Purpose To provide an update on long-term survival of patients with high-risk neuroblastoma treated with tandem cycles of myeloablative therapy and peripheral-blood stem-cell rescue (PBSCR). Patients and Methods Ninety-seven patients with high-risk neuroblastoma were treated between 1994 and 2002. Patients underwent induction therapy with five cycles of standard agents, resection of the primary tumor and local radiation, and two consecutive courses of myeloablative therapy (including total-body irradiation) with PBSCR. Results Fifty-one patients have experienced relapse or died. Median follow-up time among the 46 patients who remain alive without progression is 5.6 years (range, 15.1 months to 9.9 years). Progression-free survival (PFS) rate at 5 years from diagnosis was 47% (95% CI, 36% to 56%), and PFS rate at 7 years was 45% (95% CI, 34% to 55%). Overall survival rate was 60% (95% CI, 48% to 69%) and 53% (95% CI, 40% to 64%) at 5 and 7 years, respectively. The 5- and 7- year PFS rates from time of first transplantation for 82 patients who completed both transplants were 54% (95% CI, 42% to 64%) and 52% (95% CI, 40% to 63%), respectively. Five patients died from treatment-related toxicity after tandem transplantation. Relapse occurred in 37 (42%) of 89 patients, mainly within 3 years of transplantation and primarily in diffuse osseous sites. No primary CNS relapse or secondary leukemia was seen. One patient developed synovial cell sarcoma 8 years after therapy. Conclusion High-dose therapy with tandem autologous stem-cell rescue is effective for treating high-risk neuroblastoma, with encouraging long-term survival. CNS relapse and secondary malignancies are rare after this therapy.

Purpose/Objective: To evaluate event-free (EFS) and overall survival (OS) and to assess early and late complications in children and adolescents with favorable, early stage Hodgkin's disease (HD) who are treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy and low–dose, involved–field radiation therapy (IF RT). Materials/Methods: 110 children from three participating institutions (St. Jude, Stanford, Dana Farber) who presented with nonbulky, clinical stage I–II, favorable, (low risk) HD underwent clinical staging and were treated with four cycles of VAMP and 15 Gy IF RT for those who achieved a complete response, or 25.5 Gy for those with a partial response after two cycles of chemotherapy. Results: Patient characteristics included: 75 boys, 35 girls; 77 had classic HD, 33 lymphocyte predominant disease. The stage was I in 36 children, II in 74; 53 had a mediastinal mass. Involved nodal sites were: 1 site–34 children, 2 sites–46, 3 sites– 20, 4–6 sites–10. Laboratory studies revealed: ESR > 20 mm/h in 46 children; hemoglobin 10.5 g/dl in 4 children. The median age at study entry was 13 years (range 3–20). The response to 2 cycles of VAMP was 100 %; 49 achieved a complete response, 61 a partial response. With median follow-up of 8.9 years (range 1.7–13.7 years), the 5 year and 10 year OS are 99 % (SE 0.009) and 97 % (SE 0.029). The 5 year and 10 year EFS are 93 % (SE 0.026) and 91 % (SE 0.047). This out patient treatment is well tolerated. Blood product transfusions and hospital admissions for neutropenic fever are rare. Hair thinning is uncommon. There have been no serious bacterial infections. Two malignant tumors have been observed: One thyroid cancer 8 years after 25.5 Gy to the neck occurring within the RT field; one Ewing 's sarcoma occurring 4 years after treatment, outside the RT field. Offspring include 14 healthy babies among 107 survivors, indicating maintenance of fertility. One–quarter of irradiated patients developed laboratory evidence of hypothyroidism, easily corrected with medication. Growth abnormalities are subtle and appear to be restricted to children < 10 years old, who received doses > 15 Gy, to volumes that included the entire clavicle. There have been no cardiac, neurologic or symptomatic pulmonary abnormalities observed. Conclusions: Four cycles of VAMP and 15–25.5 Gy IF RT is effective in pediatric low–risk HD confirming that these children can be cured with limited therapy that does not include an alkylating agent, bleomycin, etoposide, or high–dose, extended field RT. With this favorable outcome, our current low–risk protocol now tests the need for RT in children/adolescents who achieve an early complete response to 2 cycles of VAMP chemotherapy.

