Stephen J. Shochat

Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study.

PURPOSE To estimate the duration of survival (S) of patients with metastatic osteosarcoma (MOS) at diagnosis treated with a multiagent, ifosfamide-containing chemotherapeutic and surgical regimen and to evaluate the toxicity of this regimen. PATIENTS AND METHODS Thirty patients aged younger than 30 years received two courses of ifosfamide followed by surgery on the primary tumor and metastatic sites. Patients then received a postsurgical multiagent chemotherapeutic regimen that consisted of high-dose methotrexate (HDMTX), ifosfamide, doxorubicin, and cisplatin. RESULTS The 5-year event-free survival (EFS) rate was 46.7% (95% confidence interval [CI]; 28.5 to 64.9) and 5-year S rate was 53.3% (95% CI; 35.1 to 71.5). Three patients with bone metastases and one patient with lymph node metastases died. Twenty-six patients presented with pulmonary metastatic nodules only. Eight of these patients had at least eight nodules at diagnosis and had an estimated 5-year EFS rate of 25.0% compared with 66.7% for the 18 patients with less than eight nodules (P=.06). Fourteen patients presented with bilateral lung metastases and had a 5-year EFS rate of 35.7% compared with the 12 patients who presented with unilateral involvement and had a 5-year EFS rate of 75.0% (P=.03). The hematopoietic toxicity experienced by the patients during the entire regimen was relatively mild. Seven patients had renal toxicity characterized by hypophosphatemia and/or hypokalemia. CONCLUSION This ifosfamide-containing regimen is tolerable and effective in the treatment of patients with osteosarcoma (OS) who present with lung metastases. However, better regimens are required for this group of patients.

Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study.

A prospective study was designed to evaluate the outcome of patients with localized resectable neuroblastoma without regional lymph node involvement when no therapy beyond surgical resection was administered. One hundred one patients observed for 3 to 60 months had a 2-year disease-free survival of 89% (SE = 5%). Of the nine patients experiencing relapse, only three have died. There were no apparent distinguishing characteristics of the nine failures. Due to the favorable prognosis of the subset of neuroblastoma patients, prognostic factor analysis had very limited power and lacked clinical importance. Complete gross removal of the localized tumors is adequate therapy to ensure the survival of the majority of these patients.

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) (≤ ten per ten high‐power fields) and calcification emerged as the most significant prognostic features after statistical analysis by stepwise log‐rank tests (P < 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 [> ten per ten high‐power fields]). Statistically significant differences in survival were observed in the grades after adjusting for age and stage (P < 0. 001). The degree of differentiation, although significant by itself, was no longer significant after adjusting for the grades, Age groups (≤ 1 versus > 1 year of age), which also emerged as an independent prognostic feature (P < 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 < 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.

Intracaval and Atrial Involvement with Nephroblastoma: Review of National Wilms Tumor Study-3

We reviewed the records of 77 children enrolled in the National Wilms Tumor Study-3 who had involvement of the inferior vena cava with tumor thrombus. None of these patients received preoperative chemotherapy or radiotherapy. Ultrasonography and inferior venacavography were more helpful than computerized tomography in the preoperative diagnosis. The median followup for the group was 2.7 years. The 3-year survival rates for patients with intracaval involvement were determined by stage (88, 89 and 62 per cent for stages II, III and IV, respectively). The most important prognostic factor was histological type. The level of vena caval involvement had no effect on survival; all 16 patients with atrial involvement survived 3 or more years. We continue to recommend appropriate surgical excision of the tumor and thrombus when it is technically feasible.

Peritoneal drainage as primary management of perforated NEC in the very low birth weight infant

Advances in perinatal and neonatal care in the past decade have produced a change in the population of infants with perforated necrotizing enterocolitis (NEC) treated at our institution: the majority are now of very low birth weight (VLBW, < 1,000 g). Peritoneal drainage has been reported as an initial resuscitative procedure for unstable infants who have complicated NEC. Initial success with peritoneal drainage prompted us to adopt an aggressive approach to its use in this patient population. Since 1987, peritoneal drainage has been the primary treatment for most infants weighing less than 1,500 g who have perforation, and for unstable infants weighing more than 1,500 g. Perforation was documented by pneumoperitoneum or aspiration of meconium by paracentesis. Intestinal resection was performed in most infants weighing more than 1,500 g and in those for whom drainage was ineffective. Twenty-nine infants with low or VLBW (mean gestational age, 27 weeks; mean birth weight, 994 g) were treated with one or two drains in the right lower quadrant. Broad spectrum antibiotics were continued until all drains were removed, usually within 10 to 14 days. Nasogastric suction was continued until patency of the gastrointestinal (GI) tract was confirmed by a nonionic upper GI series. Six (21%) infants died, although one of the deaths occurred 5 months after drainage; the patient had chronic lung disease and an intact GI tract. Seventeen of the 23 (74%) survivors required no further operative procedure, and 6 (26%) required laparotomy and resection because drainage had been ineffective. Peritoneal drainage provided definitive treatment in 18 of 29 (62%) infants in this series.(ABSTRACT TRUNCATED AT 250 WORDS)

Management of septic complications associated with silastic® catheters in childhood malignancy

