor. Pathological review of the resected tumor available in 47 cases demonstrated direct involvement of the renal parenchyma in 18 cases (38% of the nephrectomies) and in 5.2% of those undergoing resection. In children undergoing initial resection, the risk for nephrectomy (as calculated by the methods described by Gart) was more than twice compared with those undergoing resection after chemotherapy (P = .012; odds ratio, 2.32; 95% confidence interval of 1.23 to 4.42). CONCLUSIONS: This review confirms that renal parenchymal involvement does occur in a significant number of children with abdominal neuroblastoma. It also suggests that preoperative chemotherapy may decrease the number of nephrectomies required to achieve a total or subtotal resection.

Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study.

BACKGROUND: Current staging systems for unresectable or metastatic neuroblastoma do not reliably predict responses to chemotherapy in infants under 1 year of age. Previous studies have indicated that the DNA content, or ploidy, of malignant neuroblasts can discriminate between good and poor responders in this group of patients, but the clinical utility of ploidy assessment has remained in question. PURPOSE: We tested, in a prospective nonrandomized study, the hypothesis that neuroblast ploidy could be used as the sole guide for treatment selection in infants with unresectable or metastatic tumors and could differentiate between those who would respond to our previous standard regimen and those who would benefit from an immediate switch to another therapy. METHODS: One hundred seventy-seven infants were enrolled in this trial. Five of these infants were subsequently excluded (two ineligible, two lacking ploidy information, and one protocol violation); therefore, 172 patients were included in the study. One hundred thirty infants with hyperdiploid tumors (DNA index > 1.0; better prognosis in retrospective studies) were treated with a well-tolerated regimen of cyclophosphamide (150 mg/m2 per day orally or intravenously on days 1-7) and doxorubicin (35 mg/m2 intravenously on day 8). Forty-two infants with diploid tumors (DNA index = 1.0; worse prognosis in retrospective studies) received cisplatin (90 mg/m2 intravenously on day 1) and teniposide (100 mg/ m2 intravenously on day 3) after an initial course of cyclophosphamide plus doxorubicin. Statistical end points were response and long-term survival. In addition, we assessed within each ploidy group (i.e., patients with hyperdiploid tumors and those with diploid tumors) the prognostic significance of NMYC gene copy number, tumor stage, and other variables commonly measured in this disease. RESULTS: Of the 127 assessable infants with hyperdiploid tumors, 115 (91%) had complete responses--85 after receiving five courses of cyclophosphamide plus doxorubicin and 30 after receiving further therapy including cisplatin plus teniposide. The 3-year survival estimate for the entire hyperdiploid group was 94% (95% confidence interval [CI] = 89%-98%). Nineteen (46%) of 41 assessable infants with diploid tumors were complete responders. The overall 3-year survival estimate for this group was 55% (95% CI = 39%-70%). Prognostic factor analysis indicated that NMYC gene amplification and an elevated serum lactate dehydrogenase level were statistically significant markers of higher risk disease within the diploid group (two-sided P values of .005 and .003, respectively). Only NMYC was predictive in the hyperdiploid group (P = .003). CONCLUSION: Use of a prognostic staging system based on tumor cell ploidy, augmented with the NMYC gene copy number and serum level of lactate dehydrogenase, would very likely improve the treatment of infants with unresectable or metastatic neuroblastoma. Patients with diploid tumors characterized by an amplified NMYC locus represent a particularly unfavorable risk group that may benefit from innovative new therapies.

Event-free survival of children with biologically favourable neuroblastoma based on the degree of initial tumour resection: results from the Pediatric Oncology Group.

We analysed the 2-year event-free survival (EFS) of 49 patients 1 year of age and older, with stage 2B or 3 neuroblastoma, treated on Pediatric Oncology Group protocols 8742 and 9244, with respect to the degree of tumour resection at diagnosis. The 2-year EFS rate for 21 children whose tumours were completely resected at diagnosis was 85% (SE = 10%) compared with an EFS rate of 70% (SE = 9%) for the 28 children whose tumours were incompletely resected at diagnosis. Despite the observed trend in favour of complete resection, these EFS curves were not statistically significantly different (P = 0.259). Patients with favourable Shimada histology tumours had an EFS rate of 92% (SE = 7%) compared with a rate of 58% (SE = 15%) for patients with unfavourable histology tumours. EFS curves for the two histologic groups were significantly different (P = 0.009). The impact of aggressive surgery and adjuvant chemotherapy on the outcome of patients with biologically favourable regional neuroblastoma is still unclear.