Background/Purpose: The treatment approach for patients with high-risk neuroblastoma has been one of dose intensification chemotherapy and aggressive treatment of the primary tumor. Local tumor control is examined in high-risk patients treated with tandem stem cell transplant, aggressive surgery, and selected radiation therapy (XRT).Methods: Seventy-six patients with high-risk stage III/IV neuroblastoma were treated on a standard protocol incorporating aggressive surgical resection with or without local XRT followed by tandem high-dose chemotherapy and stem cell rescue. Patients were evaluated for degree of surgical resection, site of progression, and outcome.Results: Overall event-free survival for the series is 56%. Forty-eight had gross total resection, 12 had greater than 90% resection, 10 had 50% to 90% resection, and 6 had biopsy only or no surgery. Surgical complications occurred in 29% with no deaths. There were no isolated local failures. Two patients had local recurrence after gross total resection. Surgeon assessment of completeness of resection agreed with postoperative radiological findings 66% of the time.Conclusion: Aggressive surgical treatment with local XRT and myeloablative chemotherapy with stem cell rescue provides excellent local control in high-risk neuroblastoma, although distant failures, particularly osseous, remain a problem. Poor correlation exists between the surgeon's perception of completeness of resection and findings on postoperative imaging studies. (c) 2005 Elsevier Inc. All rights reserved.

Prior studies of non-T-cell-depleted (TCD) transplantation have demonstrated a reduction in relapse in patients receiving escalated doses of TBI; however, overall survival in these studies was not significantly improved due to increased treatment-related toxicity seen at the higher doses of irradiation. Toxicity was in part related to an increased incidence of GVHD. Because T-cell depletion of donor bone marrow reduces the incidence of GVHD and other treatment-related complications after allogeneic bone marrow transplantation, it was postulated that TBI dose may be safely escalated in this setting and may decrease the risk of relapse following TCD BMT. Herein, we report the results of a trial assessing the safety and impact of escalated doses of TBI after TCD BMT. Two hundred adults with hematologic malignancies were treated in consecutive cohorts defined by increasing doses of TBI (1400, 1480, and 1560 cGy) in combination with cyclophosphamide. In vitro T-cell depletion using anti-CD6 monoclonal antibody was used for GVHD prophylaxis. The incidence of grade II or greater acute GVHD in patients receiving 1560 cGy (36%) was significantly higher than in patients receiving 1400 cGy (18%) (P = .04) or 1480 cGy (13%) (P = .01). Two-year treatment-related mortality was significantly higher in patients who received 1560 cGy of TBI (33%) than in those who received 1400 cGy (20%) (P = .04) or 1480 cGy (19%) (P = .05). The increased dose of TBI did not reduce the rates of relapse, with the estimated 2-year risk of relapse being 24% (1400 cGy), 24% (1480 cGy), and 31% (1560 cGy) for the 3 cohorts of patients. Overall survival at 2 years was inferior for patients receiving 1560 cGy of TBI (36%) compared with those who received 1400 cGy (55%) or 1480 cGy (58%) (P = .01). We conclude that dose escalation of TBI is associated with increased GVHD and inferior survival following TCD BMT. Future efforts to reduce the risk of relapse after TCD BMT should focus on immunologic methods to induce the graft-versus-leukemia effect after BMT rather than intensification of the ablative regimen by escalation of irradiation dose.

