Bhaskar N. Rao

Therapy for localized Ewing's sarcoma of bone.

Fifty-two previously untreated patients with localized Ewings sarcoma of bone were treated with nonintensive chemotherapy in combination with surgery or radiation therapy (RT). RT was delivered to limited volumes in a dose dependent on the initial response to induction chemotherapy (30 to 35 Gy v 50 to 55 Gy). Fifty of the 52 patients achieved complete or partial responses with induction chemotherapy, with one nonresponding patient rendered free of tumor with surgery. Fifty patients were evaluable for local control of tumor and overall response to protocol therapy. Seventeen relapses have occurred; three metastatic, four local plus metastatic, and ten local. Two factors predicted worse disease-free survival: high WBC count (P = .03) and size of primary tumor (P = .05). Of the 14 local recurrences, 12 occurred in 28 patients who presented with primary tumors greater than 8 cm in size while only two of 22 patients with lesions less than 8 cm had local recurrence. The Kaplan-Meier estimate of disease-free survival at 3 years is 82% for those with small lesions and 64% for those with larger lesions. Site of primary was of no prognostic value (P = .27). The 5-year survival estimate for all patients is 80% (median time on study, 3.3 years).

A Prospective Study of Hickman/Broviac Catheters and Implantable Ports in Pediatric Oncology Patients

We prospectively studied the continuous function and complication rates of 286 central venous catheters consecutively placed in 264 children and young adults at a single institution over a 19-month period (median follow-up, 376 days). Externalized catheters (91 Hickman [H], 113 Broviac [B]) and implantable ports (n = 82) were compared for complications, including infection and thrombosis. The most frequent major complication of all catheters was infection, although the rates of infection varied with the duration of catheter use and were generally lower than reported by others. Overall, when catheter failures (removal) for infection, obstruction, or dislodgement were considered, ports had a significantly longer failure-free duration of use (P = .0024) than did externalized catheters. Likewise, ports had a significantly longer infection-free (P less than .01) duration of use than H and B catheters. However, differences in patient age and clinical characteristics among the three catheter groups may have affected the outcome. In analysis of pairs matched for diagnosis, therapy, and age, ports had lower infection rates than did B catheters after 100 days (P = .053). This difference became significant at 400 days of catheter use (P = .029). Although there was a trend toward lower rates of infections for ports v H catheters, this difference was not significant. In view of our results in matched pairs, selection of catheter type based on clinical characteristics and patient preferences remains a reasonable therapeutic approach despite the apparent advantages of ports. The superiority of ports for long-term use (greater than 100 days) needs to be confirmed in a large randomized clinical trial.

Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies.

Advances in systemic and local therapies have improved outcomes for patients with the Ewing sarcoma family of tumors (ESFT). As new treatments are developed, a critical review of data from past treatment eras is needed to identify clinically relevant risk groups.

Prognostic Factors for Children and Adolescents With Surgically Resected Nonrhabdomyosarcoma Soft Tissue Sarcoma: An Analysis of 121 Patients Treated at St Jude Children's Research Hospital

PURPOSE The rarity and heterogeneity of pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) has precluded meaningful analysis of prognostic factors associated with surgically resected disease. To define a population of patients at high risk of treatment failure who might benefit from adjuvant therapies, we evaluated the relationship between various clinicopathologic factors and clinical outcome of children and adolescents with resected NRSTS over a 27-year period at our institution. PATIENTS AND METHODS We analyzed the records of 121 consecutive patients with NRSTS who underwent surgical resection between August 1969 and December 1996. Demographic data, tumor characteristics, treatment, and outcomes were recorded. Univariate and multivariate analyses of prognostic factors for survival, event-free survival (EFS), and local and distant recurrence were performed. RESULTS At a median follow-up of 9.2 years, 5-year survival and EFS rates for the entire cohort were 89% +/- 3% and 77% +/- 4%, respectively. In univariate models, positive surgical margins (P =.004), tumor size > or = 5 cm (P <.001), invasivene (P =.002), high grade (P =.028), and intra-abdominal primary tumor site (P =.055) adversely affected EFS. All of these factors except invasiveness remained prognostic of EFS and survival in multivariate models. Positive surgical margins (P =.003), intra-abdominal primary tumor site (P =.028), and the omission of radiation therapy (P =.043) predicted local recurrence, whereas tumor size > or = 5 cm (P <.001), invasiveness (P <.001), and high grade (P =.004) predicted distant recurrence. CONCLUSION In this largest single-institution analysis of pediatric patients with surgically resected NRSTS, we identified clinicopathologic features predictive of poor outcome. These variables should be prospectively evaluated as risk-adapted therapies are developed.

Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979-1999.

Despite improved therapies, 30–40% of patients with Ewing tumors (ET) experience recurrence and have a poor prognosis. The authors analyzed factors prognostic of survival in patients with recurrent ET.

Chemotherapy Dose-Intensification for Pediatric Patients With Ewing's Family of Tumors and Desmoplastic Small Round-Cell Tumors: A Feasibility Study at St. Jude Children's Research Hospital

PURPOSE To evaluate the feasibility of dose-intensification for patients with Ewings family of tumors (EFT) and desmoplastic small round-cell tumors. PATIENTS AND METHODS From February 1992 to June 1996, we treated 53 consecutive patients on our Ewings protocol. Induction comprised three cycles of ifosfamide/etoposide on days 1 to 3 and cyclophosphamide (CTX)/doxorubicin on day 5, followed by granulocyte colony-stimulating factor. Local control using surgery and/or radiotherapy started at week 9 along with vincristine/dactinomycin. Maintenance included four alternating cycles of ifosfamide/etoposide and doxorubicin/CTX, with randomization to one of two CTX dose levels to determine the feasibility of dose-intensification during maintenance. RESULTS Patients had a median age of 13.4 years (range, 4.5 to 24.9 years); 34 patients were male and 43 patients were white. Nineteen patients presented with metastatic disease, 29 had tumors greater than 8 cm in diameter, and 26 had primary bone tumors. These patients received 155 induction cycles, 91% of which resulted in grade 4 neutropenia, 68% in febrile neutropenia, and 68% in grade 3 to 4 thrombocytopenia. During maintenance, grade 4 neutropenia and grade 3 to 4 thrombocytopenia occurred in 81% and 85% of cycles, respectively. Thirty-five patients (66%) completed all therapy, only 13 without significant delays; three developed secondary myeloid malignancies. The toxicity and time to therapy completion were similar in both CTX arms. Estimated 3-year survival and event-free survival were 72%+/-8% and 60%+/-9%, respectively. CONCLUSION Although intensifying therapy seems feasible for 25% of patients on this study, toxicity was considerable. Therefore, the noninvestigational use of dose-intensification in patients with EFT should await assessment of its impact on disease-free survival.

Thoracotomy for pulmonary metastatic osteosarcoma. An analysis of prognostic indicators of survival

Removal of pulmonary metastases of osteosarcoma by thoracotomy is an accepted treatment; however, few investigators have analyzed the value of various prognostic factors in estimating survival. A review of all patients undergoing thoracotomy for recurrent osteosarcoma with pulmonary metastases treated at St. Jude Childrens Research Hospital is reported. Since 1968, two thirds (39/59) of all patients who developed pulmonary metastases have had a total of 66 thoracotomies. Nine patients are alive with no evidence of disease, and six additional patients are alive with disease. Analyzed in 39 evaluable patients, the prognostic factors that correlate with survival by univariate analysis are: sex, number of nodules detected radiographically and resected, completeness of resection, and tumor location (bilateral versus unilateral). By Cox regression analysis, only sex and the number of nodules detected either radiographically or during surgery, and resected, had statistically significant correlation with survival. Thoracotomy is curative for some patients with pulmonary metastatic osteosarcoma and Prognostic factors predictive for survival are defined. Cancer 59:374–379, 1987.

Early multicenter experience with a noninvasive expandable prosthesis.

