Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk of developing life-threatening infections. We investigated whether uniform antibacterial guidelines, including mandatory antibacterial prophylaxis in afebrile patients during induction, decreases the incidence of microbiologically documented bacteremia. METHODS: Between 2012 and 2015, 230 patients with newly diagnosed ALL (aged 1-21) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 11-001 (DFCI 11-001). Induction therapy, regardless of risk group, included vincristine, prednisone, doxorubicin, methotrexate, and PEG-asparaginase. Afebrile patients received fluoroquinolone prophylaxis at the initiation of induction and those presenting with fever received broad-spectrum antibiotics; antibiotics were continued until blood count recovery. Rates of documented bacteremias and fungal infections on DFCI 11-001 were compared to those on the predecessor protocol (DFCI 05-001), which included the same induction phase without antibiotic prophylaxis guidelines. RESULTS: Sixty-six (28.7%) patients received fluoroquinolone prophylaxis, the remaining patients received broad-spectrum antibiotics. Twenty-four (36.4%) patients on prophylaxis developed fever and seven (10.6%) developed bacteremia. The overall rate of infection during induction on DFCI 11-001 was lower than on DFCl 05-001 (14.3% vs. 26.3%, P < 0.0001) due to a decreased rate of bacteremia (10.9% vs. 24.4%, P < 0.0001). The rate of fungal infections (4.8% vs. 3.6%) and induction death (0.9% vs. 2%) was not significantly different. CONCLUSION: For children with newly diagnosed ALL, uniform antibiotic administration until blood count recovery, including fluoroquinolone prophylaxis for afebrile patients, reduced the incidence of bacteremia during the induction phase. Larger, randomized studies should be performed to confirm these findings.

Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia.

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.

Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis.

BACKGROUND: Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin's lymphoma (NHL) that may be cured with intensive chemotherapy. The addition of the CD20-directed monoclonal antibody rituximab to CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, alternating with ifosfamide, etoposide, and cytarabine) has not been studied despite efficacy in other aggressive CD20-positive NHLs. PATIENTS AND METHODS: Eighty adult BL patients treated with or without rituximab were identified at our institutions. Response rate, overall survival (OS), and progression-free survival (PFS) are calculated. RESULTS: There were fewer relapses in rituximab-treated patients (3 of 40 versus 13 of 40, P = 0.01). There was a trend for improvement in outcome favoring rituximab-containing therapy, with 3-year PFS (74% versus 61%) and 3-year OS (77% versus 66%), although these did not reach statistical significance. Advanced age and central nervous system involvement were associated with poorer OS on multivariable Cox regression analysis, adjusting for treatment, human immunodeficiency virus (HIV) involvement, and risk group. CONCLUSIONS: CODOX-M/IVAC, with or without rituximab, is a highly effective regimen for the treatment of adult BL. Rituximab decreased the recurrence rate and showed a trend in favor of improvement in PFS and OS. HIV-infected patients achieved outcomes comparable with those of their non-HIV-infected counterparts.

End-of-treatment but not interim PET scan predicts outcome in nonbulky limited-stage Hodgkin's lymphoma.

BACKGROUND: Early interim positron emission tomography (PET) scans appear powerfully predictive of outcome in Hodgkin's lymphoma (HL), particularly in advanced-stage disease where it has been predominantly studied. The prognostic value of interim PET in limited-stage patients with nonbulky disease has not been well established. PATIENTS AND METHODS: Ninety-six patients with nonbulky limited-stage HL were identified who had interim and end-of-treatment PET scans. Response rate, overall survival (OS), and progression-free survival (PFS) were calculated. RESULTS: Four-year PFS and OS for the entire cohort were 88% and 97%, respectively. Interim PET did not predict outcome, with PFS in positive and negative patients 87% versus 91% (P=0.57), respectively. End-of-treatment PET result was predictive of outcome, with PFS of 94% in end PET-negative patients versus 54% in end PET-positive patients (P<0.0001). Four-year OS was 100% in end PET-negative patients and 84% in end PET-positive patients (P<0.0001). CONCLUSIONS: Interim PET scans were not predictive of outcome, compared with scans carried out at completion of therapy. End-of-treatment PET was highly predictive of PFS and OS, regardless of interim PET result. In this low-risk patient population, even patients with interim positive PET scans show a favorable prognosis.