Purpose: Risk-adapted combined modality therapy with chemotherapy and radiotherapy is currently recommended for children with Hodgkin's Disease, but analyses of prognostic factors upon which these treatments should be based are lacking. A number of pretreatment factors were reported to correlate with survival in adult patients with advanced Hodgkin's Disease and from these, a prognostic score was devised (Hasenclever D and Diehl V, A Prognostic Score for Advanced Hodgkin's Disease. N Engl J Med 1998;339:1506-14).We report an analysis of pre-treatment factors for their prognostic significance in children with Hodgkin's Disease enrolled on a collaborative study of risk-adapted therapy. Materials and Methods: Three hundred twenty pediatric patients (median age 14 years) with clinical stage I-IV Hodgkin's Disease were treated with chemotherapy and low dose involved-field radiotherapy on a risk-adapted protocols at three institutions between 8/90 and 2/00. Pretreatment factors (age ≤ vs ≥ 14 years, gender, stage, histology, presence of 'B' symptoms, WBC ≤ vs ≥ 11,500/mm3, hemoglobin ≤ vs ≥ 11.0 g/dl, ESR ≤ vs ≥ 50 mm/hr, presence of extranodal disease and presence of bulky disease) were analyzed by univariate (UV) and multivariate analysis (MV) for prognostic value for 5-year disease-free (DFS) and overall survival (OS). Based on factors significant for inferior DFS by MV, a prognostic index was then developed to identify patients with significantly worse outcome. Results: With a median follow-up of 53 months (2.3-120 months), the 5-year DFS and OS for all patients were 84% and 92%, respectively. By UV, stage IV, nodular sclerosing histology, presence of 'B' symptoms, WBC ≥ 11,500/mm3, hemoglobin ≤ 11.0 g/dl, bulky mediastinal disease, extranodal disease and ESR≥50 mm/hr were significant for inferior DFS and OS. By MV, male gender, stage IIB, IIIB or IV disease, WBC ≥ 11,500/mm3 and hemoglobin ≤ 11.0 g/dl were significant for inferior DFS and OS. A prognostic index incorporating the four significant factors from the MV was then developed. The respective 5-year DFS and OS for the group of children with: 0-1 factor was 94% and 96%; 2 factors was 78% and 95%; 3 or more factors was 63% and 77%. The DFS and OS for the latter group was significantly worse than those with 0-2 factors (p ≤ 0.001). Conclusion: Risk-adapted combined modality therapy in children with Hodgkin's Disease yields excellent results overall. However, there remain some children with a poor outcome using current therapy. Our analysis of clinically staged children treated on multi-institutional risk-adapted combined-modality protocols, identified several pretreatment factors correlated with survival which were used to develop a prognostic index to identify patients with a significantly inferior outcome. These results may be useful to further refine risk groups so to better tailor therapy, identifying those who need the most aggressive treatment, with the goal of improving their outcome, while reducing treatment and treatment-related toxicity for the others.

PURPOSE:The role of donor marrow T-cell depletion (TCD) in preventing graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic marrow remains undefined. Because different TCD methodologies differ in the degree and specificity with which T cells are removed, it is likely that transplant outcomes would depend on which technique is used. Herein, we report results in the first 48 recipients of unrelated marrow using CD6+ TCD as the sole form of GVHD prophylaxis.PATIENTS AND METHODS:Median age of patients was 46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14 Gy). To facilitate engraftment, patients also received 7.5 Gy (22 patients) [corrected] or 4.5 Gy (26 patients) [corrected] of total lymphoid irradiation (TLI) before admission. No additional immune suppressive prophylaxis was administered. Granulocyte colony-stimulating factor was administered daily from day +1 to engraftment.RESULTS:All 48 patients demonstrated neutrophil engraftment. An absolute neutrophil count of 500 x 10(6)/L was achieved at a median of 12 days (range, 9 to 23 days). There were no cases of late graft failure. The number of CD34+ cells infused/kg was associated with speed of platelet and neutrophil recovery. The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in 42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day 100 was 19%. There have been only five relapses. Estimated 2-year survival was 44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50 years of age. In multivariable analysis, age less than 50 years (P =.002), cytomegalovirus seronegative status (P =.04), and early disease status at bone marrow transplant (P =.05) were associated with superior survival.CONCLUSION:CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis results in an incidence of GVHD that compares favorably with many adult studies of unrelated transplantation using unmanipulated marrow and immune-suppressive medications, especially in light of the median age of our patients (46 years). Although event-free survival in patients less than 50 years of age is very encouraging, older patients experience frequent transplantation-related complications despite TCD.