Hernia survey of the Section on Surgery of the American Academy of Pediatrics.

The members of the Section on Surgery of the American Academy of Pediatrics were surveyed to determine the practice of North American pediatric surgeons in infants with inguinal hernia (IH). Case-scenario multiple-choice-design questionnaires regarding hernias and hydroceles were sent to all members of the Surgical Section, and responses were received from 292 (50%). In healthy full-term infant boys with asymptomatic reducible IH, 82% of responders perform repair electively, no matter what the age or weight. In full-term girls with a reducible ovary, 59% perform surgery at the next available time; if the ovary is nonreducible but asymptomatic, 44% operate emergently or urgently and 42% at the next elective slot. In former preemies, the pattern of repair is as follows. (1) For those recently discharged after 2 months in the neonatal intensive care unit (NICU) with reducible IH, 65% perform the repair when convenient. (2) A general anesthetic is used in 70%; 15% use spinal anesthesia, and 11% use caudal block with sedation. (3) If the repair is done in the hospital outpatient (same-day) unit, 36% wait until 50 weeks postconception (PC) and 33% wait until 60 weeks PC. (4) if the baby's weight is at least 1,000 g. 71% perform the repair before discharge. The pain control choice after childhood IH repair is Tylenol for 30%, local infiltration biquivacaine for 30%, caudal block for 22%, regional block for 11%, and Tylenol/codeine combined for 7%. In 6-week-old full-term infants with communicating hydroceles without definite "hernia," two thirds treat as an IH with elective repair as soon as possible. With respect to contralateral exploration in infants with unilateral IH, 65% perform it in males if they are < or = 2 years of age and 84% use it in females of up to 4 years of age. This approach is not influenced by presenting side, presence of hydrocele, or history of prematurity. Laparoscopic evaluation of the contralateral IH is performed by only 6% of responders, 40% of whom use the open ipsilateral sac for laparoscope introduction.

Results of pediatric oncology group protocol 8104 for infants with stages D and DS neuroblastoma.

PURPOSE: We determined the complete response and survival rates for infants with disseminated (stage D) neuroblastoma that followed therapy identical to that for regional disease. In those infants whose disease excluded cortical bone metastases (stage DS), we determined complete response rates achieved either spontaneously or with stage D therapy. PATIENTS AND METHODS: Eighty-eight patients with metastatic disease received induction chemotherapy followed by a second operation, the results of which determined additional therapy. Twenty-five patients were observed after diagnosis, without chemotherapy, until a second operation. RESULTS: The complete response (CR) rates for patients with stage D disease after induction chemotherapy and postinduction surgery were 26% and 52%, respectively, and for immediately treated patients with stage DS disease 69% and 77%, respectively. Fifty-four percent of initially observed patients with stage DS disease achieved CR after a second operation; 44% were never treated beyond these two operations. Five-year actuarial survival rates for patients with stage D and for all those with stage DS disease were 60% (SE = 6%) and 90% (SE = 5%), respectively. CONCLUSIONS: Improved survival rates for patients with stage D disease were achieved on this protocol but remained considerably lower than those for infants with less extensive disease. Rates of survival for patients with stage DS disease were achieved with therapy less aggressive than in published series.

Cyclophosphamide/doxorubicin vs. cisplatin/teniposide in the treatment of children older than 12 months of age with disseminated neuroblastoma: a Pediatric Oncology Group Randomized Phase II study.

This prospective study was designed to estimate the response rates and to compare two drug pairs, cyclophosphamide/doxorubicin (Cy/A) and cisplatin/teniposide (P1/VM) in previously untreated patients with disseminated neuroblastoma > 12 months of age at diagnosis. Estimated complete clinical response rates after five courses of therapy were 13% (70 patients) and 22% (64 patients) for Cy/A and P1/VM, respectively (P = 0.17). After surgical removal of residual tumors in patients with partial response, the complete response rates were 27% and 34% (P = 0.50), respectively. The overall CR/PR rates after induction and surgery were 59% and 73% (P = 0.077). There was no significant difference in event free survival (P = 0.48) or survival (P = 0.40). Five year survival on the two arms were 14% (SE = 5%) and 12% (SE = 4%), respectively. Toxicity was significant but manageable. The Cy/A arm had significantly higher hematopoietic toxicity but significantly lower GI toxicity. Significant allergic reactions were seen with the P1/VM arm, none in the Cy/A arm. Given the activity of these two regimens, further therapy with a combination of these regimens is suggested.