Intracranial hemorrhage with direct oral anticoagulants in patients with brain tumors.

Essentials Intracranial hemorrhage (ICH) is common in patients with brain tumors. We compared rates of ICH with DOACs and low molecular weight heparin. DOACs were associated with a lower incidence of ICH in primary brain tumors. DOACs appear safe to administer to patients with brain tumors. SUMMARY: Background Direct oral anticoagulants (DOACs) are efficacious in the treatment of cancer-associated thrombosis but are associated with an increased risk of hemorrhage compared with low-molecular-weight heparin in certain malignancies. Whether the DOACs increase the incidence of intracranial hemorrhage (ICH) in patients with brain tumors is not established. Objectives To determine the cumulative incidence of ICH in DOACs compared with Low-molecular-weight heparin (LMWH) in patients with brain tumors and venous thromboembolism. Patients and methods A retrospective comparative cohort study was performed. Radiographic images for all ICH events were reviewed and the primary endpoint was cumulative incidence of ICH at 12 months following initiation of anticoagulation. Results and conclusions A total of 172 patients with brain tumors were evaluated (42 DOAC and 131 LMWH). In the primary brain tumor cohort (n = 67), the cumulative incidence of any ICH was 0% in patients receiving DOACs vs. 36.8% (95% confidence interval [CI], 22.3-51.3%) in those treated with LMWH, with a major ICH incidence of 18.2% (95% CI, 8.4-31.0). In the brain metastases cohort (n = 105), DOACs did not increase the risk of any ICH relative to enoxaparin, with an incidence of 27.8% (95% CI, 5.5-56.7%) compared with 52.9% (95% CI, 37.4-66.2%). Similarly, DOAC did not increase the incidence of major ICH in brain metastases, with a cumulative incidence 11.1% (95% CI, 0.5-40.6%) vs. 17.8% (95% CI, 10.2-27.2%). We conclude that DOACs are not associated with an increased incidence of ICH relative to LMWH in patients with brain metastases or primary brain tumors.

A prospective study of pulmonary function in Hodgkin's lymphoma patients.

BACKGROUND: To prospectively study changes in lung function in Hodgkin's lymphoma (HL) patients and to explore predictors for these changes over time. METHODS: In all, 52 patients with HL receiving bleomycin-based chemotherapy with (n = 23) or without (n = 29) mediastinal radiotherapy were enrolled. Pretreatment pulmonary function tests were carried out. These were repeated at 1 month, 6 months, and 1 year after therapy. RESULTS: With chemotherapy alone, the median %DLCO declined significantly at 1 month but returned to baseline by 6 months. The median %DLCO did not further decrease with radiotherapy, but remained persistently reduced at 1 year. In patients who received radiotherapy, having >33% of lung volume receive 20 Gy (V20) and a mean lung dose (MLD) of >13 Gy significantly predicted for persistently reduced %DLCO at 6 months (P = 0.035). Smoking significantly predicted for a persistently reduced %DLCO at 1 year (P = 0.036). On multivariable analysis, significant predictors for decline in %DLCO at 1 year were higher baseline %DLCO (P = 0.01), higher MLD (P = 0.02), and a smoking history (P = 0.02). CONCLUSIONS: Several factors contribute to decline in %DLCO in HL patients who received bleomycin-based computed tomography. The identification of threshold radiation dosimetric parameters for reduced lung function may provide guidance in the radiation planning of these patients.

Characterization of T cell repertoire in patients with graft-versus-leukemia after donor lymphocyte infusion.