Purpose: To analyze the sites of relapse, relapse-free survival and overall survival in children with Groups I, II and III rhabdomyosarcoma treated with and without radiation therapy. Materials and Methods: Between 1980-1997, 135 children with rhabdomyosarcoma were evaluated at the Dana-Farber Cancer Institute. Of these, 66 had Group I, II or III disease and received their treatment with surgery, chemotherapy and/or radiation therapy at the DFCI and the Children’s Hospital of Boston. Median follow-up was 8.2 years. Patient characteristics included: median age 5 years; male (73%), female (27%); group I (17%), group II (7%) and group III (76%); sites of orbit (9%), bladder/prostate (24%), genito-urinary non-bladder/prostate (23%), parameningeal head/neck (12%), non-parameningeal head/neck (14%), and trunk/extremity (18%); and pathologic subtypes of embryonal (67%), alveolar (23%), and undifferentiated (11%). All Group I and II patients underwent a gross total resection (GTR) prior to chemotherapy or radiation therapy. Patients with Group III disease received approximately 3 months of induction chemotherapy followed by local treatment and further chemotherapy for a median total duration of 11.5 months. Median radiation dose for all patients was 5350 cGy. Two of 11 Group I patients and 4 of 5 Group II patients received radiation. For Group III patients, local treatment included a GTR alone in 9 (14%), GTR plus radiation (RT) in 15 (26%), partial resection plus RT in 6 (8%), and RT alone in 20 (41%). Of the 9 patients treated with GTR alone, sites included bladder/prostate (4), non-parameningeal head/neck (3), and trunk (2) and histologies were embryonal (7) and alveolar (2). One of the 9 treated with GTR alone to a non-parameningeal site with alveolvar histology relapsed regionally. Overall, 15 of 66 patients relapsed at local (4), regional (4) and distant (7) sites. Covariates included sex, age, site, duration of chemotherapy, presence of a gross total resection, lymph node status, embryonal histology and treatment with radiation. Fisher’s exact test was used to determine relationships between covariates, and relapse-free survival, overall survival and whether or not radiation therapy was given. Univariate and multivariate Cox proportional hazards models determined significant predictors of relapse-free and overall survival. Kaplan-Meier graphs estimated relapse-free and overall survival for all Groups and for patients with a gross total resection according to treatment with or without radiation. Log rank tests assessed differences between the Kaplan-Meier curves. Results: The Kaplan-Meier estimate of 7 year overall survival for all patients was 80% (+− 6%) and relapse free survival was 73% (+− 7%). There was no statistically significant difference in overall or relapse free survival between those patients treated with and without radiation stratified by group. Univariate Cox regression analysis revealed that gross total resection was a significant positive predictor of relapse free survival (p=0.04). Other positive predictors for relapse-free survival included embryonal histology (p=0.0002) and favorable site (p=0.038). On multivariate analysis stratified by group, the most significant predictor was embryonal histology for both relapse free survival and overall survival (p=0.0052). Conclusion: We conclude that a gross total resection should be performed in all feasible cases, including patients initially presenting with group III rhabdomyosarcoma treated with induction chemotherapy. Though current guidelines recommend radiation for Group III rhabdomyosarcoma patients after a GTR, we found that for a select group of children with embryonal histology, surgery alone may be adequate local therapy.

