Treatment of aggressive non-Hodgkin's lymphoma in elderly patients with thiotepa, Novantrone (mitoxantrone), vincristine, prednisone (TNOP).

The aging of the population and the increased incidence of non-Hodgkin's lymphoma will result in a large number of elderly patients with this disorder. Newer therapies will be required for this group of patients. This article reports a new therapy for elderly patients with diffuse aggressive non-Hodgkin's lymphoma. Patients were treated with TNOP (thiotepa 20 mg/m(2), mitoxantrone (Novantrone) 10 mg/m(2), vincristine (Oncovin) 1 mg/m(2) all on day 1 and prednisone 60 mg/m(2) on days 1 through 5 of a 21-day course. Twenty-six patients were enrolled on study. The patients' ages ranged from 66 years to 87 years, with a mean age of 75.5 years. Eleven patients had a partial response (42%) and 4 patients had a complete response (15%) for a total response of 57%. Eighty-one percent of patients survived 1 year and 54% survived for 2 years. The median survival was 26 months. Hematologic and nonhematologic toxicity was tolerable. We believe that TNOP is an excellent therapeutic option in this group of elderly patients, particularly in the palliative setting.

Phase II study of combination human recombinant GM-CSF with intermediate-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk myelodysplastic syndromes (RAEB, RAEBT, and CMML): an Eastern Cooperative Oncology Group Study.

A Phase II study of GM-CSF with intermediate-dose cytarabine and mitoxantrone was conducted in patients with high-risk myelodysplastic syndrome. It was designed to evaluate if priming with growth factor could increase the efficiency of chemotherapy. In this older population only two of 10 patients achieved a bone marrow CR, including one patient whose leukemic blasts had an "S" phase increase of 2.55x at 48 hr. Unexpected hepatotoxicity was noted. This regimen cannot be recommended for this elderly population of patients.

Granulocyte-macrophage colony-stimulating factor in the treatment of neonates with neutropenia and sepsis.

To evaluate the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in improving neutrophil counts and survival of neutropenic septic neonates, the authors studied 8 neonates with gestational or postconceptional age at least 30 weeks; weight at least 1000 g; serious infection with concomitant neutropenia (absolute neutrophil count [ANC] < 3.0 x 10(9)/L) or leukopenia (white blood cell count < 5.0 x 10(9)/L) and anticipated survival at least 48 h. Patients received 5 micrograms/kg of GM-CSF intravenously for 5 consecutive days or until the ANC reached 20 x 10(9)/L. Clinical parameters and complete blood counts were monitored. Prestudy ANCs ranged from 0.05 to 2.7 x 10(9)/L. Four patients had positive blood cultures, 4 had necrotizing enterocolitis, and 1 was in septic shock. All patients had elevated C-reactive protein. All patients had resolution of neutropenia and survived the septic episodes. The use of GM-CSF in these patients merits further exploration.

Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor.

PURPOSE: To evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk of recurrence. PATIENTS AND METHODS: Forty-eight assessable patients with stage III or IV melanoma were treated in a phase II trial with long-term, chronic, intermittent GM-CSF after surgical resection of disease. Patients with stage III disease were required to have more than four positive nodes or a more than 3-cm mass. All patients were rendered clinically disease-free by surgery before enrollment. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 microg/m(2) was delivered daily for 14 days followed by 14 days of rest. Treatment cycles continued for 1 year or until disease recurrence. Patients were evaluated for toxicity and disease-free and overall survival. RESULTS: Overall and disease-free survival were significantly prolonged in patients who received GM-CSF compared with matched historical controls. The median survival duration was 37.5 months in the study patients versus 12.2 months in the matched controls (P <.001). GM-CSF was well tolerated; only one subject discontinued drug due to an adverse event (grade 2 injection site reaction). CONCLUSION: GM-CSF may provide an antitumor effect that prolongs survival and disease-free survival in patients with stage III and IV melanoma who are clinically disease-free. These results support institution of a prospective, randomized clinical trial to definitively determine the value of surgical adjuvant therapy with GM-CSF in such patients.

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.

Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure.