The clinical efficacy of donor lymphocyte infusions (DLI) in patients with relapsed chronic myelocytic leukemia after allogeneic bone marrow transplantation has been demonstrated in several recent studies. Although it is presumed that allogeneic T cells mediate this graft-versus-leukemia (GVL) effect, the influence of DLI on the T cell compartment of recipients has not been determined. To characterize the immunologic effects of DLI and to identify T cell changes selectively associated with the GVL response, we analyzed the T cell receptor (TCR) repertoire in four patients with relapsed chronic myelocytic leukemia who achieved a complete remission after infusion of CD4+ lymphocytes from HLA-identical sibling donors. Only one of the four patients developed clinically significant graft-versus-host disease (GVHD) after infusion of donor lymphocytes. TCR repertoire was examined after PCR amplification of 24 Vbeta gene subfamilies in serial samples obtained over a 1-yr period before and after DLI. Results were compared to 10 normal donors. Before DLI, all four patients were found to have abnormal TCR Vbeta repertoire in peripheral T cells, associated with a large number of clonal and oligoclonal patterns. Abnormal TCR patterns persisted for at least 3 mo after DLI, but thereafter gradually began to normalize. By 1 yr after DLI, all patients demonstrated almost complete normalization of Vbeta repertoire with polyclonal representation within almost all Vbeta gene subfamilies. We also examined changes in the TCR Vbeta repertoire associated with the disappearance of Ph+ cells. In each patient, we were able to identify the expansion of at least 1 Vbeta gene subfamily that coincided with the time of the cytogenetic response. In one patient who was studied in greater detail, CDR3 size analysis of serial samples after DLI indicated that these changes were associated with the appearance of clonal T cells. This finding was confirmed through CDR3 sequence analysis and use of CDR3 clone-specific oligonucleotide probes. A putative GVL clone identified by this technique was not detectable in either donor or patient T cells before DLI, but persisted in peripheral T cells for approximately 1 yr. These experiments therefore provide evidence for the clonal expansion of allogeneic T cells that may be selective mediators of antileukemia activity without also mediating graft-versus-host disease.

Characterization of a novel subset of CD8(+) T cells that expands in patients receiving interleukin-12.

IL-12 has significant antitumor activity in mice that may be mediated by CD8(+) T cells. We show in this report that repeated subcutaneous injections of IL-12 in patients with cancer resulted in the selective expansion of a subset of peripheral blood CD8(+) T cells. This T cell subset expressed high levels of CD18 and upregulated IL-12 receptor expression after IL-12 treatment in vivo. In normal subjects, these CD3(+)CD8(+)CD18(bright) T cells expressed IL-12 and IL-2 receptors and adhesion/costimulatory molecules to a greater degree than other CD8(+) and CD4(+) T cells. They appeared morphologically as large granular lymphocytes, although they did not express NK cell markers such as CD56. In addition, CD8(+)CD18(bright) T cells were almost exclusively T cell receptor (TCR) alphabeta+, and exhibited a TCR Vbeta repertoire that was strikingly oligoclonal, whereas the Vbeta repertoire of CD18(dim) T cells was polyclonal. Although CD8+CD18(bright) T cells demonstrated little functional responsiveness to IL-12 or IL-2 alone in vitro, they responded to the combination of IL-12+IL-2 with strong IFN-gamma production and proliferation and enhanced non-MHC-restricted cytolytic activity. In contrast, CD18(dim) T cells were not activated by IL-12 or IL-2, alone or in combination. These findings demonstrate that CD8+CD18(bright) T cells are a unique population of peripheral blood lymphocytes with features of both memory and effector cells that are capable of TCR-independent activation through combined stimulation with IL-12+IL-2. As this activation results in IFN-gamma production and enhanced cytolytic activity, these T cells may play a role in innate as well as acquired immunity to tumors and infectious pathogens. Additional studies will be necessary to determine whether CD8+CD18(bright) T cells mediate the antitumor effect of IL-12 or IL-2 administered to cancer patients, and if so, whether maximal activation of these T cells with the combination of IL-12+IL-2 in vivo can augment the clinical effectiveness of these cytokines.

Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia.

The effectiveness of donor-lymphocyte infusion (DLI) for treatment of relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation is a clear demonstration of the graft-versus-leukemia (GVL) effect. T cells are critical mediators of GVL, but the antigenic targets of this response are unknown. To determine whether patients who respond to DLI also develop B-cell immunity to CML-associated antigens, we analyzed sera from three patients with relapsed CML who achieved a complete molecular remission after infusion of donor T cells. Sera from these individuals recognized 13 distinct gene products represented in a CML-derived cDNA library. Two proteins, Jkappa-recombination signal-binding protein (RBP-Jkappa) and related adhesion focal tyrosine kinase (RAFTK), were recognized by sera from three of 19 DLI responders. None of these antigens were recognized by sera from healthy donors or patients with chronic graft-versus-host disease. Four gene products were recognized by sera from CML patients treated with hydroxyurea and nine were detected by sera from CML patients who responded to IFN-alpha. Antibody titers specific for RAFTK, but not for RBP-Jkappa, were found to be temporally associated with the response to DLI. These results demonstrate that patients who respond to DLI generate potent antibody responses to CML-associated antigens, suggesting the development of coordinated T- and B-cell immunity. The characterization of B cell-defined antigens may help identify clinically relevant targets of the GVL response in vivo.

Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia.

The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo 2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P<0.001) for unmutated IGHV. The association between elevated birth rate and shorter TFS was observed in subjects with either mutated or unmutated IGHVs, and the use of both markers was a better predictor of TFS than either parameter alone. Thus, an increased CLL birth rate in early stage disease is a strong predictor of disease progression and earlier treatment.

Herpes zoster infection in the post-hematopoietic stem cell transplant pediatric population may be preceded by transaminitis: an institutional experience.

Herpes zoster (HZ), a varicella-zoster virus reactivation, frequently complicates hematopoietic stem cell transplantation (HSCT). Its incidence, complications, and associated risk factors in 310 children undergoing HSCT were reviewed. In all, 61 of 201(32%) patients who had undergone allogeneic and 10 of 109 (9%) patients who had undergone autologous HSCT developed HZ. Of 90 VZV seropositive allogeneic patients, 50 (53%) developed HZ. Seven (17%) of 41 VZV seropositive autologous patients developed HZ. Although a substantial number of patients develop HZ in the early post-HSCT period, risk for HZ persists and HZ can occur up to 5 years post-HSCT. Risk factors for HZ included age >10 years (P<0.0001), allogeneic HSCT (P<0.001), and total body irradiation (TBI) (P<0.059) in allogeneic recipients. Of 37, 22 (59%) patients experienced an elevated alanine aminotransferase (ALT), unassociated with GVHD, in the month preceding HZ. Of the 48/64 patients (75%) hospitalized for treatment (median stay, 6 days; range, 2-39), length of stay was unaffected by donor type but increased by cutaneous dissemination and visceral involvement (P=0.023 and 0.034, respectively) in allogeneic patients. Consideration of HZ infection particularly in patients >10 years of age with elevated ALT after TBI-conditioned allogeneic HSCT may permit earlier diagnosis and therapeutic intervention.

The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis.

Despite the pivotal role of MYC in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and many other cancers, the mechanisms underlying MYC-mediated tumorigenesis remain inadequately understood. Here we utilized a well-characterized zebrafish model of Myc-induced T-ALL for genetic studies to identify novel genes contributing to disease onset. We found that heterozygous inactivation of a tricarboxylic acid (TCA) cycle enzyme, dihydrolipoamide S-succinyltransferase (Dlst), significantly delayed tumor onset in zebrafish without detectable effects on fish development. DLST is the E2 transferase of the α-ketoglutarate (α-KG) dehydrogenase complex (KGDHC), which converts α-KG to succinyl-CoA in the TCA cycle. RNAi knockdown of DLST led to decreased cell viability and induction of apoptosis in human T-ALL cell lines. Polar metabolomics profiling revealed that the TCA cycle was disrupted by DLST knockdown in human T-ALL cells, as demonstrated by an accumulation of α-KG and a decrease of succinyl-CoA. Addition of succinate, the downstream TCA cycle intermediate, to human T-ALL cells was sufficient to rescue defects in cell viability caused by DLST inactivation. Together, our studies uncovered an important role for DLST in MYC-mediated leukemogenesis and demonstrated the metabolic dependence of T-lymphoblasts on the TCA cycle, thus providing implications for targeted therapy.

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation.

The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.

Characteristics and outcome of children with Beckwith-Wiedemann syndrome and Wilms' tumor: a report from the National Wilms Tumor Study Group.

PURPOSE: Children with Beckwith-Wiedemann syndrome (BWS) are at increased risk for developing Wilms' tumor (WT). We reviewed the National Wilms Tumor Study Group (NWTSG) records to assess clinical characteristics and outcome of patients with WT and BWS. METHODS: In the NWTSG, treating clinicians were asked to report, for each enrolled patient, whether the patient had BWS. Between 1980 and 1995, 4,669 patients were treated on two consecutive NWTSG protocols (NWTS 3 and NWTS 4). We retrospectively reviewed the clinical characteristics and treatment outcomes of BWS patients compared with patients with WT without BWS. RESULTS: Fifty-three children enrolled onto NWTS 3 and 4 were reported to have BWS. BWS patients were more likely to present with lower-stage tumors (P =.0001), with more than half (27 of 53) presenting with stage I disease. The overall treatment outcomes for the BWS patients were nearly identical to those without BWS, with overall survival at 4 years from diagnosis at 89% and 90%, respectively. Overall, 21% of the patients with BWS had bilateral disease, either at diagnosis (nine of 53) or as metachronous contralateral recurrence (two of 53). BWS patients enrolled onto NWTS 4 had smaller tumors than those enrolled onto NWTS 3 (P =.02), a trend not seen in the non-BWS patients. CONCLUSION: Like children without BWS, children with BWS and WT have an excellent prognosis with modern treatment regimens. There is a high risk of bilateral disease, and increasingly smaller tumors are being detected. This suggests that a national trial assessing the role of ultrasound screening followed by nephron-sparing surgery for some patients may be appropriate.

Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial.

PURPOSE: The purpose of this study was to determine the maximum-tolerated dose (MTD) of fluorouracil (5-FU) administered as a protracted intravenous (IV) infusion with concurrent radiation in patients with pancreaticobiliary carcinoma. METHODS: Twenty-five patients with recurrent, residual, or unresectable carcinoma of the pancreas or biliary tract were treated on a phase I trial of protracted IV infusions of 5-FU, beginning at 200 mg/m2/d, concurrent with radiation therapy (59.4 Gy in 33 fractions over 6 to 7 weeks). Chemotherapy began on the first day of radiation and continued through the entire course of treatment. After each cohort of five patients had been treated and observed, the daily dose was escalated in 25-mg/m2 increments until dose-limiting toxicity was encountered. An additional cohort of five patients was treated at the MTD. Clinical examination and computed tomography (CT) were used to evaluate response and patterns of progression. RESULTS: The MTD of 5-FU was 250 mg/m2/d. The dose-limiting toxicity was oral mucositis. The median survival duration of all patients treated was 11.9 months and the 2-year survival rate was 19%. Eleven of 25 patients remain free of local progression and four patients are without evidence of progression at 18+, 18+, 34+, and 44+ months following treatment. CONCLUSION: Concurrent radiation with protracted 5-FU infusion at 250 mg/m2/d is well tolerated and shows evidence of activity against tumors of the pancreas and biliary system.

High-dose CHOP as initial therapy for patients with poor-prognosis aggressive non-Hodgkin's lymphoma: a dose-finding pilot study.

PURPOSE: To purpose of this study was to develop a more effective approach to the treatment of patients with poor-prognosis aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty newly diagnosed patients with bulky (> or = 10 cm) advanced-stage aggressive NHL were enrolled onto a pilot study. The study was designed to determine the maximum-tolerated dosages (MTD) of cyclophosphamide and doxorubicin that could be used in a high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen with granulocyte colony-stimulating factor (G-CSF) support and to assess preliminarily the efficacy of the regimen. RESULTS: In the initial dose-finding portion of the study, cumulative thrombocytopenia was the dose-limiting toxicity. At the MTD, the regimen included four 21-day cycles of cyclophosphamide 4 gm/m2, doxorubicin 70 mg/m2, vincristine 2 mg, and prednisone 100 mg for 5 days with mesna and G-CSF support. At the MTD, 65% of treatment cycles were complicated by febrile neutropenia, 84% of patients received at least one platelet transfusion for platelet counts less than 20,000/microL, and there was one treatment-related death. Nineteen of 22 (86%; 90% confidence interval [CI], 68 to 96) patients treated at the MTD achieved an initial complete response (CR), and 79% (90% CI, 58 to 92) of the complete responders and 69% of all patients remain progression-free with 20 months median follow-up. CONCLUSION: The high-dose CHOP regimen may be an effective alternative for patients with poor-prognosis aggressive NHL.

Neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous cell carcinoma of the esophagus: a preliminary analysis of the phase II intergroup trial 0122.