From January, 1979, to December, 1984, 63 Hickman or Broviac catheters were inserted into 50 high risk pediatric oncology patients (median age, 37 months). Catheters remained in place for an average of 241 days. Possible catheter sepsis and exit site infection accounted for the majority (39 of 76) of the complications of long term central venous catheterization. Neutropenia (absolute neutrophil count under 500/mm3) was associated with 70% of the catheter-related infections and 75% of the non-catheter-related infections. Catheters inserted during neutropenic episodes (23) were associated with an increased risk of subsequent septicemia (60% vs. 25%), a finding apparently related to their exposure to further neutropenia (38% vs. 16% catheter days). Of the 32 episodes of septicemia of unknown origin, 19 involved Gram-negative bacteria, 14 involved Gram-positive bacteria and 4 were caused by fungi. Five of these episodes involved multiple organisms. Staphylococcus epidermidis was the most common Gram-positive organism isolated (7 of 14). Four episodes of septicemia resolved before therapy and are considered false positive cultures. Of the other 28 episodes of septicemia, 25 (89%) were successfully treated without catheter removal including 3 episodes of fungemia and 4 of multiple organism sepsis. These data demonstrate the efficacy of antimicrobial treatment without catheter removal in the pediatric oncology population with catheter-associated infections including those associated with neutropenia, multiple organisms and fungemia.

Minimally Invasive Surgery in Pediatric Cancer Patients

AbstractBackground: The specific use of minimally invasive surgery (MIS) in pediatric cancer patients is limited. We evaluated the 5-year experience at a single institution with MIS in children with malignancies. Methods: A retrospective review was undertaken of all MIS performed between November 1995 and October 2010434_2004_Article_340. Results: A total of 101 pediatric oncology patients underwent 113 MIS procedures—64 laparoscopic (57%) and 49 thoracoscopic (43%)—during this period. Laparoscopy was performed for diagnostic purposes in 27 cases (42%) and was successful in 25 (93%) cases. Laparoscopic tumor resection was performed in seven cases (11%). Thirty additional laparoscopic procedures (47%) were attempted for complications of the malignancy or its treatment. Four of these cases were converted to open laparotomies. Indications for thoracoscopy included the evaluation of a mediastinal mass (n = 7) or biopsy or resection of pulmonary lesions (metastatic, n = 31; infectious, n = 9). Fourteen cases (29%) had to be converted to open thoracotomy procedures, generally because of the inability to localize a lesion. The other 35 procedures were successful. The overall complication rate was 5%. No trocar site recurrences or infections were observed. Conclusions: We conclude that MIS in pediatric cancer patients is a safe and effective diagnostic modality. The role of MIS for primary tumor resection remains to be defined.

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.

Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group Trial.

Purpose Relapse remains a significant problem in patients with metastatic osteosarcoma. The response to carboplatin of patients with newly diagnosed metastatic or unresectable osteosarcoma was assessed in an upfront phase II window, which was followed-up by surgery and intensive multiagent chemotherapy. Patients and Methods Thirty-seven patients, ages 3 to 23 years with histologically confirmed diagnoses of osteosarcoma, were treated between January 1992 and November 1994 with carboplatin 1,000 mg/m2 per dose administered as a 48-hour continuous infusion. Two courses were administered in 3-week intervals, depending on marrow recovery. After radiographic reevaluation, patients underwent surgical removal of tumor (if feasible) and then 40 weeks of chemotherapy with high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin. Results One of the 37 evaluable patients demonstrated a partial response to carboplatin; there were no complete responses. Patients were additionally analyzed by the response of pulmonary metastases to therapy and the extent of tumor necrosis of the primary lesion. By these criteria, 8 of 37 (22%) of patients showed a response at one or more sites, whereas 20 of 37 (54%) had unequivocal disease progression. Severe myelosuppression was the major toxicity. The projected 3-year event-free and overall survival rates were 23.9% and 31.9%, respectively. Only 1 of 17 patients with unresectable disease or distant bone metastases remains alive, in contrast to 6 of 17 patients with the lung as their only metastatic site and two of three patients with resected regional bone metastases. Conclusions Continuous-infusion carboplatin demonstrated limited activity as an upfront agent in patients with metastatic osteosarcoma at diagnosis, even at doses that result in severe and prolonged myelosuppression. Patients with isolated pulmonary metastases or resectable bone metastases have a longer median survival time and greater chance of long-term survival than do patients with unresectable bone disease, for whom the prognosis remains dismal.

Biological variables in thoracic neuroblastoma: A Pediatric Oncology Group study

The prognosis for patients with neuroblastoma is related to the age and stage at time of presentation, as well as to the presence or absence of biological markers such as N-myc amplification and the degree of DNA ploidy. However, previous studies have shown that neuroblastoma in the thoracic site also is a favorable prognostic indicator, in that children with mediastinal neuroblastoma have a better survival rate, regardless of age or stage at time of presentation. This study was designed to evaluate the biological differences between thoracic and nonthoracic neuroblastoma with respect to N-myc amplification, DNA index as a measure of DNA ploidy, serum lactate dehydrogenase levels, and serum ferritin levels. Patients enrolled in the Pediatric Oncology Group study protocols for neuroblastoma were evaluated retrospectively, and log-rank analysis allowed the impact of each biological variable on survival to be determined for each cohort of patients. There were 1,335 neuroblastoma patients in the data base; 227 had thoracic-site neuroblastoma. Through analysis, it was apparent that patients with thoracic neuroblastoma have better survival rates than do their nonthoracic counterparts (P < .0001), and they are less likely to have N-myc amplification (P = .001), more likely to have an LDH level of less than 1,500 (P < .0001), and usually have a DNA index of greater than 1 (P < .003). Both thoracic and nonthoracic patients have low serum ferritin levels (86% of thoracic versus 83% of nonthoracic patients).(ABSTRACT TRUNCATED AT 250 WORDS)