BACKGROUND: Although previous studies suggested that TNF may contribute to heart failure progression, it is unclear whether antagonizing TNF is beneficial in heart failure patients. METHODS AND RESULTS: Eighteen NYHA class III heart failure patients were randomized into a double-blind dose-escalation study to examine the safety and potential efficacy of etanercept, a specific TNF antagonist (Enbrel). Patients received placebo (6 patients) or an escalating dose (1, 4, or 10 mg/m2) of etanercept (12 patients) given as a single intravenous infusion. Safety parameters and patient functional status were assessed at baseline and at days 1, 2, 7, and 14. There were no significant side effects or clinically significant changes in laboratory indices. There was, however, a decrease in TNF bioactivity and a significant overall increase in quality-of-life scores, 6-minute walk distance, and ejection fraction in the cohort that received 4 or 10 mg/m2 of etanercept; there was no significant change in these parameters in the placebo group. CONCLUSIONS: A single intravenous infusion of etanercept was safe and well tolerated in patients with NYHA class III heart failure. These studies provide provisional evidence that suggests that etanercept is sufficient to lower levels of biologically active TNF and may lead to improvement in the functional status of patients with heart failure.

Recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and autologous melanoma vaccine mediate tumor regression in patients with metastatic melanoma.

In mice, significant immunoprotection was achieved using B16 melanoma cells transfected with granulocyte-macrophage colony-stimulating factor (GM-CSF) as vaccines (Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993;90:3539-43). The aim of this study is to test the hypothesis that recombinant human GM-CSF (rhGM-CSF) injected with autologous melanoma vaccine may result in tumor rejection in melanoma patients. Twenty stage IV melanoma patients were treated as outpatients with multiple cycles of autologous melanoma vaccine and bacillus Calmette-Guérin (BCG) plus rhGM-CSF injection in the vaccine sites. Two patients (10%) showed a complete response, with one patient showing resolution of subcutaneous, hepatic, and splenic metastases. In the second patient, buccal, subcutaneous, pulmonary, paraaortic, hepatic, splenic, and retroperitoneal metastases regressed completely. Two patients (10%) showed partial response, with regression of a paraaortic metastasis in one patient. In the second patient, there was shrinkage (> 75%) of a large hepatic lesion. One patient has been rendered free of disease after resection of a single pulmonary metastatic nodule. Three patients (15%) had stable disease during treatment but subsequently developed progression of disease. In 12 patients (60%), the disease progressed. Side effects were minimal. In a separate pilot study, 15 stage IV melanoma patients were also treated with autologous melanoma vaccine with BCG but not with rhGM-CSF; none responded. The fact that four patients showed objective responses to active specific immunotherapy with rhGM-CSF demonstrates that melanoma patients bearing a significant tumor burden may respond specifically to their autologous melanoma.

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.

Conventional versus modified morphologic criteria for ganglioneuroblastoma. A review of cases from the Pediatric Oncology Group.

BACKGROUND: Conventional criteria for ganglioneuroblastoma (GNB) do not require the presence of ganglioneuromatous component for pathologic diagnosis. This leads to inclusion of a mixed variety of neuroblastic tumors in the category of GNB. Therefore, GNB diagnosed by conventional criteria includes tumors showing more than 5% ganglion cells but no predominant ganglioneuromatous component, as well as tumors containing predominant ganglioneuromatous component. By previously described modified criteria, the former would be considered differentiating neuroblastoma (NB), and only the latter would be considered GNB. Data on Pediatric Oncology Group cases were analyzed to compare the prognostic subgroups of GNB diagnosed by conventional and modified criteria. The two prognostic subgroups (low risk and high risk) were defined on the basis of previously described prognostic differences between histologic grades of differentiating NBs and subtypes of GNB. METHODS: Pathologic data from cases of neuroblastic tumors registered on Pediatric Oncology Group NB protocols 8104 and 8441 were reviewed. The GNBs diagnosed by conventional and modified criteria were divided into low-risk and high-risk histology subgroups as follows: (1) GNB by conventional criteria: low-risk group, differentiating NB of histologic grades 1 and 2 and GNB of intermixed and borderline subtypes; high-risk group, differentiating NB of histologic grade 3 and GNB of nodular subtype; (2) GNB by modified criteria: low-risk group, GNB of intermixed and borderline subtypes; high-risk group, GNB of nodular subtype. RESULTS: The low- and high-risk subgroups of GNBs diagnosed by conventional (69 cases) and modified (36 cases) criteria showed statistically significant differences in survival (P = .03 and .01, respectively). However, from the histologic point of view, GNBs diagnosed by modified criteria form a more uniform morphologic group, which can be divided into low- and high-risk subgroups by a single set of morphologic criteria. In contrast, GNBs diagnosed by conventional criteria form a heterogeneous group, which requires two sets of criteria (ie, histologic grade and subtypes of GNB) for its classification into low- and high-risk subgroups. CONCLUSIONS: The modified criteria for GNB define a morphologically uniform group of neuroblastic tumors to which a single set of prognostic criteria can be applied. It is recommended that the term GNB should be used both clinically and pathologically to designate a distinctive subgroup of neuroblastic tumors, in contrast to the current use, which designates both NB and GNB.