Purpose: To quantify the long-term risk of developing a second malignancy (SM) after Hodgkin’s disease (HD), to determine its timing with respect to initial HD therapy, and to identify factors contributing to that risk. Methods: Between 1969 and 1997, 1445 patients were treated for clinical stage IA to IVB HD. The relative risks (RR) and absolute excess risks (AR, expressed as number of excess cases per 10,000 person-years) were determined using SEER data. The effect of treatment exposure on the RR of SM was evaluated using the chi-square test. Results: Median follow-up time was 12 years. A total of 199 SM and 24 third malignancies were observed (non-melanoma skin cancers excluded). The median times to development of leukemia, non-Hodgkin’s lymphoma (NHL) and solid tumors were 4.8, 7.3, and 12.7 years, respectively. The RR and AR for selected tumor types are summarized in the table. The 3 most common solid second tumors were breast, lung and gastrointestinal cancer. Other solid tumors with significantly elevated RR were sarcoma, head and neck cancer, melanoma and thyroid cancer. The RR for breast cancer in women diagnosed with HD at age < 15, 15-19, 20-25, 26-29, 30-35 was significantly increased at 110.8, 31.01, 16.4, 8.3, and 3.7, respectively, but it was not significantly elevated in women diagnosed after age 35. The difference in RR of SM overall between male and female patients was not statistically significant. The RR of SM at 0-5, 5-10, 10-15, 15-20 and > 20 years after initial treatment were significantly elevated at 2.1, 3.3, 3.9, 7.2 and 11.4, and the corresponding AR were 22.9, 56.5, 85.5, 222.4 and 449.2, respectively. We then limited the analysis to the 1047 patients with > 10 years of follow-up and analyzed by treatment. The RR of SM after radiation therapy alone was significantly lower than that after combined modality therapy (RR= 3.9 vs 5.9, p=0.02). However, the difference in RR was not significant between patients who relapsed and received salvage therapy after initial radiation therapy (RR=5.0), or after initial chemotherapy/combined modality therapy (RR=6.2, p=0.63). The 5-year survival rates in patients who developed leukemia, NHL and solid tumors after HD were 4.1%, 53.2%, and 41.4%, respectively. Conclusion: The risk of SM after HD remains significantly increased beyond 20 years after initial treatment. Strategies to reduce overall HD treatment exposure are needed to lower the risk. Furthermore, patients at high risk for SM need to be identified and targeted for more intensive surveillance and follow-up. Tabled 1Second MalignancyObservedExpectedRR (95% C.I.)AR (/10,000 person-yrs)All Sites19944.844.4 (3.9, 5.1)91.3Acute Leukemia270.3285.7 (56.0, 121.1)15.8NHL261.6315.9 (10.3, 23.1)14.4Multiple Myeloma30.387.9 (1.6, 23.0)1.6Solid Tumors14241.753.4 (2.9, 4.0)59.4Breast396.406.1 (4.3, 8.1)19.3Lung275.325.1 (3.3, 7.2)12.8Gastrointestinal257.103.5 (2.4, 5.1)10.6 Open table in a new tab

The outcome for 82 pediatric patients with Ewing sat-coma (ES) and primitive neuroectodermal tumor (PNET) of bone is reported; the patients were treated at the Dana-Farber Cancer Institute (DFCI) and Children's Hospital (CH) in Boston, MA (USA) from 1971-1988. The charts of all patients with ES/PNET of bone treated during this period were reviewed for disease status, therapy, sites of relapse, information on second malignancies, and survival status. Eighty-two patients with ES/PNET of bone treated at DFCI/CH were identified. The 10-year event-free survival (EFS) rates were 12% (95% confidence interval [CI] 0, 27%) and 38% (95% CI 26, 51%) for patients with and without metastases, respectively (P = 0.002), the overall survival(OS) rates were 17% (95% CI 1, 33%) and 48% (95% CI 35, 61%) for patients with and without metastases (P = 0.001). Median follow-up for surviving patients is 10.2 years. Primary site in the pelvis also was associated with a poor outcome for patients with no metastatic disease (P = 0.006 OS, P = 0.03 EFS). Thirty-one patients survived in first remission at least 5 years from diagnosis, and of these, five experienced relapse of original disease, and five experienced secondary malignancies. Pediatric patients treated for ES/PNET of bone remain at risk for life-threatening events into the second decade of follow-up. After 5 years, the risk of second malignant neoplasm is at least as high as the risk of late relapse. Prolonged follow-up of patients with ES and PNET of bone is indicated.