PURPOSE: To determine the preliminary acute toxicity and survival results of neoadjuvant chemotherapy followed by concurrent chemotherapy plus high-dose radiation therapy in patients with local/regional squamous cell carcinoma of the esophagus. MATERIALS AND METHODS: Forty-five patients with clinical stage T1-4N0-1M0 squamous cell carcinoma were entered onto the trial. Eight patients were declared ineligible after registration. Patients received three monthly cycles of fluorouracil (5-FU; 1,000 mg/m2/24hr for 5 days) and cisplatin (100 mg/m2 on day 1) (neoadjuvant segment) followed by two additional monthly cycles of 5-FU (1,000 mg/m2/24hr for 5 days) and cisplatin (75 mg/m2 on day 1) plus concurrent 64.8 Gy (combined modality segment). RESULTS: With a median follow-up of 15 months in surviving patients, the incidence of total grade 3+ toxicity during the neoadjuvant chemotherapy segment was 61%, and during the combined modality segment was 72%. Of the 33 patients who started radiation therapy, 91% were able to complete the full course. There were six deaths during treatment, five of which (11%), because of nadir sepsis and/or dehydration, were treatment-related. For the 37 eligible patients, the median disease-free survival duration was 9 months, and the overall median survival was 20 months. CONCLUSION: The preliminary analysis of this trial demonstrated that the incidence of grade 3+ toxicity was similar to that reported in the combined modality arm of the prior Radiation Therapy Oncology Group (RTOG) intergroup esophageal trial RTOG 85-01. However, because of the increased incidence of treatment-related mortality, this treatment program will not be used as an experimental arm of intergroup trial INT 0123 (RTOG 94-05).

Early restaging gallium scans predict outcome in poor-prognosis patients with aggressive non-Hodgkin's lymphoma treated with high-dose CHOP chemotherapy.

PURPOSE: This prospective study assessed the predictive value of early restaging gallium (Ga) and computed tomographic (CT) scans in poor-prognosis patients with aggressive non-Hodgkin's lymphoma (NHL) who were treated with high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. PATIENTS AND METHODS: Thirty newly diagnosed patients with bulky (> or = 10 cm) advanced-stage aggressive NHL were treated with a four-cycle high-dose CHOP regimen (22 patients at maximum-tolerated dose [MTD]: cyclophosphamide 4 g/m2, doxorubicin 70 mg/m2, vincristine 2 mg, and prednisone 100 mg orally for 5 days). All patients had chest/abdominal/pelvic CT scans and 10-mCi Ga scans at baseline and following two and four cycles of therapy. Scans were reviewed in a blinded manner for CT-documented rates of response and sizes of residual masses and Ga avidity of residual masses. The results of early (post-cycle 2) and final (post-cycle 4) restaging were subsequently associated with clinical outcome. RESULTS: CT-documented rates of response and residual mass sizes were indistinguishable in complete responders who remained continuously disease-free (CR-Cont), complete responders who subsequently relapsed (CR-Rel), and partial responders who then progressed (PR/Prog). In marked contrast, early restaging (post-cycle 2) Ga scans accurately delineated these three categories of patients: CR-Cont 90% Ga-negative (18 of 20 patients) versus CR-Rel 25% Ga-negative (one of four patients) versus PR/Prog 0% Ga-negative (zero of six patients) (P = .000014). At a median follow-up duration of 31 months (range, 21 to 46), 94% of patients who had negative early restaging Ga scans remain free from progression (FFP), whereas only 18% of patients who had positive early restaging Ga scans remain FFP (P = .000007). Early restaging Ga scans were more predictive for FFP than final restaging Ga scans because patients who required four full cycles of therapy to become Ga-negative were more likely to develop recurrent disease. CONCLUSION: Early restaging Ga scans delineate patients who are likely to have prolonged disease-free survival from those who fail to respond to intensive induction therapy. Patients whose tumors remain Ga-positive midway through high-dose CHOP therapy have a poor outcome and may be candidates for alternative treatment.

Phase II study of goserelin for patients with postmenopausal metastatic breast cancer.

PURPOSE: To determine the response rate of postmenopausal breast cancer patients to the gonadotropin-releasing hormone (GN-RH) agonist, Zoladex (goserelin; ICI Pharma, Wilmington, DE). PATIENTS AND METHODS: A multi-institutional single-agent trial in postmenopausal patients was conducted. Serum levels of follicle-stimulating hormone (FSH), testosterone, and estradiol were requested before and after Zoladex treatment. RESULTS: For estrogen receptor-positive (ER+) patients, the response rate was 11%, with one complete response (CR) and three partial responses (PRs) among 36 eligible patients. Responses were of short duration. There were no responses among 16 estrogen receptor-negative (ER-) patients. CONCLUSION: GN-RH agonists have activity in ER+ postmenopausal patients, but response rates are not as high as with other available endocrine therapies and the duration of response is short.