Granulocyte-macrophage colony-stimulating factor as infection prophylaxis in high-risk oncologic surgery.

BACKGROUND: A method of augmenting host defenses against bacterial pathogens could result in a decrease in postoperative infections. Given its effects on leukocyte proliferation and function, it is possible that prophylactic granulocyte-macrophage colony-stimulating factor (GM-CSF) could reduce the incidence and severity of infections in high-risk surgical patients. The current study was undertaken to determine the safety and hematologic effects of perioperative GM-CSF. METHODS: Cancer patients undergoing operations with a high risk of postoperative infection were treated perioperatively for 10 days with subcutaneous GM-CSF. Cohorts were treated with GM-CSF at 125 micrograms/m2/day (12 patients) and 250 micrograms/m2/day (11 patients). RESULTS: There were no severe or life-threatening toxicities associated with GM-CSF. Mean maximum neutrophil counts during the first 5 postoperative days were 16.3 +/- 9.14 and 24.5 +/- 7.60 at 125 and 250 micrograms/m2, respectively (P = 0.04). Only one wound infection was diagnosed during this study. CONCLUSIONS: GM-CSF may be safely administered perioperatively at doses that augment neutrophil number and function. An ongoing randomized clinical trial will determine the impact of GM-CSF on postoperative infection.

Chest wall resection for Ewing's sarcoma of the rib: an unnecessary procedure. 1988. Updated in 1995.

Approximately 10% of all cases of Ewing's sarcoma arise from a rib. Conventional management has included chest wall resection (3 or more ribs) and radiation therapy. These forms of therapy have led to complications such as scoliosis and local deformity. The addition of radiation therapy can result in damage to the lung and adjacent viscera and also potentiate pulmonary restrictive disease. Between 1971 and 1978, 9 patients were treated with surgery, radiation therapy, and combination chemotherapy (three- or four-drug regimen). Only 2 patients (22%) survive. Since 1979, 14 patients were entered into a new protocol consisting of sequential induction chemotherapy, followed by delayed surgical resection whenever feasible. Three patients had complete resection of their primary lesion at onset. Initially, 7 patients had either biopsy (N = 4) or incomplete chest wall resection N = 3). All 4 patients with biopsy only at diagnosis had excellent responses to induction chemotherapy, allowing delayed resection of the involved rib without chest wall resection. Overall, 12 of 14 patients (86%) treated since 1979 survive, with only 2 receiving radiation therapy for residual disease in the primary rib site.

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.

A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490).

The treatment of adult patients greater than 55 to 70 years of age with acute myelogenous leukemia (AML) is associated with a treatment-related mortality of approximately 25%. This prospective, double-blind randomized study was designed to see if the use of granulocyte-macrophage colony stimulating factor (GM-CSF; yeast-derived) could shorten the period of neutropenia and to determine any effect this would have on therapy-related morbidity and mortality. A total of 124 patients entered this study. Induction consisted of standard daunorubicin and cytarabine. A day-10 bone marrow was examined; if this was aplastic without leukemia, patients received blinded placebo or GM-CSF from day 11 until neutrophil recovery. Patients who entered complete remission received the identical study medication (blinded GM-CSF or placebo) in consolidation that they had received during induction. The overall complete remission rate was 52%; 60% for the GM-CSF arm and 44% for the placebo arm (P = .08). Median times to neutrophil recovery were significantly shortened on the GM-CSF arm. The overall treatment-related toxicity from start of GM-CSF/placebo was reduced on the GM-CSF arm (P = .049). Similarly, the infectious toxicity was significantly reduced on the GM-CSF arm (P = .015). The median survival for all patients was 10.6 months in the GM-CSF group and 4.8 months in the placebo arm (P = .048). It appears that GM-CSF is safe and efficacious for adult patients greater than 55 to 70 years of age with AML; its major impact is in reducing the duration of neutropenia and therapy-related mortality and morbidity. This may result in a better response rate.

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.

Phase II investigational window using carboplatin, iproplatin, ifosfamide, and epirubicin in children with untreated disseminated neuroblastoma: a Pediatric Oncology Group study.