Stern, J. W.*; Mogul, M.*; Adams, R.*; Grier, H.; Gorlin, J.*; Marcus, K.*; Weinstein, H.*; Diller, L.*; Grupp, S. A.*; Brodeur, G. M. Author Information

Purpose: Patients with relapsed acute myelogenous leukemia (AML), who are not eligible for bone marrow transplantation, have a poor prognosis when treated with chemotherapy alone. Total body irradiation (TBI) is an effective modality against AML when used in doses of 1000-1400 cGy with hematopoietic stem cell support. We undertook a phase I study of TBI with granulocyte-colony-stimulating factor (G-CSF) support, without stem cell support in patients with AML either in relapse or second or subsequent remission.Methods and Materials: Patients with relapsed AML, or AML in second or subsequent remission were treated in a phase I study of TBI followed by G-CSF, The first dose level was 200 cGy, After the initial cohort of patients it was clear that patients with overt leukemia did not benefit from this treatment, and subsequent patients were required to be in remission at the time of TBI.Results: Eleven patients were treated, 4 in overt relapse, and 7 in remission. 200 cGy was used in all, and dose escalation was not possible due to prolonged thrombocytopenia in all patients but one. Neutrophil recovery was adequate in those patients who remained in remission after TBI. Patients with overt leukemia had transient reduction in blast counts, but rapid recurrence of their leukemia. Patients treated in remission had short remissions, with the exception of one patient who is in remission 32 months after treatment,Conclusion: There is some antileukemic effect of TBT even at 200 cGy, though this dose appears to be too low to help a significant number of patients. If TBI is to be escalated without stem cell support, then a thrombopoietic agent will need to be used. (C) 1998 Elsevier Science Inc.

The appropriate timing of bone marrow transplantation (BMT) for adults with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) is controversial. Although allogeneic transplantation results in a lower risk of disease recurrence than intensive chemotherapy alone, overall outcome following BMT may not be improved due to the higher incidence of therapy-related fatal complications, frequently as a result of the development of graft-versus-host disease (GVHD). Selective T-cell depletion of donor marrow can reduce the incidence of GVHD and thereby limit transplant-related toxicity. Herein we report the risk of GVHD, incidence of transplant related mortality (TRM), likelihood of disease relapse, and overall survival in adult patients undergoing BMT with CD6 depleted allogeneic marrow for acute leukemia in first remission. Forty-one consecutive allogeneic transplants were performed on patients with acute leukemia and high-risk features (28 AML, 13 ALL) using T12 monoclonal antibody and complement to remove CD6+ T cells from donor marrow. No pre- or posttransplant immune suppressive medications for GVHD prophylaxis were administered. The actuarial estimated risk of grade 2 to 4 acute GVHD was 15% in patients receiving HLA identical grafts. Chronic GVHD developed in five patients. The estimated risk of TRM for patients in first complete remission was 5% at Day +100 and 16% at 2 years. Fatalities attributable to infection with cytomegalovirus or Epstein-Barr virus occurred in only three patients. Estimated probabilities of relapse, overall survival, and event-free survival at 4 years were 25%, 71%, and 63%, respectively. No significant differences in GVHD, TRM, relapse rate, or survival was observed for patients with AML compared with those with ALL. Allogeneic transplantation with CD6 depleted bone marrow is effective in consolidating remissions of high-risk patients with acute leukemia in first remission without excessive toxicity.