A noninvasive expandable prosthesis for skeletally immature children after limb salvage surgery has been developed. Between 1998 and 2001, 18 Phenix prostheses were implanted in 15 pediatric patients who had been diagnosed and treated for osteosarcoma about the knee. Of the 15 original prostheses, 10 were implanted at the time of primary tumor resection and five were revisions from an endoprosthetic modular knee system. Sixty expansions of the 18 prostheses were done, with all but two done as outpatient procedures. An average 8.5 mm was obtained per lengthening (range, 1–30 mm). The average followup was 21.5 months (range, 12–33 months) and the latest Musculoskeletal Tumor Society functional scores averaged 90%. Eight revisions were required for stem fracture or loosening. There was one amputation because of a postoperative arterial thrombosis. The principle of the Phenix prosthesis involves storage of energy in a spring compressed by a locking system. Lengthening is achieved via exposure to an electromagnetic field that allows controlled release of the spring. This is a unique expandable custom prosthesis that offers many benefits in maintaining limb length equality in growing patients. Although the early experience is promising, additional data are required regarding the long-term structural integrity of the prosthesis. We are optimistic that this technology will prove beneficial, not only for patients with malignant bone tumors but in applications requiring serial limb length equalizations or for spinal deformities.

EWING'S SARCOMA: LOCAL TUMOR CONTROL AND PATTERNS OF FAILURE FOLLOWING LIMITED-VOLUME RADIATION THERAPY

Sixty children with localized osseous Ewings sarcoma were treated between 1978 and 1988 with induction chemotherapy (cyclophosphamide, adriamycin), irradiation and/or surgery, and 10 months of maintenance chemotherapy (cyclophosphamide, adriamycin, dactinomycin, vincristine). Following induction chemotherapy, 43 patients received primary radiation therapy to limited radiation volumes defined by post-chemotherapy residual soft tissue tumor extension and initial osseous tumor extent. Irradiation was defined as low dose at 30-36 Gy (median 35 Gy) for 31 cases with objective response to induction chemotherapy and high dose at 50-60 Gy (median 50.4 Gy) for 12 patients with poor response to induction chemotherapy or with tumors greater than or equal to 8 cm. Overall event-free survival at 5 years is 59% and local tumor control is 68%. Initial failures have been local (12), simultaneous local and distant failures (7), and distant (6). In the surgical resection group, 14 patients had complete resection without radiation therapy, and 3 patients had microscopic residual plus 35-41 Gy; 100% local control has been maintained. In 43 patients with primary radiation therapy group, local tumor control is 58% (p = .004). Despite limited radiation volume, 18/19 local failures occurred centrally within the bone, well within the radiation volume. Imaging response to induction chemotherapy predicted local tumor control in the radiation therapy group: 62% with complete response/partial response versus 17% with no response/progressive disease (p less than 0.01). Local tumor control related strongly to primary tumor size in the radiation therapy group; among 31 cases receiving 35 Gy, local tumor control is 90% for lesions less than 8 cm versus 52% for tumors greater than or equal to 8 cm (p = .054). The central pattern of local failure in this experience suggests the effectiveness of limited radiation volume. The overall local tumor control rate following the tested dose level of 35 Gy appears to be inadequate, although results in selected cases with tumors less than 8 cm in greatest tumor dimension indicate potential efficacy in a yet limited experience.

Colorectal Carcinoma in Childhood and Adolescence : A Clinicopathologic Review

PURPOSE Pediatric colorectal carcinoma (CRC) is rare, but the available data suggest that it is more likely than adult CRC to be advanced at presentation and to have a poor outcome. We sought to better characterize pediatric CRC. PATIENTS AND METHODS We reviewed the clinical and pathologic features, prognostic factors, and outcome of CRC in 77 children and adolescents (ages 7 to 19 years) referred to St Jude Childrens Research Hospital between 1964 and 2003. RESULTS At presentation, 76 patients had one or more signs or symptoms of CRC (abdominal pain, altered bowel habits, weight loss, anemia). Tumors were evenly distributed between the right and left colon; 62% were mucinous adenocarcinoma. At presentation, 86% of patients had advanced-stage disease; more than half had distant metastases. Overall outcome was poor. Advanced stage and mucinous histology were significant predictors of adverse outcome. Stage-specific survival at 10 years was 67% +/- 27% (stage 1), 38% +/- 15% (stage 2), 28% +/- 11% (stage III), and 7% +/- 4% (stage 4). Although no patient had a diagnosis of polyposis syndrome before diagnosis of CRC, 17 (22%) had colon polyps and eight (including two who previously underwent pelvic radiotherapy) had multiple polyps. CONCLUSION Initial signs and symptoms of CRC are similar in pediatric and adult patients. The strikingly higher frequency of mucinous histology suggests that the biology of CRC differs in pediatric and adult patients and may contribute to poor outcomes. Children should be included in prospective clinical trials for CRC.