PURPOSE: Children less than 1 year of age with metastatic neuroblastoma NB are at high risk of death. The need to identify new and effective chemotherapy agents is clear. A study was conducted by the Pediatric Oncology Group (POG) to determine the efficacy and safety of administering two courses of a single phase II agent before conventional treatment as a means to evaluate new agents in this setting. PATIENTS AND METHODS: One hundred seventy-three eligible patients more than 1 year of age with disseminated neuroblastoma received two courses of one of the following: ifosfamide (IFOS) 2 g/m2/d for 4 days intravenously (IV) plus mesna; carboplatin (CARB) 560 mg/m2 i.v. over 1 hour; iproplatin (CHIP) 325 mg/m2 IV over 2 hours; or epirubicin (EPIR) 90 mg/m2 i.v. push. Following evaluation for response and toxicity, eligible patients were randomized to receive either cisplatin 90 mg/m2 i.v. on day 1, etoposide 200 mg/m2 i.v. on day 3, cyclophosphamide 150 mg/m2/d orally on days 7 to 13, doxorubicin 35 mg/m2 i.v. on day 14 (CECA), or cisplatin 40 mg/m2 IV on days 1 to 5 and etoposide 200 mg/m2 i.v. on days 2 to 4 alternating at 3-week intervals with cyclophosphamide 150 mg/m2/d orally on days 1 to 7 and doxorubicin 35 mg/m2 IV on day 8 (HDP/VP/CA). An additional 86 patients were randomized to receive either CECA or HDP/VP/CA without initial phase II therapy. RESULTS: After phase II therapy, only 20% of patients experienced grade 3/4 hematopoietic toxicity. No toxic deaths occurred. Objective response rates (partial responses [PRs] plus minor responses [MRs]) following IFOS, CARB, CHIP, and EPIR were 70%, 77%, 67%, and 26%, respectively. Following phase III treatment, there was no statistically significant difference in rates of complete response (CR)/PR or progressive disease (PD), or in time to PD of patients who participated in the phase II window versus those who received only CECA or HDP/VP/CA. CONCLUSION: IFOS, CARB, and CHIP are efficacious in neuroblastoma, are well tolerated, and should be incorporated into primary treatment regimens. Combination regimens using these agents may be possible, since most repeat courses were given within 2 weeks. Administering phase II therapy to untreated patients with high-risk tumors provides a unique and sensitive method to assess new agents without compromising patient outcome.

Systematization of primary histopathologic and fine-needle aspiration cytologic features and description of unusual histopathologic features of neuroblastic tumors: a report from the Pediatric Oncology Group.

On the basis of a detailed review of the primary histopathologic features of 239 cases and the fine-needle aspiration cytologic features of seven cases, a systematized schema of differentiation, progressive maturation and organization, and biologic behavior in neuroblastic tumors (NTs) is presented. The differentiation is of the gangliocytic and schwannian lineages. Maturation occurs in differentiating neuroblasts, leading to the formation of various stages of ganglion cells and Schwann cells. Organization is characterized by nesting pattern, rosette formation, parallel arrangement of neuropil, and alignment of Schwann cells along the neurites. According to this schema the NTs can be arranged in the following order: undifferentiated, poorly differentiated, and differentiating neuroblastoma; nodular, intermixed, and borderline ganglioneuroblastoma; and ganglioneuroma. Formulation of such a schema is helpful in gaining a better understanding of the complex pathologic features and in defining the criteria for various types of NTs. Therefore, the schema also would be helpful in achieving uniformity and reproducibility of the diagnosis of various types of NTs. Previously unreported features related to shape, size, nucleus, and cytoplasm of neuroblasts; secondary changes and patterns; changes in the fibrovascular septa; and other morphologic aspects of NTs and features (such as large tumor cells, karyorrhectic cells in fine-needle aspiration biopsy, tumor giant cells, anaplasia, and nesting pattern of tumor cells that have not been sufficiently emphasized) also are described. The importance of these previously unreported and insufficiently emphasized features relates to the histologic and cytologic diagnosis of NTs. For example, some of the features, such as starry sky appearance and spindle-shaped neuroblasts, may be misleading if seen in a small biopsy specimen. Others, such as tumor giant cells resembling ganglion cells and nesting pattern, will provide clues to the correct diagnosis. Some of the features, such as sclerosing pattern, hyalinization, and dense lymphoplasmacytic infiltration, may be related to the phenomenon of regression exhibited by neuroblastomas.

Thoracic neuroblastoma: a Pediatric Oncology Group study.

Ninety-six patients with thoracic neuroblastoma were studied in a prospective fashion. Median age at presentation was 0.9 years. Forty-eight percent of the patients presented with stage A disease, 20% stage B, 13% stage C, 17% stage D, and 2% stage DS. Seventy-five patients have been followed for greater than 4 years. A posterior mediastinal mass was diagnosed on incidental chest roentgenograms performed for nontumor-related symptoms in 49% of the cases. Sixteen percent of the cases presented with neurological symptoms and 14% of the patients presented with acute respiratory distress. Urinary catecholamines were elevated in 76% of the cases. Complete surgical resection was carried out in 47% of the cases, while incomplete resection or biopsy was performed in 45%. No operation was performed in 3 patients. Minor surgical complications occurred in 20% of the patients, and 3% of the patients had significant perioperative complications. One patient died as a complication of therapy. Overall actuarial survival was 88% at 4 years. This study confirms the favorable outcome in children with mediastinal neuroblastoma. The basic biology of thoracic neuroblastomas seems to differ from that of other sites in that the majority of patients present at a younger age with localized disease or regional lymph node metastases, and have an improved survival even after correcting for age and stage. While complete excision is recommended, if possible, radical surgical procedures are not indicated since an excellent prognosis is associated with combined modality therapy.

Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study.

PURPOSE: Infants less than or equal to 1 year of age with neuroblastoma (NB) have a favorable outlook with minimal to moderate therapy. Patients with complete or partial removal of the primary tumor but positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) have a higher risk for recurrent disease. To determine the importance of distinguishing infants with POG stage C NB from those with POG stage B disease and to assess the efficacy and toxicity of treating POG stage C infants with limited, postoperative chemotherapy, a study was conducted by the POG. PATIENTS AND METHODS: Forty-four eligible POG stage C infants received cyclophosphamide 150 mg/m2 orally on days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR), every 3 weeks for five courses followed by second-look surgery. No continuation therapy was given if surgical and pathologic complete response (CR) was achieved. Secondary therapy with five courses of cisplatin 90 mg/m2 on day 1 followed by teniposide (VM-26) 100 mg/m2 on day 3 (CDP/VM) was given to infants with gross residual tumor after CYC/ADR and second-look surgery. RESULTS: Thirty-four infants achieved CR after CYC/ADR alone, three after CYC/ADR and second-look surgery, two after CYC/ADR, surgery, and maintenance therapy, and two after alternative treatment with CDP/VM (total CR rate, 42 of 44). The 3-year survival and disease-free survival are both 93%. Toxicity was nominal. CONCLUSIONS: Infants with POG stage C NB have a favorable outlook, which is similar to infants with POG stage B NB; the surgical staging procedure for distinguishing these infant subsets may not be necessary. Future studies should focus on the reduction of treatment toxicity and efficacy maintenance, and address methods to identify infants at risk for failure.

Age-linked prognostic categorization based on a new histologic grading system of neuroblastomas. A clinicopathologic study of 211 cases from the Pediatric Oncology Group.

Histologic sections (minimum of four sections per patient) from 211 patients with neuroblastoma were reviewed. The tumors were resected before therapy, which was standardized according to age and stage. Low mitotic rate (MR) (less than or equal to ten per ten high-power fields) and calcification emerged as the most significant prognostic features after statistical analysis by stepwise log-rank tests (P less than 0.0001 and P = 0.0065, respectively). Histologic Grades 1, 2, and 3 were defined on the basis of the presence of both, any one, or none of these two prognostic features, respectively (Grade 3 had absence of low MR, i.e., these tumors had high MR [greater than ten per ten high-power fields]). Statistically significant differences in survival were observed in the grades after adjusting for age and stage (P less than 0.001). The degree of differentiation, although significant by itself, was no longer significant after adjusting for the grades. Age groups (less than or equal to 1 versus greater than 1 year of age), which also emerged as an independent prognostic feature (P less than 0.001), were linked with the grades to define two risk groups as follows: (1) a low-risk (LR) group consisting of patients in both age groups with Grade 1 tumors and patients 1 year of age or younger with Grade 2 tumors and (2) a high-risk (HR) group consisting of patients older than 1 year of age with Grade 2 tumors and patients in both age groups with Grade 3 tumors. The difference in survival between LR (160 cases) and HR groups (51 cases) was statistically significant (P less than 0.001). Concordance between these LR and HR groups and the Shimada classification was observed in 84% of cases. The new histologic grading system has the following advantages: (1) use of familiar terminology and histologic features in the grading system and (2) relative ease of assessment because the degree of differentiation does not need to be determined. The grading system should be tested on a new data set with an appropriate histologic sample of similar size to confirm these results.